IMR Press / FBE / Volume 14 / Issue 2 / DOI: 10.31083/j.fbe1402008
Open Access Review
The Association of Inflammatory Gut Diseases with Neuroinflammatory and Auditory Disorders
Show Less
1 Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
*Correspondence: s.vlajkovic@auckland.ac.nz (Srdjan M. Vlajkovic)
Academic Editor: Arthur J. Chu
Front. Biosci. (Elite Ed) 2022 , 14(2), 8; https://doi.org/10.31083/j.fbe1402008
Submitted: 21 December 2021 | Revised: 11 February 2022 | Accepted: 24 February 2022 | Published: 22 March 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Disorders such as inflammatory bowel disease (IBD) and celiac disease (CeD) result in intestinal hyperpermeability or ‘leaky’ gut. The increased permeability of the intestinal barrier allows microbial metabolites, toxins, and pathogens to infiltrate the bloodstream and extraintestinal tissues, causing systemic inflammation. Despite differences in aetiology and pathophysiology, IBD and CeD share several extraintestinal manifestations such as neuroinflammation, neurological and psychiatric manifestations, and sensorineural hearing loss (SNHL). This narrative review focuses on the association between intestinal hyperpermeability with the brain and inner ear diseases. We postulate that the microbial metabolites and pathogens released from the gut increase the permeability of natural barriers, such as the blood-brain barrier (BBB) and blood-labyrinth barrier (BLB). The barrier breakdown allows the spreading of inflammatory processes to the brain and inner ear, leading to disease.

Keywords
inflammatory bowel disease
celiac disease
gut dysbiosis
microbiota
neuroinflammation
hearing loss
1. Introduction

If an inflammatory response in the gut does not naturally resolve, it may lead to a state of chronic inflammation. This development may result in pathologies such as inflammatory bowel disease (IBD) and celiac disease (CeD) [1]. Evidence shows that these conditions are associated with a pathological shift in gut bacteria [2, 3, 4].

An imbalance of intestinal flora results in gut dysbiosis, bringing about changes to the permeability of the intestinal barrier (IB) [5, 6]. Consequently, pathogens can then infiltrate the circulation, enabling them to spread to other organ systems, thus resulting in secondary extraintestinal infections, which are often life-threatening [5]. Indeed, both IBD and CeD have been linked with extraintestinal manifestations (EIMs), including neuroinflammatory diseases and sensorineural hearing loss (SNHL) [7, 8, 9]. However, despite reported associations between diet and hearing loss, the current literature does not recognise IBD-induced gut dysbiosis as an aetiology of SNHL. Instead, it advocates that SNHL in IBD has an autoimmune background [10].

IBD is an umbrella term used to label two disorders that involve chronic inflammation of the gastrointestinal tract (GIT): Crohn’s disease (CD) and ulcerative colitis (UC) [11]. Interestingly, IBD and sub-clinical manifestations of the inflammatory gut disease have been associated with gut dysbiosis and significantly increased levels of bacterial plasma components such as lipopolysaccharide (LPS) [12, 13, 14]. These findings provide evidence for IB hyperpermeability. In both IBD and CeD, bacterial metabolites leak from the intestinal lumen into the bloodstream, where they can potentially infiltrate the brain, producing local neuroinflammatory processes [15, 16] and other neurological conditions, including the so-called “celiac brain” [15]. Similarly, we previously postulated that, in gut dysbiosis caused by a high-fat diet (HFD), systemic immune responses might enhance the permeability of the blood-labyrinth barrier (BLB), thus causing cochlear inflammation following the infiltration of inflammatory cells and cytokines and the deposition of immune complexes [17]. However, IBD and CeD do not rely on HFD to trigger increased IB permeability. Instead, these disorders are multifactorial “leaky gut” diseases resulting from immune system malfunctioning and autoimmunity [18, 19, 20, 21, 22].

This review entails the existence of a gut-inner ear axis that links IBD and CeD with SNHL. This concept is analogous to the gut-brain axis, linking inflammatory gut diseases with brain disorders.

A broad literature search spanning from 1998 to 2021 was conducted using PubMed, Google Scholar, and Embase medical databases. References from the relevant papers were used. Following Boolean search logic, the main keywords included: “inflammatory bowel disease” OR “Crohn’s disease” OR “ulcerative colitis” OR “celiac disease” OR “coeliac disease” OR “gut dysbiosis”) AND (“hearing loss” OR “sensorineural hearing loss” OR cochlea OR “blood-labyrinth barrier” OR “blood-brain barrier” OR inflammation OR lipopolysaccharides). The search results were subsequently examined according to their relevance to this review. Only publications in the English language were included.

2. A “Leaky Gut” does not only Affect the Gut

Since first described by Samuel Wilks in 1859, IBD has been associated with altering the gut microbiome [23, 24]. Even though the aetiology of IBD is not yet fully understood, it has been tightly linked with IB hyperpermeability (“leaky gut”) [25], similar to CeD [2, 26]. Consequently, these conditions are often referred to as “leaky gut disorders” [27, 28, 29].

A compromised IB can result in systemic pathological processes, such as increased oxidative stress (OS) [30], inflammation [31], and decreased insulin sensitivity, affecting various organs and tissues [32]. Interestingly, it appears that CeD represents a risk factor for IBD and vice versa [33]. Pinto-Sanchez et al. [34] found a 9-fold increase in the risk of developing IBD in CeD patients compared with the control population.

However, CeD and IBD are very different in their aetiology and pathophysiology. Nevertheless, they share similarities, such as gut dysbiosis, increased IB permeability, and inflammatory responses. In addition, both diseases present with similar EIMs, including neuroinflammation, neurodegeneration, and hearing loss. Based on the similitudes between CeD and IBD, it is prudent to assume their EIMs might have comparable pathophysiology. Here, we discuss the links between these gut diseases and the potential mechanisms of their EIMs.

2.1 Intestinal Barrier

The intestinal wall coating is a single epithelial layer that connects the host to the external environment, known as the IB. Intestinal epithelial cells (IECs) are responsible for maintaining a functional barrier. The lining of intestinal epithelia exhibits distinctive intercellular connections known as tight junctions (TJ), desmosomes, and adherent junctions. These connections have a role in the selective permeability of gut lining by permitting the passage of nutrients and fluid absorption while preventing the displacement of microbial metabolites and antigens from the gut [35, 36]. TJs function as an active structural barrier in the paracellular space [36]. TJ protein composition includes claudins, occludins, and junctional adhesion molecules (JAM) [35]. The cytokines that regulate the immune system, such as tumour necrosis factor-α (TNF-α), interleukins (IL), interferon-γ(IFN-γ), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, fulfil a role in regulating TJs’ function [37]. The lamina propria beneath the IECs contains an array of immune cells, including T-cells, B-cells, macrophages, and dendritic cells, that contribute to the maintenance of tissue homeostasis [38]. In addition, mucin, a highly glycosylated protein that coats the gut lumen, contributes to tissue’ defence by trapping pathogens and preventing microbial colonisation [39].

2.2 The Immune System in the Gut

The mammalian immune system comprises two integrated subsystems: the innate and adaptive (Fig. 1). The innate immune system is the first to respond to pathogens and is evolutionarily older. If the pathogenic challenge persists, the adaptive immune system will engage with the pathogen with specificity and memory [40, 41, 42]. The innate immune system in the gut includes several physiological barriers that protect the body from the insurgence of pathogens. These barriers include mucus, TJs, IECs, antimicrobial enzymes, pattern recognition receptors, transforming growth factor-β (TGF-β) releasing stromal cells, and mesenchymal cells, to name a few [40, 43, 44]. Pattern recognition receptors, such as Toll-like receptors (TLRs) or Nucleotide-binding Oligomerization Domain-like receptors (NODs), recognise pathogens and their metabolites such as LPS via pathogen associated-molecular patterns (PAMPs) [45]. These receptors also recognise reactive oxygen species (ROS) produced by microbiota [46]. Activation of TLRs can lead to stimulation of cytoplasmic protein NF-κB, a ubiquitous transcription factor involved in inflammatory and immune responses and the regulation of the expression of many other genes related to cell survival, proliferation, and differentiation [47, 48]. Activation of the NF-κB pathway triggers a pro-inflammatory response by upregulating the release of pro-inflammatory mediators such as adhesion molecules and multiple cytokines (TNF-α, IL-1, IL-6 and IL-8) to neutralise the pathogen [37, 40, 49]. The immune system development and functioning are conditioned by the microbiome that colonises the intestinal lumen and prevents infections [50]. However, oral antibiotics, high-fat or high-sugar diet can negatively affect the microbial landscape, promoting IB’ hyperpermeability [50]. Experimental studies have shown that introducing a healthy microbiome in germ-free (GF) animals can reverse some immunological abnormalities associated with IBD [51] and CeD [52, 53, 54]. For example, Cinova et al. [54] have demonstrated that the intestinal tissue of GF rats, when exposed to enterobacteria, bifidobacteria and/or CeD-triggering agents (gliadin and IFN-γ), reacts differently to each of these elements. Intestinal tissue in the presence of gliadin alone or with IFN-γ, E. Coli CBL2 or Shigella CBD8 had altered mucin production and presented with impaired TJs, allowing the penetration of gliadin deeper into the tissue, increasing IB permeability. However, a spontaneous addition of B. bifidum IATA-ES2 increased the number of goblet cells and production of chemotactic factors and inhibitors of metalloproteinases, which play a role in mucosal protection, thus decreasing IB’ permeability [54].

Fig. 1.

Overview of the mammalian immune system.

2.3 Critical Time for the Development of Gut Health: Early Childhood and Microbiome

In the first 2–3 years of life, the microbial landscape of the gut rapidly changes, by the end reaching similar functionality to the one seen in adults [55]. During this period of weaning from breastmilk to solid food, the changing microbiota leads to “weaning rejection” of the immune system. At this point, several studies have observed shifts in the global gene expression in the intestines, including genes encoding defensins (a major family of host defence peptides expressed predominantly in neutrophils and epithelial cells), chemokine receptors, and mucins [56]. At the weaning stage, commensal microbiota induces gene expression of the pro-inflammatory cytokines (TNF-α, IL-1β, and IFN-γ) in rodents [56, 57].

Antibiotic administration in early childhood may impact the microbiome for life via so-called pathological imprinting [56, 58]. In South Korea, children up to two years of age receive an average of 3.4 courses of antibiotics per year [59]. In New Zealand, clinical studies demonstrated that 94% of children received at least one course of antibiotics by the age of five, with an average of eight courses by the same age [60]. Several studies have identified multiple early childhood factors that are directly associated with the risk of developing IBD later in life, such as mode of delivery [61], feeding type [62], childhood hygiene [63], and antibiotic use [64]. Antibiotics in infancy also increase the chance of developing obesity [65] and CeD [66], both linked with gut dysbiosis.

2.4 Inflammatory Bowel Disease (IBD)

IBD denotes diseases that involve chronic inflammation within the GIT, with two apparent phenotypes [67]. In the first phenotype (CD), the inflammation can develop in any part of the GIT, often characterised by patchy and transmural damage through the IB. The second phenotype (UC) involves confluent inflammation in the colonic mucosa [68]. IB impairment leads to a leaky gut in both cases [11]. IBD is considered by many as having an autoimmune origin [69]; however, some authors have suggested a novel, autoinflammatory background [70].

IBD’s aetiology is multifactorial, complex, and still not fully understood. It combines genetic, environmental, and microbial factors, which influence the immune system; however, none of these factors can cause disease alone [68]. The genetic factors constitute only a relatively small proportion of IBD cases [68, 71]. Therefore, if the host carries genetic risk variants, they must be exposed to environmental or microbial challenges to develop IBD [68]. Rapidly increasing IBD incidence in the modern world indicates the significance of diet, lifestyle, and a changing environment [72].

The increased incidence of IBD parallels the “westernisation” of countries [73, 74]. IBD affects around 3.1 million people in the USA alone, with cases increasing worldwide. Between 2003 and 2013, the number of new IBD cases in NZ increased by an average of 8.1% per year [75]. The incidence of IBD in NZ among adults and children is considered very high [76, 77, 78], with NZ and Australia among the top five countries for incidence of CD [78]. In Asia, the incidence rate for UC has risen by 60% since 1988 and 70% for CD [79]. The number of new IBD cases in South Korea is one of the highest globally and rapidly increases [80].

2.5 Celiac Disease

Another inflammatory gut disorder that results in a “leaky gut” is celiac disease (CeD). It is an autoimmune condition that results from an immune response to gluten in genetically predisposed adults and children [81]. CeD affects approximately 1% of the global population [82]. Over the past 50 years, CeD prevalence has increased 4-fold [83].

The severity of the disease might be influenced by genetic and environmental factors and immune imbalance [84]. Like IBD, genetic background on its own is insufficient to develop the disorder; gluten is a crucial contributor [85]. However, gut dysbiosis may trigger pathogenic pathways leading to CeD progression [81]. In response to the build-up of gluten fragments (such as gliadin) in the intestines, the adaptive and innate immune responses lead to villous atrophy, crypt hyperplasia, and IB hyperpermeability [86].

3. Pathogenesis of IBD and Celiac Disease - Where is the Common Ground?

Several established factors can alter homeostasis between gut microbiota and the immune system; however, the multifactorial aetiology of IBD is still not fully understood [40].

IBD and CeD have common immunological, genetic, and environmental factors contributing to their manifestations. Genome-wide association studies (GWAS) have shown that CeD and CD share genetic risk loci [87]. Moreover, CeD and IBD share elements of aetiology such as increased IB permeability [88], compromised regulatory T cell (Treg) function [89, 90], upregulation of pro-inflammatory cytokines ( IL-13, IL-17, IL-21 and IFN-γ) [1, 91, 92] and a paradigm shift in the microbiome [93, 94].

In a healthy individual, commensal microbiota, IECs, and immune cells function in concinnity. When a soluble antigen enters the GIT, local immunity is suppressed due to immune tolerance. However, many factors can disturb this homeostasis between pro-, and anti-inflammatory mediators, favouring pro-inflammatory responses in susceptible individuals. Prolonged activation of the innate immune system leads to a state of unresolved, chronic inflammation, such as IBD. IB hyperpermeability in IBD allows harmful molecules (such as LPS, CpG motifs, pathogens, luminal antigens) to infiltrate the bloodstream, causing the release of pro-inflammatory cytokines, which can alter homeostasis in distant organs [59, 72, 95]. In CD, increased IB permeability has been observed prior to clinical relapse, suggesting its role in disease exacerbation [96, 97]. However, it is still unclear if the immune activation in IBD results from gut dysbiosis or loss of immune tolerance in the gut’s immune system [40].

The prevalence of genetic factors in IBD is relatively low, making environmental factors a key player. Interestingly, the incidence of IBD is higher in urban than rural areas [98, 99], and there is a clear association between diet and incidence [73, 100, 101, 102, 103, 104]. Factors that impact gut microbiota, such as early exposure to animals, having many siblings [105, 106], natural mode of delivery [61], and breastfeeding [107], effectively decrease the chances of developing IBD in contrast to the mode of delivery via C-section [61, 74], excessive paediatric hygiene [63] and early-life antibiotic therapies [64, 108, 109]. Furthermore, treatments that typically affect microbiota, such as faecal diversion and antibiotic therapy, are often used for IBD management [110, 111, 112, 113, 114, 115]. However, an extensive nested case-control analysis of the population-based University of Manitoba Inflammatory Bowel Disease Epidemiologic Database has demonstrated that antibiotic use may be a risk factor for developing IBD, as a significant number of patients included in this study had been prescribed antibiotics 2–5 years prior to being diagnosed with IBD [108]. Moreover, a random-effects meta-analysis demonstrated that antibiotic use increases the risk of CD development [116]. Interestingly, the lesions characteristic for IBD coincide with higher concentrations of commensal bacteria [117, 118], and IBD patients present higher yields of antibodies against commensal bacteria than healthy individuals [119].

Over the years, the increase in IBD incidence has been associated with the increased consumption of the western diet, which is higher in fats and additives, but with a decreased amount of fruits, vegetables, and fibre [59, 72, 120, 121, 122]. Even though regional differences of the western diet have been observed [72, 123, 124], dietary factors associated with that diet commonly induce gut dysbiosis in obesity and metabolic syndrome [122, 125, 126, 127, 128]. Moreover, many pro-inflammatory cytokines common for CeD and IBD (e.g., TNF-α, IFN-γ, IL-6, IL-17) are altered by a high-fat diet [129]. However, there is a lack of studies on the specific dietary components (other than gluten) influencing IBD development. Other environmental risk factors may also contribute to increasing IBD prevalence. Modern agricultural practices have been proposed as contributing factors for gastro-intestinal disorders [130]. Crop desiccation using glyphosate has been attributed to carcinogenic and cytotoxic effects on the body [131]. Moreover, it has been suggested that glyphosate negatively affects gut microbiota and is especially harmful to commensal bacteria [130]. Ingestion of glyphosate has been associated with an impact on mental health via altering the microbiome landscape [130].

The other established aspect of IBD aetiology is a failure of the immune regulatory control in the active phases of the disease [132]. The increased population of T-cells and increased expression of pro-inflammatory cytokines, including TNF-α, IL-6, IFN-γ (15), promote chronic inflammation instead of resolution and recovery processes [40]. Inflammatory processes in the epithelial gut layer facilitate microbiome infiltration of the deeper gut tissue and elicit a local immune response [43]. Gut dysbiosis and IB hyperpermeability are thus significant factors causing activation of the immune system [40]. Immune system activation and cytokine secretion result in the stimulation of naïve T-cells and proliferation and activation of effector and memory T-cells. Effector T-cells migrate to intestinal lamina propria and nearby circulation, where cell adhesion molecules (selectins and integrins) on endothelial cells facilitate the homing of effector cells [40]. Macrophages activate the adaptive immune system locally, whereas dendritic cells migrate to lymphoid tissue and activate T helper (Th1) cells and cytotoxic T cells and allow for maturation of regulatory T-cells. IBD immunopathology can thus be defined as the dysfunctional immune response and activation of either Th1 or Th2 cells in the mucosa, particularly in CD [133]. Cytokines such as IL-1, IL-6, IL-23, and transforming growth factor β (TGF-β) can activate Th17 pathways responsible for the secretion of the pro-inflammatory IL-17 family of cytokines that recruit Treg cells and neutrophils contributing to UC pathogenesis [134, 135, 136]. IL-23 may play an essential role in controlling the Th1/Th17 balance in both UC and CD [135].

Interestingly, GF animals tend to have impaired Th17 cell development, decreased IL-17 cytokine production in the colon [137], and impaired Treg cells [138], suggesting an essential role for microbiota in IBD immunopathology. GF animals also have an altered mucus layer [139], further implicating gut microbiota in IBD pathophysiology. While healthy subjects can generally tolerate autologous microbiome, in some cases, the breakdown of this symbiosis is associated with chronic intestinal inflammation [40, 140, 141]. It was proposed that gut dysbiosis negatively impacts the interaction between the immune response and microbiome, leading to an overactivation of the immune system [40].

In comparison, dietary gluten in CeD stimulates innate and adaptive immune systems in a susceptible individual, increasing the production of IL-15, which plays a major role in developing inflammatory and protective immune responses to microbial invaders and parasites. IL-15 also causes epithelial cell death in the gut and increases IB permeability, enabling gluten peptides to infiltrate lamina propria [142, 143]. At the same time, transglutaminase type 2 stimulates deamination of gluten-derived peptides producing epitopes that bind to HLA-DQ2/DQ8 heterodimers on antigen-presenting cells, thus provoking a T-cell response [144, 145]. Moreover, gliadin (a prolamine component of gluten) accelerates the dissembling of intercellular junctional proteins via epidermal growth factor receptor (EGFR) pathway activation [3, 146, 147]. As a consequence of uncontrolled antigen trafficking from the lumen through the IB, immunoregulatory deficits are further escalated. It was suggested that the onset of inflammation with a secondary production of pro-inflammatory cytokines (TNF-α, IFN-γ) increases the IB permeability by activating the myosin light chain kinase (MLCK) pathway [146, 148, 149]. Activation of this pathway may lead to the onset of chronic inflammatory disease depending on host genetic predisposition [146].

Interestingly, CeD and IBD share genetic backgrounds associated with the innate immune response against pathogens and pro-inflammatory activation [133]. However, the Th17 response pathways and autophagy (natural cell degradation that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism) are only involved in IBD. Autophagy also plays a role in recognising and eliminating pathogens [133, 150, 151].

3.1 Gut Dysbiosis in IBD and Celiac Disease

It is now well established that CeD and IBD need external, environmental stimuli to activate the immune system. Known environmental triggers include diet [152, 153], smoking, microorganisms, hygiene, early antibiotic exposure, and urban living, to mention a few [154]. Not surprisingly, the initial trigger is different for each disorder [133].

The bacterial species Bacteroides and Firmicutes make up 90% of eubiotic human gut microbiota [155], where along with other phyla, they orchestrate pro-and anti-inflammatory responses [156]. For example, in a healthy microbiome, Bacteroides engage in the recruitment of cytotoxic T cells to target immune cells (microbial antigen-loaded, antigen-presenting cells) that can trigger IBD, thus preventing IBD development [157]. Gut dysbiosis in CD is characterised by a decrease in Bacteroides and Firmicutes and an increase in Gammaproteobacteria and Actinobacteria, which leads to disease progression [71]. Interestingly, enterotoxigenic Bacteroides fragilis has been strongly associated with IBD and colorectal cancer [158, 159, 160]. In addition, 33% of IBD patients have an increased quantity of E.coli in the gut [161]. These strains of bacteria can cross the mucosal barrier, disturbing the epithelial lining [4, 71], thus allowing bacterial metabolites and pathogens to translocate into the systemic circulation [4, 25, 39, 156, 162]. Gram-negative bacterial metabolites such as LPS can also induce colitis and local inflammation in the intestines [163].

Gut dysbiosis in CeD is characterised by an increase of Gram-negative and a decrease of Gram-positive bacteria [2]. The increased presence of Bacteroides fragilis has been found in celiac patients and was associated with IB hyperpermeability and CeD pathogenesis [164]. Intriguingly, celiac patients presenting with EIM and those with typical GIT symptoms have different microbiome landscapes [165]. Wacklin et al. [165] demonstrated that CeD patients with only GIT symptoms had lower microbial diversity dominated by Proteobacteria compared to those with EIMs. The latter had a high abundance of Firmicutes [165].

CeD facilitates barrier breaches in the immune-privileged organs (brain, cochlea); however, the mechanism is unknown [16, 166, 167]. CeD can also increase the risk of developing sepsis due to the increased mucosal permeability and altered composition of the intestinal glycocalyx (the layer of gut epithelial cells considered the primary site for adhesion of commensal bacteria) [167].

3.2 Extraintestinal Manifestations (EIMs)

The EIMs of IBD are widespread and include the brain and the inner ear [168, 169] (Fig. 2). The IBD-related EIMs occur in approximately 50% of patients [170]. The therapy of IBD and associated EIMs is primarily concerned with the dietary modifications and systemic anti-bacterial and immunosuppressive agents (antibiotics, sulfasalazine, corticosteroids, azathioprine, and dapsone) [171, 172]. IBD likely results in low-grade systemic inflammatory responses, which can spill over to the extraintestinal organs. Although the cause of EIMs is unknown, they have been linked to IB hyperpermeability [25]. Both IBD [173] and CeD [174] have been associated with gut dysbiosis and significantly increased levels of bacterial plasma components such as LPS [12, 13, 14]. Remarkably, after eliminating gluten from the diet in celiac patients, LPS levels decrease [174], and the IB regains its integrity. Therefore, it can be postulated that, as the pathogens infiltrate the circulation, they breach the natural barriers of immune-privileged organs, allowing pathogens in and causing localised inflammatory reactions.

Fig. 2.

Extraintestinal manifestations of gut dysbiosis. Gut dysbiosis contributes to intestinal tissue damage, leading to intestinal barrier hyperpermeability (leaky gut). The pathogens and their metabolites infiltrate the bloodstream, leading to a spread of inflammation, which can reach remote organs and thus cause extraintestinal manifestations.

Despite the general hypothesis that EIMs of IBD are related to immune reactions [175, 176, 177, 178, 179], their pathogenesis is not fully understood. There is increasing evidence that IBD results from a malfunction of the immune system and autoimmunity. Being diagnosed with IBD also increases the likelihood of developing other autoimmune diseases [180]. Due to shared epitopes, the “leaky intestine” of the damaged GIT mucosa may trigger immune responses at various extraintestinal sites [175, 178]. Resultant from IB hyperpermeability, commensal bacteria metabolites and pathogens in the bloodstream may trigger autoimmune reactions due to the similarity between the bacterial and host epitopes [169, 175, 178].

Not all IBD and CeD patients develop EIMs. Genetic factors play a significant role in presenting IBD EIMs [181], with a concordance rate of 70% of parent-child pairs and 84% of sibling pairs [182]. Studies investigating the relationships between EIMs and major histocompatibility complex loci have shown that UC and CD do not share HLA genotypes [181, 183, 184]. CD patients are more likely to express HLA-A2, HLA-DR1, and HLA-DQw5 genotypes, whereas UC patients tend to express HLA-DR103, -B27, and -B58 genotypes [181, 183]. It appears that the specific HLA genotypes are related to different EIMs [181, 184, 185]. For example, HLA-DR3 is associated with the increased risk of primary sclerosing cholangitis in UC, HLA-B27 and HLA-B58 are associated with EIMs related to skin and eyes, and HLA-B27 to ankylosing spondylitis in 90% of IBD patients [183, 184, 186].

3.3 Neurological EIMs of CeD and IBD

EIMs of CeD and IBD include neuroinflammation and psychiatric disorders [15, 105, 187, 188, 189]. A substantial proportion of adult CeD patients develop neuroinflammatory and neurological conditions [15, 188, 189, 190]. Neurological deficits have been reported in 22.5% of adults and up to 24.5% of children in clinical studies [191, 192, 193]. In IBD, patients carry an increased risk of developing neurodegenerative diseases such as Parkinson’s disease (PD) or Alzheimer’s disease (AD) (PD: adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.24–1.97; AD: adjusted HR, 1.14; 95% CI, 1.05–1.25) [194]. Younger IBD patients are more likely to develop PD than their healthy counterparts [194]. Furthermore, the incidence of dementia is significantly increased in IBD patients when compared to age-matched controls (5.5% vs 1.4%; HR, 2.54) and occurs earlier in life (76.24 years old on average, compared with 83.45 among controls) [195]. In addition, Elsehety and Bertorini found neurological or psychiatric EIMs in 84 of 253 patients with CD (frequency 33.2%) [196].

Neuropsychiatric manifestations of IBD and CeD can be stress-related due to the difficulty living with these diseases [40, 197, 198]. Nevertheless, opinions regarding the association between mental health, stress, and IBD are conflicting [40]. The alteration of the gut-brain axis compromises relationships between gut microbiota, gut-associated lymphoid tissues, neuroendocrine network, and neuro-cognitive functions [16]. Gut dysbiosis could cause a breach of the blood-brain barrier (BBB) via hormonal secretion, small molecules such as LPS [199], vascular endothelial growth factors [200] and free radicals [201]. The metabolic cofactors (e.g., homocysteine [202] and nicotinamide adenine dinucleotide [203]) and inflammatory mechanisms [16, 204] have also been postulated. For example, Matisz et al. [205] suggested that chronic inflammation due to gut dysbiosis remodels anterior cingulate cortex physiology, resulting in the inaccurate judgment of danger. This remodelling was induced by chronic stimulation of the threat-coping system by endocrine signalling and anxiety [205]. LPS overproduction and release from the leaky gut likely plays a crucial role in developing neurodegenerative diseases [16, 206, 207]. In PD, LPS-CD14 complexes interact with toll-like receptor TLR4, initiating signalling events involving mitogen-activated protein kinases (MAPK) and transcription factors such as NF-κB [208, 209]. NF-κB activation upregulates cytokines such as TNFα and IL-1β, involved in neuroinflammation [210, 211]. Furthermore, stimulation of inducible nitric oxide synthase (iNOS) results in the release of prostaglandins and nitric oxide, which combines with superoxide to form highly toxic peroxynitrite (ONOO-) free radical [212, 213]. The joint insult by cytokines released from microglia, ROS and lipid metabolites results in the death of dopaminergic neurons vulnerable to OS [209]. Similarly, LPS may play an important role in the aetiology of AD. Zhan et al. [214] found that LPS co-localizes with amyloid plaques, neurons, and oligodendrocytes in the AD brain and may cause neuronal injury via TLR4-CD14/TLR2 pathways.

It appears that CeD, IBD, and mental disorders (autism, schizophrenia) share mechanisms involving microbial-derived metabolites that can cause neuroinflammation and damage in different brain regions [16, 215, 216, 217]. The process starts with gut dysbiosis and leads to neurodegeneration and cognitive deficits via inflammatory pathways [16, 214, 215, 216, 217, 218]. It has been established that gut dysbiosis induced by ageing, diet, obesity, alcohol abuse, and antibiotics could underpin the dysfunctional gut-brain axis [189], leading to inflammatory processes in the brain. Early antibiotic use is also a risk factor in developing autism and other neurological conditions [219].

Accordingly, the expression of the peroxisome proliferator-activated receptor-gamma (PPARγ) gene is significantly reduced in CeD [95, 220, 221, 222] and UC [223]. PPARγ is an essential anti-inflammatory [224] and probiotic gene [225]. PPARγ downregulation is associated with a shift in the microbiome, causing expansion of Enterobacteriaceae (phylum Proteobacteria) and decrease in otherwise abundant obligate anaerobic bacteria [225]. In macaque monkeys with CeD, downregulation of intestinal TJ proteins zona occludens-1 (ZO1) and claudin-1 with reduced or even absent occludin was observed [226, 227]. TJ proteins maintain the integrity of the blood-brain barrier [227] and blood-labyrinth barrier [228]. These studies suggest that the downregulation of the PPARγ gene and TJ proteins may promote gut dysbiosis, intestinal inflammation, and EIMs associated with neurodegeneration [227]. Furthermore, Mohan et al. [227] have suggested that LPS can cross the BBB, activate microglia, and initiate neurodegeneration via micro-RNA (miRNA) mechanisms targeting genes associated with the innate immune system and TJs.

Micro-RNAs are small RNA molecules (~20–23 nucleotide long), which regulate gene expression post-transcription by binding to homologous sequences on the 3’ untranslated regions (UTRs; homologous base pairings between miRNA seed nucleotides 2 to 7 and the 3’ UTR) [227]. Micro-RNAs control most cellular processes such as cell proliferation, differentiation, apoptosis, cell signalling, immune and inflammatory responses [227]. Biopsies of intestinal tissue of celiac patients showed downregulation of miRNAs: miR-192-5p, miR-31-5p, miR-338-3p, and miR-197 and upregulation of chemokine C-X-C motif ligand 2 (CXCL2) and nucleotide oligomerisation domain-2 (NOD2) at mRNA and protein expression levels [229]. These miRNAs play a significant role in innate immune responses. For example, miR-192-5p, a critical player in intestinal homeostasis, is downregulated in UC [230] and CeD [229, 231]. Moreover, miR-449a, responsible for negative regulation of Notch receptor 1 (Notch1) and krüppel like factor 4 (KLF4) that regulate goblet cell proliferation and differentiation, are upregulated in pediatric CeD patients, thus explaining the reduced amount of goblet cells in CeD [232]. Another study demonstrated elevated miR-204 in rhesus macaques with CeD [226]. This miRNA directly targets the intestinal TJ protein claudin-1, reducing its expression [227]. The loss of TJ proteins can compromise the BBB, leading to the translocation of intestinal LPS to the brain, activation of microglia, and neuroinflammation [227].

3.4 Hearing Loss as an Extraintestinal Manifestation of CeD and IBD

EIMs of IBD and CeD include SNHL (Tables 1 and 2) [9, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246] . Between 40–60% of pediatric CeD patients demonstrate at least unilateral SNHL [234, 236, 237]. Therefore, it was suggested that children presenting with idiopathic hearing loss should also be checked for CeD [236]. Correspondingly, if the child is diagnosed with CeD, the audiometric examination is warranted to identify early hearing deficits [237]. However, the pathophysiology of CeD-induced SNHL is still enigmatic. Several hypotheses have been put forward, including vasculitis, malnutrition, labyrinth infiltration by activated lymphocytes, anti-neuronal antibodies, and deposition of immune complexes [245]. The endolymphatic sac contains and recirculates IL-2-producing immunocompetent cells, which regulate immune responses [245]. IL-2 activation in endothelial cells of the spiral modiolar vein stimulates intercellular adhesion molecule-1 (ICAM-1) to attract more leukocytes to the target tissue and initiate immune and inflammatory reactions [247, 248, 245]. The autoimmune aetiology of IBD-induced SNHL was also proposed [10], even though the presentation of SNHL in IBD patients is more consistent with chronic inflammation, similar to the neuroinflammatory processes in the brain.

Table 1.Clinical studies demonstrating the association between IBD and hearing loss.
Year Authors Title Methodology Results Conclusion
2005 Akbayir et al. [233] Sensorineural hearing loss in patients with inflammatory bowel disease: a subclinical extraintestinal manifestation Clinical study involving 39 patients with IBD (21 Crohn’s disease, 18 ulcerative colitis) and 25 healthy age- and sex-matched controls. To assess auditory function, otoscopy, tympanometry, and pure tone audiometry were carried out. o ll patients and control subjects had normal otoscopy findings, and tympanometry was unremarkable, excluding middle ear disease and conductive hearing loss. “(…) it was demonstrated that a subclinical SNHL may be associated with UC and somewhat with CD, affecting mainly the high frequencies. In light of this finding, it may be advisable to investigate labyrinth functions as well as other extraintestinal manifestations in patients with IBD.”
o The average hearing thresholds were raised significantly in the IBD group at higher frequencies (2, 4, and 8 kHz).
o There is a significant threshold increase for the UC group at frequencies 2, 4, and 8 kHz and for the CD group only at 4 kHz.
o A trend of SNHL worsening with the patient age and extent of ulcerative colitis was observed.
o No significant correlation between SNHL and sex, involvement site in GI tract, medication history for IBD, and coexistence of other EIMs.
2009 Karmody et al. [240] Sensorineural hearing loss in patients with inflammatory bowel disease A clinical study was conducted over 11 years. Medical and audiometric documentation of 38 patients with a diagnosis of IBD (ulcerative colitis and Crohn’s disease) was reviewed. o Of 38 patients with a history of IBD, 58% (n = 22) recorded SNHL. “(…) this study demonstrates a correlation between SNHL and IBD, but a larger controlled investigation is needed. If IBD is an autoimmune disorder, the inner ear could be affected by the underlying systemic immune dysfunction. Unravelling the pathophysiology of IBD should explain the mechanism of its association with dysfunction of the inner ear.”
o 19 patients with SNHL had no other identifiable aetiology for their inner ear dysfunction.
o 14 patients with SNHL had been diagnosed with UC, and 5 had CD.
o 16 had bilateral SNHL, and 3 patients had unilateral SNHL.
o 70% developed hearing loss before the age of 50 years.
o Only one SNHL patient had a lasting response to medical treatment.
2014 Wengrover et al. [241] Hearing loss in patients with inflammatory bowel disease A prospective blinded comparative study was conducted over 3 years. o 21% (n = 16) of the IBD patients complained of hearing loss since the first IBD diagnosis; 13% had hearing deficits. “Sensorineural hearing loss may be another EIM of IBD. It is found in 30% of IBD patients and in up to 43% of patients with other EIMs. Early hearing evaluation should be recommended to IBD patients who have other EIMs.”
o Audiometric examination showed hearing loss (mild to severe) in 23 (30%) of the IBD patients, matched with 3 (10%) of the controls.
A total of 105 participants (76 patients and 29 controls), where 59 (77%) had CD, and 17 (23%) had UC. The mean age was 36 years; 51% were males, and 40% were hospitalised due to IBD exacerbation. o SNHL constituted 93% of hearing deficits. Out of 46 patients whose EIM status was clearly documented, 20 (43%) had SNHL.
o IBD phenotype, hospitalisation, and disease type were not different between the groups.
2016 Wengrower et al. [9] Hearing loss in patients with inflammatory bowel disease A prospective blinded comparative study was conducted over three years. 76 IBD patients and 29 controls underwent a complete otorhinolaryngological examination and audiometry test. o Hearing loss (mild to severe) was found in 29 (38%) of the IBD patients, and 4 (14%) of the control group. “Hearing loss may be another EIM of IBD. It is found in 38% of IBD patients and up to 52% of patients with other EIMs; hearing loss increases over the age of 40. Early hearing evaluation should be recommended to these high-risk IBD patients.”
o Moderate to severe hearing loss was found in 7/33 (21%) in the EIM-positive group compared to 4/43 (9%) in the EIM-negative group.
o Out of 11 patients over 40 with other EIMs, all (100%) had hearing loss compared to 8/12 (66%) of patients over 40 without other EIMs.
2020 Polat et al. [242] Assessment of hearing function in children with inflammatory bowel disease The clinical study involved 32 pediatric patients with IBD and 31 age-matched controls. Examinations involved detailed ENT examination, pure tone audiometry (PTA), high-frequency audiometry (HFA), signal-to-noise ratio (SNR) and distortion product (DP) otoacoustic emissions testing. o No differences in age and gender and PTA thresholds at low frequencies between controls and children with IBD. “(…) SNHL in pediatric patients with IBD was seen at the high frequencies. It could represent a potential early indicator of SNHL in this population. We recommend hearing function tests twice a year for early diagnosis. HFA and DPOAE can be used safely in this population for monitoring the hearing loss.”
o The mean PTA responses at 1,000; 8,000; 10,000; 12,500; 16,000; SNR1400; SNR2000; SNR2800; and SNR4000Hz of the IBD group were significantly higher than those of the controls (p < 0.05 for all).
2021 Yozgat et al. [243] Ulcerative colitis may be a risk factor for sensorineural hearing loss The clinical study involved 53 patients with IBD and 20 matched controls within period of 4 months. Examinations involved tympanometry, otoscopy and audiometry. o No significant difference in terms of gender and age between the IBD and control groups. “SNHL has been detected in a significant number of UC patients. Also, the hearing function deteriorated significantly as the age of the patients and the duration of the disease increases. It should be recommended to evaluate UC patients over 40 years of age and with the long-term disease for SNHL.”
o No significant difference in air and bone conduction in both ears in patients with CD.
o A significant difference in both air and bone conduction in ulcerative colitis (p = 0.0001 in the left ear, p = 0.004 in the right ear).
o SNHL was detected in 45.2% (n = 14) of UC patients and 13.6% (n = 3) of CD patients using audiometry.
o Three UC patients had moderate, one had moderate to severe, and one had profound hearing loss.
Table 2.Clinical studies regarding the association between celiac disease and hearing loss.
Year Authors Title Methodology Results Conclusion
2011 Hizli et al. [234] Sensorineural hearing loss in pediatric celiac patients A sample of 32 biopsies and serologically proven newly diagnosed pediatric celiac patients and matched healthy subjects (control group) were involved in this study. Pure-tone audiometry at frequencies 250–8000 Hz was performed in all subjects. Slight/mild SNHL was defined as a loss of sound detection within the 16–40 dB range. The mean age of the patient and control group was 11.9 and 11.3, respectively (p > 0.05). · SNHL was found in 40.6% (n = 13) celiac pediatric patients (6 unilateral and 7 bilateral), and 3.1% (n = 1) control group. “(…) a higher prevalence of SNHL in pediatric celiac patients than in controls, suggesting an association between CeD and SNHL. The findings of this study suggest that hearing impairment should be investigated in newly diagnosed pediatric CeD patients. Further longitudinal investigations on a larger sample size will be necessary to confirm the present data and to search the immunological processes which could be the basis of the association between CD and SNHL.”
2011 Karabulut et al. [244] Audiological findings in celiac disease 41 pediatric celiac patients and 31 controls were included in the study. Both groups were evaluated with audiometry, tympanometry, transiently evoked otoacoustic emission (TEOAE), distortion product otoacoustic emission (DPOAE), and contralateral suppression of the TEOAE. · The average PTA thresholds at 250 Hz of the CeD patients were significantly higher (p < 0.05) in CeD compared to the control group. “(…)CeD seems to have an important impact on the auditory system and results in an elevation of the PTA thresholds at 250 Hz and a decrease in the amplitudes of DPOAE and linear TEOAE at 1 kHz in children.”
· The signal-to-noise ratio (SNR) amplitudes in DPOAE testing and SNR with and without contralateral acoustic stimulus in TEOAE testing were significantly lower at 1 kHz in the CeD group than in the control group.
· There was no significant difference between the CeD and the control group regarding contralateral suppression amplitudes.
2012 Solmaz et al. [236] Celiac disease and sensorineural hearing loss in children 25 pediatric patients with biopsy-proven celiac disease were diagnosed in the pediatric gastroenterology department, and 25 healthy control subjects were included in the study. All subjects underwent tympanometry and pure tone audiometry at frequencies 250–8000 Hz. · Tympanometry showed normal peak compliance, gradient, peak pressure, ear canal volume, and acoustic reflexes in the patients and controls. Sensorineural hearing loss (SNHL) and celiac disease (CeD) may be observed coincidentally. Children with clinical signs of hearing deficiency of unknown aetiology should be assessed for CeD.
· There was no air-bone gap in any of the participants.
· There was a statistically significant difference (p < 0.05) between the PTA thresholds in the celiac and control groups in both ears.
2012 Leggio et al. [245] Coeliac disease and hearing loss: Preliminary data on a new possible association Twenty-four adult celiac patients and 24 healthy subjects matched for gender, age, smoking and drinking habits were enrolled in the study. Among the celiac patients, 6 were newly diagnosed, and 18 patients were on a gluten-free diet for at least one year. · A hearing loss was found in 47.1% (n = 10) of celiac patients and 9.1% (n = 2) controls. “Despite the low number of subjects evaluated, the present study showed a higher prevalence of hearing loss in celiac patients than in healthy controls, suggesting an association between CeD and hearing loss. Immunological processes such as ear-specific and non-specific autoantibodies and vasculitis could be the basis of this association. Further longitudinal investigations on a larger sample size will be necessary to confirm the present data. ”
· All celiac patients with hearing impairment developed SNHL.
· The prevalence of SNHL was not significantly different between untreated (33.3%) and treated (44.4%) coeliac patients.
2015 Urganci et al. [237] Sensorineural hearing loss in pediatric patients with celiac disease Otoscopy, tympanometry and pure tone audiometry were performed in 44 pediatric patients with celiac disease and 20 matched controls. · SNHL was detected in only 6.8% (n = 3) patients within 1−3 years after diagnosing CeD. “(…) subclinical sensorineural hearing loss was demonstrated in adult patients with CeD; therefore, we recommend to perform audiometric examinations in pediatric patients for recognising hearing loss early during the course of the disease.”
· None of the patients or controls had symptoms such as hearing loss, tinnitus or balance disturbance.
· All group members had normal otoscopy and tympanometry, excluding middle ear disease and conductive hearing loss. Pure tone audiometry showed no abnormality.
2015 Sahin et al. [235] Evaluation of hearing loss in pediatric celiac patients The study included 110 pediatric patients with biopsy-confirmed celiac disease and 41 matched controls. The hearing was evaluated using tympanometry and pure tone audiometry (250–8000 Hz frequency). · Audiometric bone conduction thresholds were significantly (p < 0.05) different between the celiac patients and the controls. “These results indicate that subclinical hearing loss may be present in children with CeD, which could precede more serious hearing impairments at older ages and later stages of the disease. Hearing screenings should be recommended for children with CeD in order to prevent the potentially unfavourable effects of hearing loss on the emotional, behavioural, cognitive, and sensorimotor development of these patients.”
· There were no significant differences in pure-tone averages for air conduction (p > 0.05).
· When the results for celiac patients were analysed according to the duration of disease (36 months and >36 months), a significant difference in bone conduction thresholds (p < 0.05) was observed, with substantial increments at the later stages of the disease. However, this difference was insufficient to define clinical hearing loss, as the pure tone average thresholds remained below 20 dB.
2019 Yazici et al. [246] Does celiac disease cause autoimmune sensorineural hearing loss? The prospective study included 103 adult celiac patients and 79 healthy controls between 2012 and 2018. Celiac patients were divided into two groups: remission or active, according to their gluten-free diet duration and serum levels of anti-tissue transglutaminase. They underwent pure-tone audiometry after detailed ear examination. · Only 3.88% (n = 4) of celiac patients showed SNHL. “In this study with a higher number of CeD patients when compared with the previous studies, it has been shown that CeD does not appear to cause autoimmune SNHL. In addition, patients in the remission of CeD did not show different PTA thresholds than the active cases.”
· There was no statistically significant difference between the hearing levels of the celiac patients and the control group in air and bone conductions measurements.
· The PTA thresholds comparing the remission and active celiac patients did not differ in air and bone conduction frequencies.
2020 Yaprak et al. [239] Hearing evaluation with ABR in pediatric patients with celiac disease 38 pediatric celiac patients were included in the study. The patients had confirmed diagnosis of Celiac disease through duodenal biopsies and transglutaminase antibody. The control group consisted of 18 children aged 3 to 17 years old who were all admitted to the pediatric gastroenterology department due to complaints of constipation and transglutaminase Ab. All children underwent Auditory-Brain-Stem-Evoked Responses (ABR). · The results of the ABR examination did not show any difference between the patient group and control group as regards the latency of the waves I, III, V. “The exact pathogenesis of neurological damage observed in CeD is still unknown. Humoral immune mechanisms are the most frequently attributed cause. Although no significant difference was found in ABR responses between the study group and healthy control group, there is a need for further research on this subject.”
· No difference was observed between the two groups in the interpeak latencies of the ABR waves I–III, I–V and III–V. None of the patients was observed to have clinical hearing loss.
4. Blood-brain and Blood-labyrinth Barrier and Gut Dysbiosis
4.1 Hyperpermeability of the Blood-brain Barrier in CeD and IBD

The blood-brain barrier (BBB) is a critical anatomical and physiological structure protecting neural tissue. The BBB is formed by the blood vessels of the central nervous system (CNS). In the CNS, the blood vessels are not permissive, restricting the infiltration of pathogens into neural tissue [249, 250, 251]. The integrity of the BBB can be affected by multiple mechanisms, which, in turn, allow pathogens and inflammatory cells to infiltrate neural tissues [249, 252]. This can result in neuroinflammatory disorders, such as multiple sclerosis [253, 254], acute disseminated encephalomyelitis [255], or transverse myelitis [256]. Neuroinflammation can also be triggered by an injury, exposure to a neurotoxin, neurodegenerative disease, or ageing [257, 258, 259].

The leaky gut and resulting systemic inflammation can negatively impact the integrity of the BBB. As a result, the BBB’s ability to selectively restrict the passage of pathogens and neurotoxic agents to the brain is diminished. Inflammation and hypoxia can be classified as primary culprits [16], often by weakening the TJ of the BBB [16]. Han et al. [260] demonstrated that dextran sodium sulfate (DSS)-induced colitis in mice could provoke systemic inflammation leading to cortical brain inflammation via up-regulation of inflammatory cytokines in the serum. Other studies demonstrated that colitis induced by trinitrobenzene sulphonic acid (TNBS), which affects the IB permeability, can also disturb the integrity of the BBB [252, 261]. In monkeys, the alteration of the gut microbiome by antibiotics can also increase BBB permeability [262] due to gut dysbiosis [260, 263]. The permeability of the BBB can be increased by pro-inflammatory cytokines such as IL-1β, which can affect the BBB by breaking down and translocating TJ proteins [264].

Interestingly, germ-free (GF) mice show increased resistance to neuroinflammatory diseases [265]. However, Braniste et al. [204] reported an increase in the permeability of the BBB in GF mice. A possible explanation is that the normal gut microbiota also regulates the TJ structure and function within the BBB; thus, a lack of commensal bacteria may lead to an aberrant formation of TJs, such as occludin and claudin-5 [204].

In conclusion, there is strong evidence that “leaky gut” disorders can induce a variety of EIMs resulting from breached barriers of immune-privileged organs, such as the BBB.

4.2 Can IBD and CeD Increase Permeability of the BLB?

Despite the anatomical differences between the IB, BBB, and BLB, these barriers also have several commonalities [263, 266]. Diseases associated with pathological alterations of gut microbiota (e.g., diabetes, obesity, IBD, CeD) also share an ability to affect the permeability of all three barriers. Therefore, we postulate that gut dysbiosis and leaky gut have a similar influence on both the BBB and BLB via a feedback loop driven by microbial solutes and the innate immune system.

One of the factors that consistently affects the permeability of the BLB is inflammation. Another potential mechanism that might affect the permeability of the BLB and the BBB in IBD and CeD is OS [11, 15, 267, 268, 269].

OS results from the overproduction of reactive oxygen species (ROS) [267, 270, 271]. Along with inflammation, it is considered one of the primary mechanisms in CeD. It was suggested that OS might predispose CeD patients to other autoimmune disorders [267]. Previous studies have shown that brain-derived microvascular endothelial cells of the BBB, when exposed to OS, express elevated matrix metallopeptidase 9 (MMP-9) activity that affects TJ protein occludin [264, 272]. Similarly, elevated OS markers such as inducible nitric oxide synthase (iNOS) show that vascular endothelial cells of the BLB are also prone to oxidative damage, triggering inflammatory pathways within the cochlea [273].

In mice, specific cytokines (IL-1, IL-6, and MIP-1α) enhance the permeability of the BLB, allowing ototoxic drugs to enter the cochlea [274]. LPS-induced low-grade endotoxemia can also increase BLB permeability via toll-like receptor 4 (TLR4) [275]. However, LPS is not sufficient to alter BBB permeability on its own [276, 277], but it can induce inflammation and production of pro-inflammatory cytokines [274], which can disturb the BBB and the BLB (Fig. 3). In rodents, LPS can enter the brain by the lipoprotein-mediated transport mechanism and bind to its receptors CD14 and TLR4 [278]. Upon activation of these receptors, the regional pro-inflammatory cascade starts [208]. The cochlea houses both receptors - CD14 and TLR4, which can induce an ototoxic response to cisplatin [279, 280, 281]. TLR4 activation could also cause sensory cell degeneration and cochlear dysfunction after a noise-induced trauma [281].

Fig. 3.

Leaky gut can cause systemic inflammation resulting in a breach of the blood-brain and blood-labyrinth barrier and local low-grade chronic inflammation in the brain and the cochlea. Abbreviations: BM, basement membrane; EC, endothelial cell; PVM/M, perivascular-resident macrophage-like melanocyte; TJ, tight junction; SV, stria vascularis; SL, spiral ligament; SG, spiral ganglion.

CpG motifs can also activate innate and adaptive immune responses via TLR9 receptor-mediated MAPK and NF-κB pathways in immune and epithelial cells [282, 283]. The innate immune system then releases pro-inflammatory cytokine IL-18, followed by the recruitment of neutrophils and leukocytes to the sites of infection [37]. During cochlear inflammation, resident macrophages of the cochlea can additionally increase BLB permeability [284, 285, 286]. This, in turn, allows infiltrating macrophages from the systemic circulation to migrate to the inner ear to resolve the inflammation [287, 288].

Cytokines and chemokines increase the permeability of the BBB by stripping off its protective glycocalyx [269]. The glycocalyx is an equivalent of the superficial unstirred mucus layer in the IB and forms both the BBB and the BLB [289]. As a result, the endothelial cells are exposed to inflammatory mediators, allowing for their erosion [269].

5. Conclusions

“Leaky gut” disorders, such as IBD and CeD, lead to an increase in IB permeability. The compromised IB allows pathogens and microbial metabolites to infiltrate the circulatory system and spread to distant organs. The immune-privileged organs (brain, cochlea) are protected by barriers with a similar structure; thus, these barriers are more likely to be compromised by the same type of stimuli. EIMs of CeD and IBD include dysfunctions of the blood-brain and the blood-labyrinth barrier (Fig. 3). Based on the current literature, we postulate that the breach of these barriers causes neuroinflammation and inflammation-induced SNHL. We have coined the term gut-inner ear axis to describe the crosstalk between the gut and inner ear, analogous to the gut-brain axis.

Author Contributions

DK designed the study and performed the literature search, and SMV provided advice. DK analysed the literature and drafted the review. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

We thank Mr Corey Beran for proofreading this manuscript.

Funding

This study was funded by Eisdell Moore Centre (Auckland, New Zealand), grant number 3721994.

Conflict of Interest

The authors declare no conflicts of interest.

References
[1]
Hisamatsu T, Erben U, Kühl AA. The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: more Common Mechanisms or more Differences? Inflammatory Intestinal Diseases. 2016; 1: 52–62.
[2]
Girbovan A, Sur G, Samasca G, Lupan I. Dysbiosis a risk factor for celiac disease. Medical Microbiology and Immunology. 2017; 206: 83–91.
[3]
Kim SM, Mayassi T, Jabri B. Innate immunity: actuating the gears of celiac disease pathogenesis. Best Practice & Research. Clinical Gastroenterology. 2015; 29: 425–435.
[4]
Baldelli V, Scaldaferri F, Putignani L, Del Chierico F. The Role of Enterobacteriaceae in Gut Microbiota Dysbiosis in Inflammatory Bowel Diseases. Microorganisms. 2021; 9: 697.
[5]
Takiishi T, Fenero CIM, Câmara NOS. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers. 2017; 5: e1373208.
[6]
Maguire M, Maguire G. Gut dysbiosis, leaky gut, and intestinal epithelial proliferation in neurological disorders: towards the development of a new therapeutic using amino acids, prebiotics, probiotics, and postbiotics. Reviews in the Neurosciences. 2019; 30: 179–201.
[7]
Lerman-Garber I, Cuevas-Ramos D, Valdés S, Enríquez L, Lobato M, Osornio M, et al. Sensorineural hearing loss—a common finding in early-onset type 2 diabetes mellitus. Endocrine Practice. 2012; 18: 549–557.
[8]
Volta U, Ferri G, De Giorgio R, Fabbri A, Parisi C, Sciajno L, et al. Sensorineural Hearing Loss and Celiac Disease: A Coincidental Finding. Canadian Journal of Gastroenterology. 2009; 23: 531–535.
[9]
Wengrower D, Koslowsky B, Peleg U, Mazuz B, Cohen L, Ben-David A, et al. Hearing Loss in Patients with Inflammatory Bowel Disease. Digestive Diseases and Sciences. 2016; 61: 2027–2032.
[10]
Fousekis FS, Saridi M, Albani E, Daniel F, Katsanos KH, Kastanioudakis IG, et al. Ear Involvement in Inflammatory Bowel Disease: a Review of the Literature. Journal of Clinical Medicine Research. 2018; 10: 609–614.
[11]
Michielan A, D’Incà R. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. Mediators of Inflammation. 2015; 2015: 628157.
[12]
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56: 1761–1772.
[13]
Dlugosz A, Nowak P, D’Amato M, Mohammadian Kermani G, Nyström J, Abdurahman S, et al. Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterology and Motility. 2015; 27: 1747–1754.
[14]
Kim K, Gu W, Lee I, Joh E, Kim D. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE. 2012; 7: e47713.
[15]
Pennisi M, Bramanti A, Cantone M, Pennisi G, Bella R, Lanza G. Neurophysiology of the “Celiac Brain”: Disentangling Gut-Brain Connections. Frontiers in Neuroscience. 2017; 11: 498.
[16]
Obrenovich MEM. Leaky Gut, Leaky Brain? Microorganisms. 2018; 6: 107.
[17]
Kociszewska D, Chan J, Thorne PR, Vlajkovic SM. The Link between Gut Dysbiosis Caused by a High-Fat Diet and Hearing Loss. International Journal of Molecular Sciences. 2021; 22: 13177.
[18]
Cardoso-Silva D, Delbue D, Itzlinger A, Moerkens R, Withoff S, Branchi F, et al. Intestinal Barrier Function in Gluten-Related Disorders. Nutrients. 2019; 11: 2325.
[19]
van Elburg RM, Uil JJ, Mulder CJ, Heymans HS. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut. 1993; 34: 354–357.
[20]
Vanuytsel T, Tack J, Farre R. The Role of Intestinal Permeability in Gastro-intestinal Disorders and Current Methods of Evaluation. Frontiers in Nutrition. 2021; 8: 717925.
[21]
López Casado M, Lorite P, Ponce de León C, Palomeque T, Torres M. Celiac Disease Autoimmunity. Archivum Immunologiae Et Therapiae Experimentalis. 2018; 66: 423–430.
[22]
Sommer K, Wiendl M, Müller TM, Heidbreder K, Voskens C, Neurath MF, et al. Intestinal Mucosal Wound Healing and Barrier Integrity in IBD–Crosstalk and Trafficking of Cellular Players. Frontiers in Medicine. 2021; 8: 643973.
[23]
Kirsner JB. The Historical Basis of the Idiopathic Inflammatory Bowel Diseases. Inflammatory Bowel Diseases. 1995; 1: 2–26.
[24]
Hawkins HP. An Address on the NATURAL HISTORY of ULCERATIVE COLITIS and its BEARING on TREATMENT. British Medical Journal. 1909; 1: 765–770.
[25]
Khan I, Ullah N, Zha L, Bai Y, Khan A, Zhao T, et al. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens. 2019; 8: 126.
[26]
Chibbar R, Dieleman LA. The Gut Microbiota in Celiac Disease and probiotics. Nutrients. 2019; 11: 2375.
[27]
Al-Ayadhi L, Zayed N, Bhat RS, Moubayed NMS, Al-Muammar MN, El-Ansary A. The use of biomarkers associated with leaky gut as a diagnostic tool for early intervention in autism spectrum disorder: a systematic review. Gut Pathogens. 2021; 13: 54.
[28]
Hollander D. Intestinal permeability, leaky gut, and intestinal disorders. Current Gastroenterology Reports. 1999; 1: 410–416.
[29]
Rocha BS, Correia MG, Fernandes RC, Gonçalves JS, Laranjinha J. Dietary nitrite induces occludin nitration in the stomach. Free Radical Research. 2016; 50: 1257–1264.
[30]
Marciano F, Vajro P. Oxidative Stress and Gut Microbiota. In Gracia-Sancho J, Salvadó J (eds.) Gastro-intestinal Tissue (pp. 113–123). Academic Press. 2017.
[31]
Gasmi A, Mujawdiya PK, Pivina L, Doşa A, Semenova Y, Benahmed AG, et al. Relationship between Gut Microbiota, Gut Hyperpermeability and Obesity. Current Medicinal Chemistry. 2021; 28: 827–839.
[32]
Régnier M, Van Hul M, Knauf C, Cani PD. Gut microbiome, endocrine control of gut barrier function and metabolic diseases. Journal of Endocrinology. 2021; 248: R67–R82.
[33]
Shah A, Walker M, Burger D, Martin N, von Wulffen M, Koloski N, et al. Link between Celiac Disease and Inflammatory Bowel Disease. Journal of Clinical Gastroenterology. 2019; 53: 514–522.
[34]
Pinto-Sanchez MI, Seiler CL, Santesso N, Alaedini A, Semrad C, Lee AR, et al. Association between Inflammatory Bowel Diseases and Celiac Disease: a Systematic Review and Meta-Analysis. Gastroenterology. 2020; 159: 884–903.e31.
[35]
Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harbor Perspectives in Biology. 2009; 1: a002584.
[36]
Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Experimental & Molecular Medicine. 2018; 50: 1–9.
[37]
Kany S, Vollrath JT, Relja B. Cytokines in Inflammatory Disease. International Journal of Molecular Sciences. 2019; 20: 6008.
[38]
Mahapatro M, Erkert L, Becker C. Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut. Cells. 2021; 10: 111.
[39]
Boltin D, Perets TT, Vilkin A, Niv Y. Mucin function in inflammatory bowel disease: an update. Journal of Clinical Gastroenterology. 2013; 47: 106–111.
[40]
Tavakoli P, Vollmer-Conna U, Hadzi-Pavlovic D, Grimm MC. A Review of Inflammatory Bowel Disease: A Model of Microbial, Immune and Neuropsychological Integration. Public Health Reviews. 2021; 42: 1603990.
[41]
Mann ER. Intestinal antigen-presenting cells in mucosal immune homeostasis: Crosstalk between dendritic cells, macrophages and B-cells. World Journal of Gastroenterology. 2014; 20: 9653.
[42]
Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in Immunology. 2014; 5: 491.
[43]
Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Advances in Medical Sciences. 2017; 62: 1–16.
[44]
Dignass AU, Baumgart DC, Sturm A. The aetiopathogenesis of inflammatory bowel disease - immunology and repair mechanisms. Alimentary Pharmacology & Therapeutics. 2004; 20: 9–17.
[45]
Lotz M, Gütle D, Walther S, Ménard S, Bogdan C, Hornef MW. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. The Journal of Experimental Medicine. 2006; 203: 973–984.
[46]
Kumar A, Wu H, Collier-Hyams LS, Hansen JM, Li T, Yamoah K, et al. Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species. The EMBO Journal. 2007; 26: 4457–4466.
[47]
May MJ, Ghosh S. Signal transduction through NF-kappa B. Immunology Today. 1998; 19: 80–88.
[48]
Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harbor Perspectives in Biology. 2009; 1: a000034.
[49]
Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduction and Targeted Therapy. 2017; 2: 17023-.
[50]
Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014; 157: 121–141.
[51]
Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial Exposure during Early Life has Persistent Effects on Natural Killer T Cell Function. Science. 2012; 336: 489–493.
[52]
Laparra JM, Olivares M, Gallina O, Sanz Y. Bifidobacterium longum CECT 7347 modulates immune responses in a gliadin-induced enteropathy animal model. PLoS ONE. 2012; 7: e30744.
[53]
Lindfors K, Blomqvist T, Juuti-Uusitalo K, Stenman S, Venäläinen J, Mäki M, et al. Live probiotic Bifidobacterium lactis bacteria inhibit the toxic effects induced by wheat gliadin in epithelial cell culture. Clinical and Experimental Immunology. 2008; 152: 552–558.
[54]
Cinova J, De Palma G, Stepankova R, Kofronova O, Kverka M, Sanz Y, et al. Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats. PLoS ONE. 2011; 6: e16169.
[55]
Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, et al. Succession of microbial consortia in the developing infant gut microbiome. Proceedings of the National Academy of Sciences. 2011; 108: 4578–4585.
[56]
Al Nabhani Z, Dulauroy S, Marques R, Cousu C, Al Bounny S, Déjardin F, et al. A Weaning Reaction to Microbiota is Required for Resistance to Immunopathologies in the Adult. Immunity. 2019; 50: 1276–1288.e5.
[57]
Mengheri E, Ciapponi L, Vignolini F, Nobili F. Cytokine gene expression in intestine of rat during the postnatal developmental period: increased IL-1 expression at weaning. Life Sciences. 1996; 59: 1227–1236.
[58]
Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014; 158: 705–721.
[59]
Youngster I, Avorn J, Belleudi V, Cantarutti A, Díez-Domingo J, Kirchmayer U, et al. Antibiotic Use in Children - a Cross-National Analysis of 6 Countries. The Journal of Pediatrics. 2017; 182: 239–244.e1.
[60]
Hobbs MR, Grant CC, Ritchie SR, Chelimo C, Morton SMB, Berry S, et al. Antibiotic consumption by New Zealand children: exposure is near universal by the age of 5 years. The Journal of Antimicrobial Chemotherapy. 2017; 72: 1832–1840.
[61]
Bager P, Simonsen J, Nielsen NM, Frisch M. Cesarean section and offspring’s risk of inflammatory bowel disease: a national cohort study. Inflammatory Bowel Diseases. 2012; 18: 857–862.
[62]
Xu L, Lochhead P, Ko Y, Claggett B, Leong RW, Ananthakrishnan AN. Systematic review with meta-analysis: breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Alimentary Pharmacology & Therapeutics. 2017; 46: 780–789.
[63]
Klement E, Lysy J, Hoshen M, Avitan M, Goldin E, Israeli E. Childhood hygiene is associated with the risk for inflammatory bowel disease: a population-based study. The American Journal of Gastroenterology. 2008; 103: 1775–1782.
[64]
Kronman MP, Zaoutis TE, Haynes K, Feng R, Coffin SE. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics. 2012; 130: e794–e803.
[65]
Stark CM, Susi A, Emerick J, Nylund CM. Antibiotic and acid-suppression medications during early childhood are associated with obesity. Gut. 2019; 68: 62–69.
[66]
Dydensborg Sander S, Nybo Andersen A, Murray JA, Karlstad Ø, Husby S, Størdal K. Association between Antibiotics in the first Year of Life and Celiac Disease. Gastroenterology. 2019; 156: 2217–2229.
[67]
Shen X, Wan Q, Zhao R, Wu Y, Wang Y, Cui Y, et al. Inflammatory bowel diseases and the risk of adverse health outcomes: Umbrella review of meta-analyses of observational studies. Digestive and Liver Disease. 2021; 53: 809–816.
[68]
Flynn S, Eisenstein S. Inflammatory Bowel Disease Presentation and Diagnosis. The Surgical Clinics of North America. 2019; 99: 1051–1062.
[69]
Wen Z, Fiocchi C. Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis? Clinical & Developmental Immunology. 2004; 11: 195–204.
[70]
Ciccarelli F, De Martinis M, Ginaldi L. An update on autoinflammatory diseases. Current Medicinal Chemistry. 2014; 21: 261–269.
[71]
Torres J, Mehandru S, Colombel J, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017; 389: 1741–1755.
[72]
Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017; 152: 313–321.e2.
[73]
Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. The American Journal of Gastroenterology. 2011; 106: 563–573.
[74]
Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nature Reviews. Gastroenterology & Hepatology. 2015; 12: 205–217.
[75]
Kahui S, Snively S, Ternent M. Reducing the Growing Burden of IBD in New Zealand. A study on the burden of inflammatory bowel disease in New Zealand. 2017. Available at: https://cdn.fld.nz/uploads/sites/crohns/files/files/IBD_-_Burden_of_Disease.pdf (Accessed: 3 February 2022).
[76]
Gearry RB, Richardson A, Frampton CMA, Collett JA, Burt MJ, Chapman BA, et al. High incidence of Crohn’s disease in Canterbury, New Zealand: results of an epidemiologic study. Inflammatory Bowel Diseases. 2006; 12: 936–943.
[77]
Su HY, Gupta V, Day AS, Gearry RB. Rising Incidence of Inflammatory Bowel Disease in Canterbury, New Zealand. Inflammatory Bowel Diseases. 2016; 22: 2238–2244.
[78]
Day AS, Lemberg DA, Gearry RB. Inflammatory bowel disease in australasian children and adolescents. Gastroenterology Research and Practice. 2014; 2014: 703890.
[79]
Thia KT, Loftus EV, Sandborn WJ, Yang S. An update on the epidemiology of inflammatory bowel disease in Asia. The American Journal of Gastroenterology. 2008; 103: 3167–3182.
[80]
Park J, Cheon JH. Incidence and Prevalence of Inflammatory Bowel Disease across Asia. Yonsei Medical Journal. 2021; 62: 99.
[81]
Wu X, Qian L, Liu K, Wu J, Shan Z. Gastro-intestinal microbiome and gluten in celiac disease. Annals of Medicine. 2021; 53: 1797–1805.
[82]
Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clinical Gastroenterology and Hepatology. 2018; 16: 823–836.e2.
[83]
Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009; 137: 88–93.
[84]
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018; 391: 70–81.
[85]
Bai JC, Ciacci C. World Gastroenterology Organisation Global Guidelines: Celiac Disease February 2017. Journal of Clinical Gastroenterology. 2017; 51: 755–768.
[86]
Yuan J, Jiang X, Hu S, Gao J, Chen H. Recent advances in celiac disease. Journal of Food Safety and Quality. 2015; 6: 4510–4515.
[87]
Festen EAM, Goyette P, Green T, Boucher G, Beauchamp C, Trynka G, et al. A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn’s disease and celiac disease. PLoS Genetics. 2011; 7: e1001283.
[88]
Camilleri M, Madsen K, Spiller R, Greenwood-Van Meerveld B, Van Meerveld BG, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterology and Motility. 2012; 24: 503–512.
[89]
Hmida NB, Ben Ahmed M, Moussa A, Rejeb MB, Said Y, Kourda N, et al. Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease? The American Journal of Gastroenterology. 2012; 107: 604–611.
[90]
Soukou S, Brockmann L, Bedke T, Gagliani N, Flavell RA, Huber S. Role of IL-10 Receptor Signaling in the Function of CD4+ T-Regulatory Type 1 cells: T-Cell Therapy in Patients with Inflammatory Bowel Disease. Critical Reviews in Immunology. 2018; 38: 415–431.
[91]
Jabri B, Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nature Reviews. Immunology. 2015; 15: 771–783.
[92]
Meisel M, Mayassi T, Fehlner-Peach H, Koval JC, O’Brien SL, Hinterleitner R, et al. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. The ISME Journal. 2017; 11: 15–30.
[93]
Caminero A, Meisel M, Jabri B, Verdu EF. Mechanisms by which gut microorganisms influence food sensitivities. Nature Reviews. Gastroenterology & Hepatology. 2019; 16: 7–18.
[94]
Harris K, Chang E. The intestinal microbiota in the pathogenesis of inflammatory bowel diseases: new insights into complex disease. Clinical Science. 2018; 132: 2013–2028.
[95]
Acharya S, Venkatesan D, Mohanty SL, Mohapatra P. A STUDY of SENSORINEURAL HEARING LOSS in PATIENTS of INFLAMMATORY BOWEL DISEASE. Journal of Evidence Based Medicine and Healthcare. 2019; 6: 736–740.
[96]
Weber CR, Turner JR. Inflammatory bowel disease: is it really just another break in the wall? Gut. 2007; 56: 6–8.
[97]
Xu P, Elamin E, Elizalde M, Bours PPHA, Pierik MJ, Masclee AAM, et al. Modulation of Intestinal Epithelial Permeability by Plasma from Patients with Crohn’s Disease in a Three-dimensional Cell Culture Model. Scientific Reports. 2019; 9: 2030.
[98]
Loftus EV. Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gut. 2000; 46: 336–343.
[99]
Loftus EV, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn’s disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gastroenterology. 1998; 114: 1161–1168.
[100]
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505: 559–563.
[101]
Wu GD, Chen J, Hoffmann C, Bittinger K, Chen Y, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011; 334: 105–108.
[102]
Farzaei MH, Rahimi R, Abdollahi M. The role of dietary polyphenols in the management of inflammatory bowel disease. Current Pharmaceutical Biotechnology. 2015; 16: 196–210.
[103]
Olendzki BC, Silverstein TD, Persuitte GM, Ma Y, Baldwin KR, Cave D. An anti-inflammatory diet as treatment for inflammatory bowel disease: a case series report. Nutrition Journal. 2014; 13: 5.
[104]
Persson PG, Ahlbom A, Hellers G. Diet and inflammatory bowel disease: a case-control study. Epidemiology. 1992; 3: 47–52.
[105]
Bernstein CN, Hitchon CA, Walld R, Bolton JM, Sareen J, Walker JR, et al. Increased Burden of Psychiatric Disorders in Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2019; 25: 360–368.
[106]
Timm S, Svanes C, Janson C, Sigsgaard T, Johannessen A, Gislason T, et al. Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe. European Journal of Epidemiology. 2014; 29: 429–437.
[107]
Barclay AR, Russell RK, Wilson ML, Gilmour WH, Satsangi J, Wilson DC. Systematic Review: the Role of Breastfeeding in the Development of Pediatric Inflammatory Bowel Disease. The Journal of Pediatrics. 2009; 155: 421–426.
[108]
Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. The American Journal of Gastroenterology. 2010; 105: 2687–2692.
[109]
Virta L, Auvinen A, Helenius H, Huovinen P, Kolho K. Association of repeated exposure to antibiotics with the development of pediatric Crohn’s disease–a nationwide, register-based finnish case-control study. American Journal of Epidemiology. 2012; 175: 775–784.
[110]
Dickinson RJ, O’Connor HJ, Pinder I, Hamilton I, Johnston D, Axon AT. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut. 1985; 26: 1380–1384.
[111]
Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004; 126: 1620–1633.
[112]
Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Abadir A, et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. The American Journal of Gastroenterology. 2011; 106: 661–673.
[113]
Mennigen R, Heptner B, Senninger N, Rijcken E. Temporary fecal diversion in the management of colorectal and perianal Crohn’s disease. Gastroenterology Research and Practice. 2015; 2015: 286315.
[114]
Singh S, Ding NS, Mathis KL, Dulai PS, Farrell AM, Pemberton JH, et al. Systematic review with meta-analysis: faecal diversion for management of perianal Crohn’s disease. Alimentary Pharmacology & Therapeutics. 2015; 42: 783–792.
[115]
Yamamoto T, Allan RN, Keighley MR. Effect of fecal diversion alone on perianal Crohn’s disease. World Journal of Surgery. 2000; 24: 1258–1253.
[116]
Ungaro R, Bernstein CN, Gearry R, Hviid A, Kolho K, Kronman MP, et al. Antibiotics Associated with Increased Risk of New-Onset Crohn’s Disease but not Ulcerative Colitis: a Meta-Analysis. American Journal of Gastroenterology. 2014; 109: 1728–1738.
[117]
Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nature Reviews. Neuroscience. 2011; 12: 453–466.
[118]
Lyte M, Vulchanova L, Brown DR. Stress at the intestinal surface: catecholamines and mucosa-bacteria interactions. Cell and Tissue Research. 2011; 343: 23–32.
[119]
Tannock GW. Exploring the relationships between intestinal microflora and inflammatory conditions of the human bowel and spine. Antonie Van Leeuwenhoek. 2002; 81: 529–535.
[120]
Bibbò S, Ianiro G, Giorgio V, Scaldaferri F, Masucci L, Gasbarrini A, et al. The role of diet on gut microbiota composition. European Review for Medical and Pharmacological Sciences. 2016; 20: 4742–4749.
[121]
Dixon LJ, Kabi A, Nickerson KP, McDonald C. Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis. Inflammatory Bowel Diseases. 2015; 21: 912–922.
[122]
Zinöcker MK, Lindseth IA. The Western Diet-Microbiome-Host Interaction and its Role in Metabolic Disease. Nutrients. 2018; 10: 365.
[123]
Chaumard N, Limat S, Villanueva C, Nerich V, Fagnoni P, Bazan F, et al. Incidence and risk factors of anemia in patients with early breast cancer treated by adjuvant chemotherapy. Breast. 2012; 21: 464–467.
[124]
Perrin A, Dallongeville J, Ducimetière P, Ruidavets J, Schlienger J, Arveiler D, et al. Interactions between traditional regional determinants and socio-economic status on dietary patterns in a sample of French men. The British Journal of Nutrition. 2005; 93: 109–114.
[125]
Drake I, Sonestedt E, Ericson U, Wallström P, Orho-Melander M. A Western dietary pattern is prospectively associated with cardio-metabolic traits and incidence of the metabolic syndrome. The British Journal of Nutrition. 2018; 119: 1168–1176.
[126]
Heinonen I, Rinne P, Ruohonen ST, Ruohonen S, Ahotupa M, Savontaus E. The effects of equal caloric high fat and western diet on metabolic syndrome, oxidative stress and vascular endothelial function in mice. Acta Physiologica. 2014; 211: 515–527.
[127]
Kopp W. How Western Diet and Lifestyle Drive the Pandemic of Obesity and Civilization Diseases. Diabetes, Metabolic Syndrome and Obesity. 2019; 12: 2221–2236.
[128]
Noble EE, Hsu TM, Kanoski SE. Gut to Brain Dysbiosis: Mechanisms Linking Western Diet Consumption, the Microbiome, and Cognitive Impairment. Frontiers in Behavioral Neuroscience. 2017; 11: 9.
[129]
Rohr MW, Narasimhulu CA, Rudeski-Rohr TA, Parthasarathy S. Negative Effects of a High-Fat Diet on Intestinal Permeability: A Review. Advances in Nutrition. 2020; 11: 77–91.
[130]
Barnett JA, Gibson DL. Separating the Empirical Wheat From the Pseudoscientific Chaff: A Critical Review of the Literature Surrounding Glyphosate, Dysbiosis and Wheat-Sensitivity. Frontiers in Microbiology. 2020; 11: 556729–556729.
[131]
Van Bruggen AHC, He MM, Shin K, Mai V, Jeong KC, Finckh MR, et al. Environmental and health effects of the herbicide glyphosate. The Science of the Total Environment. 2018; 616-617: 255–268.
[132]
Wendelsdorf K, Bassaganya-Riera J, Hontecillas R, Eubank S. Model of colonic inflammation: Immune modulatory mechanisms in inflammatory bowel disease. Journal of Theoretical Biology. 2010; 264: 1225–1239.
[133]
Pascual V, Dieli-Crimi R, López-Palacios N, Bodas A, Medrano LM, Núñez C. Inflammatory bowel disease and celiac disease: overlaps and differences. World Journal of Gastroenterology. 2014; 20: 4846–4856.
[134]
Caza T, Landas S. Functional and Phenotypic Plasticity of CD4(+) T Cell Subsets. BioMed Research International. 2015; 2015: 521957.
[135]
Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008; 57: 1682–1689.
[136]
Singh RP, Hasan S, Sharma S, Nagra S, Yamaguchi DT, Wong DTW, et al. Th17 cells in inflammation and autoimmunity. Autoimmunity Reviews. 2014; 13: 1174–1181.
[137]
Ivanov II, Frutos RDL, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host & Microbe. 2008; 4: 337–349.
[138]
Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules. 2017; 22: 134.
[139]
Guarner F, Malagelada J. Gut flora in health and disease. Lancet. 2003; 361: 512–519.
[140]
Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Büschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clinical and Experimental Immunology. 1995; 102: 448–455.
[141]
Garside P, Mowat AM, Khoruts A. Oral tolerance in disease. Gut. 1999; 44: 137–142.
[142]
Patankar JV, Becker C. Cell death in the gut epithelium and implications for chronic inflammation. Nature Reviews Gastroenterology & Hepatology. 2020; 17: 543–556.
[143]
De Nitto D, Monteleone I, Franze E, Pallone F, Monteleone G. Involvement of interleukin-15 and interleukin-21, two gamma-chain-related cytokines, in celiac disease. World Journal of Gastroenterology. 2009; 15: 4609–4614.
[144]
Molberg O, Mcadam SN, Körner R, Quarsten H, Kristiansen C, Madsen L, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Medicine. 1998; 4: 713–717.
[145]
Shan L, Molberg Ø, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002; 297: 2275–2279.
[146]
Valitutti F, Fasano A. Breaking down Barriers: how Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments. Digestive Diseases and Sciences. 2019; 64: 1748–1758.
[147]
Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008; 135: 194–204.e3.
[148]
Fasano A. Celiac disease–how to handle a clinical chameleon. The New England Journal of Medicine. 2003; 348: 2568–2570.
[149]
Sellitto M, Bai G, Serena G, Fricke WF, Sturgeon C, Gajer P, et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE. 2012; 7: e33387.
[150]
Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nature Genetics. 2011; 43: 1193–1201.
[151]
Medrano LM, Garcia-Magarinos M, Dema B, Espino L, Maluenda C, Polanco I, et al. Th17-related genes and celiac disease susceptibility. PLoS ONE. 2012; 7: e31244.
[152]
Gujral N, Freeman HJ, Thomson ABR. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World Journal of Gastroenterology. 2012; 18: 6036–6059.
[153]
Khalili H, Chan SSM, Lochhead P, Ananthakrishnan AN, Hart AR, Chan AT. The role of diet in the aetiopathogenesis of inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology. 2018; 15: 525–535.
[154]
Piovani D, Danese S, Peyrin-Biroulet L, Nikolopoulos GK, Lytras T, Bonovas S. Environmental Risk Factors for Inflammatory Bowel Diseases: an Umbrella Review of Meta-analyses. Gastroenterology. 2019; 157: 647–659.e4.
[155]
Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011; 473: 174–180.
[156]
Hakansson A, Molin G. Gut microbiota and inflammation. Nutrients. 2011; 3: 637–682.
[157]
Hebbandi Nanjundappa R, Ronchi F, Wang J, Clemente-Casares X, Yamanouchi J, Sokke Umeshappa C, et al. A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis. Cell. 2017; 171: 655–667.e17.
[158]
Zamani S, Taslimi R, Sarabi A, Jasemi S, Sechi LA, Feizabadi MM. Enterotoxigenic Bacteroides fragilis: A Possible Etiological Candidate for Bacterially-Induced Colorectal Precancerous and Cancerous Lesions. Frontiers in Cellular and Infection Microbiology. 2019; 9: 449.
[159]
Rabizadeh S, Rhee K, Wu S, Huso D, Gan CM, Golub JE, et al. Enterotoxigenic bacteroides fragilis: a potential instigator of colitis. Inflammatory Bowel Diseases. 2007; 13: 1475–1483.
[160]
Cao Y, Wang Z, Yan Y, Ji L, He J, Xuan B, et al. Enterotoxigenic Bacteroides fragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p. Gastroenterology. 2021; 161: 1552–1566.e12.
[161]
Miquel S, Peyretaillade E, Claret L, de Vallée A, Dossat C, Vacherie B, et al. Complete genome sequence of Crohn’s disease-associated adherent-invasive E. coli strain LF82. PLoS ONE. 2010; 5: e12714.
[162]
Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microbial Ecology in Health and Disease. 2015; 26: 26191.
[163]
Gronbach K, Flade I, Holst O, Lindner B, Ruscheweyh HJ, Wittmann A, et al. Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice. Gastroenterology. 2014; 146: 765–775.
[164]
Sánchez E, Laparra JM, Sanz Y. Discerning the role of Bacteroides fragilis in celiac disease pathogenesis. Applied and Environmental Microbiology. 2012; 78: 6507–6515.
[165]
Wacklin P, Kaukinen K, Tuovinen E, Collin P, Lindfors K, Partanen J, et al. The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease. Inflammatory Bowel Diseases. 2013; 19: 934–941.
[166]
Doran KS, Banerjee A, Disson O, Lecuit M. Concepts and Mechanisms: Crossing Host Barriers. Cold Spring Harbor Perspectives in Medicine. 2013; 3: a010090–a010090.
[167]
Ludvigsson JF, Olén O, Bell M, Ekbom A, Montgomery SM. Coeliac disease and risk of sepsis. Gut. 2008; 57: 1074–1080.
[168]
Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterology & Hepatology. 2011; 7: 235–241.
[169]
Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Rogler G. Extraintestinal Manifestations of Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2015; 21: 1982–1992.
[170]
Juillerat P, Manz M, Sauter B, Zeitz J, Vavricka S. Therapies in Inflammatory Bowel Disease Patients with Extraintestinal Manifestations. Digestion. 2020; 101: 83–97.
[171]
Philpot HC, Elewski BE, Banwell JG, Gramlich T. Pyostomatitis vegetans and primary sclerosing cholangitis: markers of inflammatory bowel disease. Gastroenterology. 1992; 103: 668–674.
[172]
Jose FA, Heyman MB. Extraintestinal manifestations of inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition. 2008; 46: 124–133.
[173]
Pastor Rojo O, López San Román A, Albéniz Arbizu E, de la Hera Martínez A, Ripoll Sevillano E, Albillos Martínez A. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflammatory Bowel Diseases. 2007; 13: 269–277.
[174]
Ferreira S, Masi J, Gimenez V, Carpinelli MM, Laterza O, Hermoso M, et al. Effect of gluten-free diet on levels of soluble CD14 and lipopolysaccharide-binding protein in adult patients with celiac disease. Central European Journal of Immunology. 2021; 46: 225–230.
[175]
Bhagat S, Das KM. A shared and unique peptide in the human colon, eye, and joint detected by a monoclonal antibody. Gastroenterology. 1994; 107: 103–108.
[176]
Ardizzone S, Puttini PS, Cassinotti A, Porro GB. Extraintestinal manifestations of inflammatory bowel disease. Digestive and Liver Disease. 2008; 40: S253–S259.
[177]
Biancone L, Mandal A, Yang H, Dasgupta T, Paoluzi AO, Marcheggiano A, et al. Production of immunoglobulin G and G1 antibodies to cytoskeletal protein by lamina propria cells in ulcerative colitis. Gastroenterology. 1995; 109: 3–12.
[178]
Das KM, Vecchi M, Sakamaki S. A shared and unique epitope(s) on human colon, skin, and biliary epithelium detected by a monoclonal antibody. Gastroenterology. 1990; 98: 464–469.
[179]
Geng X, Biancone L, Dai HH, Lin JJ, Yoshizaki N, Dasgupta A, et al. Tropomyosin isoforms in intestinal mucosa: production of autoantibodies to tropomyosin isoforms in ulcerative colitis. Gastroenterology. 1998; 114: 912–922.
[180]
Snook JA, de Silva HJ, Jewell DP. The association of autoimmune disorders with inflammatory bowel disease. The Quarterly Journal of Medicine. 1989; 72: 835–840.
[181]
Roussomoustakaki M, Satsangi J, Welsh K, Louis E, Fanning G, Targan S, et al. Genetic markers may predict disease behavior in patients with ulcerative colitis. Gastroenterology. 1997; 112: 1845–1853.
[182]
Satsangi J, Grootscholten C, Holt H, Jewell DP. Clinical patterns of familial inflammatory bowel disease. Gut. 1996; 38: 738–741.
[183]
Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP. Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes. Gastroenterology. 2002; 123: 714–718.
[184]
Orchard TR, Thiyagaraja S, Welsh KI, Wordsworth BP, Hill Gaston JS, Jewell DP. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology. 2000; 118: 274–278.
[185]
Jang H, Kang B, Choe B. The difference in extraintestinal manifestations of inflammatory bowel disease for children and adults. Translational Pediatrics. 2019; 8: 4–15.
[186]
Ott C, Schölmerich J. Extraintestinal manifestations and complications in IBD. Nature Reviews Gastroenterology & Hepatology. 2013; 10: 585–595.
[187]
Thomann AK, Mak JWY, Zhang JW, Wuestenberg T, Ebert MP, Sung JJY, et al. Review article: bugs, inflammation and mood-a microbiota-based approach to psychiatric symptoms in inflammatory bowel diseases. Alimentary Pharmacology & Therapeutics. 2020; 52: 247–266.
[188]
Zelnik N, Pacht A, Obeid R, Lerner A. Range of Neurologic Disorders in Patients with Celiac Disease. Pediatrics. 2004; 113: 1672–1676.
[189]
Daulatzai MA. Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia. CNS & Neurological Disorders Drug Targets. 2015; 14: 110–131.
[190]
Casella G, Bordo BM, Schalling R, Villanacci V, Salemme M, Di Bella C, et al. Neurological disorders and celiac disease. Minerva Gastroenterologica E Dietologica. 2016; 62: 197–206.
[191]
Lionetti E, Francavilla R, Maiuri L, Ruggieri M, Spina M, Pavone P, et al. Headache in Pediatric Patients with Celiac Disease and its Prevalence as a Diagnostic Clue. Journal of Pediatric Gastroenterology & Nutrition. 2009; 49: 202–207.
[192]
Niskar AS, Kieszak SM, Holmes A, Esteban E, Rubin C, Brody DJ. Prevalence of hearing loss among children 6 to 19 years of age: the third National Health and Nutrition Examination Survey. Journal of the American Medical Association. 1998; 279: 1071–1075.
[193]
Catassi C, Fasano A. Celiac disease. Current Opinion in Gastroenterology. 2008; 24: 687–691.
[194]
Kim GH, Lee YC, Kim TJ, Kim ER, Hong SN, Chang DK, et al. Risk of neurodegenerative diseases in patients with inflammatory bowel disease: a nationwide population-based cohort study. Journal of Crohn’s and Colitis. 2021. (in press)
[195]
Zhang B, Wang HE, Bai Y, Tsai S, Su T, Chen T, et al. Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study. Gut. 2021; 70: 85–91.
[196]
Elsehety A, Bertorini TE. Neurologic and Neuropsychiatric Complications of Crohnʼs Disease. Southern Medical Journal. 1997; 90: 606–610.
[197]
Singh S, Kumar N, Loftus EV, Kane SV. Neurologic complications in patients with inflammatory bowel disease: increasing relevance in the era of biologics. Inflammatory Bowel Diseases. 2013; 19: 864–872.
[198]
Nikpour S. Neurological manifestations, diagnosis, and treatment of celiac disease: a comprehensive review. Iranian Journal of Neurology. 2012; 11: 59–64.
[199]
Stolp HB, Dziegielewska KM, Ek CJ, Habgood MD, Lane MA, Potter AM, et al. Breakdown of the blood–brain barrier to proteins in white matter of the developing brain following systemic inflammation. Cell and Tissue Research. 2005; 320: 369–378.
[200]
Jiang S, Xia R, Jiang Y, Wang L, Gao F. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier. PLoS ONE. 2014; 9: e86407.
[201]
Gu Y, Dee CM, Shen J. Interaction of free radicals, matrix metalloproteinases and caveolin-1 impacts blood-brain barrier permeability. Frontiers in Bioscience (Scholar Edition). 2011; 3: 1216–1231.
[202]
Beard RS, Reynolds JJ, Bearden SE. Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. Blood. 2011; 118: 2007–2014.
[203]
Braidy N, Grant R. Kynurenine pathway metabolism and neuroinflammatory disease. Neural Regeneration Research. 2017; 12: 39–42.
[204]
Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, et al. The gut microbiota influences blood-brain barrier permeability in mice. Science Translational Medicine. 2014; 6: 263ra158.
[205]
Matisz CE, Gruber AJ. Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders. Neuroscience & Biobehavioral Reviews. 2021; 133: 104497.
[206]
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007; 55: 453–462.
[207]
Batista CRA, Gomes GF, Candelario-Jalil E, Fiebich BL, de Oliveira ACP. Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration. International Journal of Molecular Sciences. 2019; 20: 2293.
[208]
Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cellular and Molecular Life Sciences. 2021; 78: 1233–1261.
[209]
Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundamental & Clinical Pharmacology. 2008; 22: 453–464.
[210]
Murphy CE, Walker AK, Weickert CS. Neuroinflammation in schizophrenia: the role of nuclear factor kappa B. Translational Psychiatry. 2021; 11: 528.
[211]
Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspectives in Biology. 2009; 1: a001651.
[212]
Kim SF. The role of nitric oxide in prostaglandin biology; update. Nitric Oxide. 2011; 25: 255–264.
[213]
Oates JC, Gilkeson GS. The biology of nitric oxide and other reactive intermediates in systemic lupus erythematosus. Clinical Immunology. 2006; 121: 243–250.
[214]
Zhan X, Stamova B, Sharp FR. Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: a Review. Frontiers in Aging Neuroscience. 2018; 10: 42.
[215]
Obrenovich ME, Donskey CJ, Schiefer IT, Bongiovanni R, Li L, Jaskiw GE. Quantification of phenolic acid metabolites in humans by LC-MS: a structural and targeted metabolomics approach. Bioanalysis. 2018; 10: 1591–1608.
[216]
Siniscalco D, Schultz S, Brigida AL, Antonucci N. Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders. Pharmaceuticals. 2018; 11: 56.
[217]
Main BS, Minter MR. Microbial Immuno-Communication in Neurodegenerative Diseases. Frontiers in Neuroscience. 2017; 11: 151.
[218]
Obrenovich M, Rai H, Mana T, Shola D, McCloskey B, Sass C, et al. Dietary co-metabolism within the microbiota-gut-brain-endocrine metabolic interactome. 2017. Available at: https://www.researchgate.net/profile/Mark-Obrenovich/publication/314091205_Dietary_Co-Metabolism_within_the_Microbiota-Gut-Brain-Endocrine_Metabolic_Interactome/links/58b4c675aca2725b541c3e3a/Dietary-Co-Metabolism-within-the-Microbiota-Gut-Brain-Endocrine-Metabolic-Interactome.pdf (Accessed: 3 February 2022).
[219]
Łukasik J, Patro-Gołąb B, Horvath A, Baron R, Szajewska H. Early Life Exposure to Antibiotics and Autism Spectrum Disorders: a Systematic Review. Journal of Autism and Developmental Disorders. 2019; 49: 3866–3876.
[220]
Luciani A, Villella VR, Vasaturo A, Giardino I, Pettoello-Mantovani M, Guido S, et al. Lysosomal accumulation of gliadin p31-43 peptide induces oxidative stress and tissue transglutaminase-mediated PPAR downregulation in intestinal epithelial cells and coeliac mucosa. Gut. 2010; 59: 311–319.
[221]
Soares FLP, de Oliveira Matoso R, Teixeira LG, Menezes Z, Pereira SS, Alves AC, et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. The Journal of Nutritional Biochemistry. 2013; 24: 1105–1111.
[222]
Sziksz E, Molnar K, Lippai R, Pap D, Onody A, Veres-Szekely A, et al. Peroxisome proliferator-activated receptor-gamma and thymic stromal lymphopoietin are involved in the pathophysiology of childhood coeliac disease. Virchows Archiv. 2014; 465: 385–393.
[223]
Vetuschi A, Pompili S, Gaudio E, Latella G, Sferra R. PPAR-gamma with its anti-inflammatory and anti-fibrotic action could be an effective therapeutic target in IBD. European Review for Medical and Pharmacological Sciences. 2018; 22: 8839–8848.
[224]
Villapol S. Roles of Peroxisome Proliferator-Activated Receptor Gamma on Brain and Peripheral Inflammation. Cellular and Molecular Neurobiology. 2018; 38: 121–132.
[225]
Byndloss MX, Olsan EE, Rivera-Chavez F, Tiffany CR, Cevallos SA, Lokken KL, et al. Microbiota-activated PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 2017; 357: 570–575.
[226]
Mohan M, Chow CT, Ryan CN, Chan LS, Dufour J, Aye PP, et al. Dietary Gluten-Induced Gut Dysbiosis is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease. Nutrients. 2016; 8: 684.
[227]
Mohan M, Okeoma CM, Sestak K. Dietary Gluten and Neurodegeneration: A Case for Preclinical Studies. International Journal of Molecular Sciences. 2020; 21: 5407.
[228]
Wolburg H, Lippoldt A. Tight junctions of the blood-brain barrier: development, composition and regulation. Vascular Pharmacology. 2002; 38: 323–337.
[229]
Magni S, Buoli Comani G, Elli L, Vanessi S, Ballarini E, Nicolini G, et al. MiRNAs affect the expression of innate and adaptive immunity proteins in celiac disease.The American Journal of Gastroenterology. 2014; 109: 1662–1674.
[230]
Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology. 2008; 135: 1624–1635.e24.
[231]
Vaira V, Roncoroni L, Barisani D, Gaudioso G, Bosari S, Bulfamante G, et al. MicroRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts. Clinical Science. 2014; 126: 417–423.
[232]
Capuano M, Iaffaldano L, Tinto N, Montanaro D, Capobianco V, Izzo V, et al. MicroRNA-449a overexpression, reduced NOTCH1 signals and scarce goblet cells characterize the small intestine of celiac patients. PLoS ONE. 2011; 6: e29094.
[233]
Akbayir N, Caliş AB, Alkim C, Sökmen HMM, Erdem L, Ozbal A, et al. Sensorineural hearing loss in patients with inflammatory bowel disease: a subclinical extraintestinal manifestation. Digestive Diseases and Sciences. 2005; 50: 1938–1945.
[234]
Hizli S, Karabulut H, Ozdemir O, Acar B, Abaci A, Dağli M, et al. Sensorineural hearing loss in pediatric celiac patients. International Journal of Pediatric Otorhinolaryngology. 2011; 75: 65–68.
[235]
Şahin Y, Durucu C, Şahin DA. Evaluation of hearing loss in pediatric celiac patients. International Journal of Pediatric Otorhinolaryngology. 2015; 79: 378–381.
[236]
Solmaz F, Unal F, Apuhan T. Celiac disease and sensorineural hearing loss in children. Acta Oto-Laryngologica. 2012; 132: 146–151.
[237]
Urganci N, Kalyoncu D, Calis AB. Sensorineural hearing loss in pediatric patients with celiac disease. European Archives of Oto-Rhino-Laryngology. 2015; 272: 2149–2151.
[238]
Volta U, Ferri GG, De Giorgio R, Fabbri A, Parisi C, Sciajno L, et al. Sensorineural Hearing Loss and Celiac Disease: a Coincidental Finding. Canadian Journal of Gastroenterology. 2009; 23: 531–535.
[239]
Yaprak N, Sayar E, Derin AT, Bostanci A, Turhan M, Yilmaz A. Hearing evaluation with ABR in pediatric patients with celiac disease. The Turkish Journal of Gastroenterology. 2020; 31: 163–166.
[240]
Karmody CS, Valdez TA, Desai U, Blevins NH. Sensorineural hearing loss in patients with inflammatory bowel disease. American Journal of Otolaryngology. 2009; 30: 166–170.
[241]
Wengrower D, Shaul C, Peleg U, Leore C, Menahem G, Koslowsky B. Hearing Loss in Patients With Inflammatory Bowel Disease. Gastroenterology. 2014; 146: S378–S378.
[242]
Polat E, Cinar Z, Keskindemirci G, Yigit O, Kutluk G, Ture M, et al. Assessment of Hearing Function in Children with Inflammatory Bowel Disease. The Journal of International Advanced Otology. 2020; 16: 362–366.
[243]
Yozgat A, Gürler M. Ulcerative colitis is a risk factor for sensorineural hearing loss. Journal of Health Sciences and Medicine. 2021; 4: 267–271.
[244]
Karabulut H, Hizli S, Dagli M, Karabulut I, Acar B, Celik E, et al. Audiological findings in celiac disease. ORL; Journal for Oto-Rhino-Laryngology and its Related Specialties. 2011; 73: 82–87.
[245]
Leggio L, Cadoni G, D’Angelo C, Mirijello A, Scipione S, Ferrulli A, et al. Coeliac disease and hearing loss: Preliminary data on a new possible association. Scandinavian Journal of Gastroenterology. 2007; 42: 1209–1213.
[246]
Yazici A, Yildirim AE, Konduk BT. Does celiac disease cause autoimmune sensorineural hearing loss? The Turkish Journal of Gastroenterology. 2019; 30: 776–781.
[247]
Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. European Journal of Gastroenterology & Hepatology. 1999; 11: 1185–1194.
[248]
Fowler KB, McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. The Journal of Pediatrics. 1997; 130: 624–630.
[249]
Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008; 57: 178–201.
[250]
Gloor SM, Wachtel M, Bolliger MF, Ishihara H, Landmann R, Frei K. Molecular and cellular permeability control at the blood-brain barrier. Brain Research. Brain Research Reviews. 2001; 36: 258–264.
[251]
Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annual Review of Neuroscience. 1999; 22: 11–28.
[252]
Natah SS, Mouihate A, Pittman QJ, Sharkey KA. Disruption of the blood-brain barrier during TNBS colitis. Neurogastroenterology and Motility. 2005; 17: 433–446.
[253]
Nishihara H, Engelhardt B. Brain Barriers and Multiple Sclerosis: Novel Treatment Approaches from a Brain Barriers Perspective. Handbook of Experimental Pharmacology. 2020. (in press)
[254]
Kamphuis WW, Derada Troletti C, Reijerkerk A, Romero IA, de Vries HE. The blood-brain barrier in multiple sclerosis: microRNAs as key regulators. CNS & Neurological Disorders Drug Targets. 2015; 14: 157–167.
[255]
Caldemeyer KS, Smith RR, Harris TM, Edwards MK. MRI in acute disseminated encephalomyelitis. Neuroradiology. 1994; 36: 216–220.
[256]
Gozzard P, Orr D, Sanderson F, Sandberg M, Kennedy A. Acute transverse myelitis as a rare manifestation of Campylobacter diarrhoea with concomitant disruption of the blood brain barrier. Journal of Clinical Neuroscience. 2012; 19: 316–318.
[257]
DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. Journal of Neurochemistry. 2016; 139: 136–153.
[258]
Pizza V, Agresta A, D’Acunto CW, Festa M, Capasso A. Neuroinflamm-aging and neurodegenerative diseases: an overview. CNS & Neurological Disorders Drug Targets. 2011; 10: 621–634.
[259]
Chen W, Zhang X, Huang W. Role of neuroinflammation in neurodegenerative diseases (Review). Molecular Medicine Reports. 2016; 13: 3391–3396.
[260]
Han Y, Zhao T, Cheng X, Zhao M, Gong S, Zhao Y, et al. Cortical Inflammation is Increased in a DSS-Induced Colitis Mouse Model. Neuroscience Bulletin. 2018; 34: 1058–1066.
[261]
Hathaway CA, Appleyard CB, Percy WH, Williams JL. Experimental colitis increases blood-brain barrier permeability in rabbits. The American Journal of Physiology. 1999; 276: G1174–G1180.
[262]
Wu Q, Zhang Y, Zhang Y, Xia C, Lai Q, Dong Z, et al. Potential effects of antibiotic‐induced gut microbiome alteration on blood–brain barrier permeability compromise in rhesus monkeys. Annals of the New York Academy of Sciences. 2020; 1470: 14–24.
[263]
Daneman R, Rescigno M. The Gut Immune Barrier and the Blood-Brain Barrier: are they so Different? Immunity. 2009; 31: 722–735.
[264]
Wardill HR, Mander KA, Van Sebille YZA, Gibson RJ, Logan RM, Bowen JM, et al. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. International Journal of Cancer. 2016; 139: 2635–2645.
[265]
Luczynski P, McVey Neufeld K, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a Bubble: Using Germ-Free Animals to Assess the Influence of the Gut Microbiota on Brain and Behavior. International Journal of Neuropsychopharmacology. 2016; 19: pyw020.
[266]
Nyberg S, Abbott NJ, Shi X, Steyger PS, Dabdoub A. Delivery of therapeutics to the inner ear: the challenge of the blood-labyrinth barrier. Science Translational Medicine. 2019; 11: eaao0935.
[267]
Rowicka G, Czaja-Bulsa G, Chełchowska M, Riahi A, Strucińska M, Weker H, et al. Oxidative and Antioxidative Status of Children with Celiac Disease Treated with a Gluten Free-Diet. Oxidative Medicine and Cellular Longevity. 2018; 2018: 1324820.
[268]
Rezaie A, Parker RD, Abdollahi M. Oxidative stress and pathogenesis of inflammatory bowel disease: an epiphenomenon or the cause? Digestive Diseases and Sciences. 2007; 52: 2015–2021.
[269]
Trune DR, Nguyen-Huynh A. Vascular Pathophysiology in Hearing Disorders. Seminars in Hearing. 2012; 33: 242–250.
[270]
Granot E, Kohen R. Oxidative stress in childhood–in health and disease states. Clinical Nutrition. 2004; 23: 3–11.
[271]
Cabello-Verrugio C, Ruiz-Ortega M, Mosqueira M, Simon F. Oxidative Stress in Disease and Aging: Mechanisms and Therapies. Oxidative Medicine and Cellular Longevity. 2016; 2016: 8786564.
[272]
Liu W, Hendren J, Qin X, Shen J, Liu KJ. Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. Journal of Neurochemistry. 2009; 108: 811–820.
[273]
Ishiyama G, Wester J, Lopez IA, Beltran-Parrazal L, Ishiyama A. Oxidative Stress in the Blood Labyrinthine Barrier in the Macula Utricle of Meniere’s Disease Patients. Frontiers in Physiology. 2018; 9: 1068.
[274]
Quintanilla-Dieck L, Larrain B, Trune D, Steyger PS. Effect of systemic lipopolysaccharide-induced inflammation on cytokine levels in the murine cochlea: a pilot study. Otolaryngology–Head and Neck Surgery. 2013; 149: 301–303.
[275]
Koo J, Quintanilla-Dieck L, Jiang M, Liu J, Urdang ZD, Allensworth JJ, et al. Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Science Translational Medicine. 2015; 7: 298ra118.
[276]
Banks WA, Gray AM, Erickson MA, Salameh TS, Damodarasamy M, Sheibani N, et al. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. Journal of Neuroinflammation. 2015; 12: 223.
[277]
Banks WA, Robinson SM. Minimal penetration of lipopolysaccharide across the murine blood–brain barrier. Brain, Behavior, and Immunity. 2010; 24: 102–109.
[278]
Vargas-Caraveo A, Sayd A, Maus SR, Caso JR, Madrigal JLM, García-Bueno B, et al. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Scientific Reports. 2017; 7: 13113.
[279]
Babolmorad G, Latif A, Pollock NM, Domingo IK, Delyea C, Rieger AM, et al. Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity. bioRxiv. 2020. (in press)
[280]
Oh G, Kim H, Choi J, Shen A, Kim C, Kim S, et al. Activation of lipopolysaccharide-TLR4 signaling accelerates the ototoxic potential of cisplatin in mice. Journal of Immunology. 2011; 186: 1140–1150.
[281]
Vethanayagam RR, Yang W, Dong Y, Hu BH. Toll-like receptor 4 modulates the cochlear immune response to acoustic injury. Cell Death & Disease. 2016; 7: e2245.
[282]
Dalpke A, Zimmermann S, Heeg K. CpG DNA in the prevention and treatment of infections. BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy. 2002; 16: 419–431.
[283]
Wooldridge JE, Ballas Z, Krieg AM, Weiner GJ. Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma. Blood. 1997; 89: 2994–2998.
[284]
Floc’h JL, Tan W, Telang RS, Vlajkovic SM, Nuttall A, Rooney WD, et al. Markers of cochlear inflammation using MRI. Journal of Magnetic Resonance Imaging. 2014; 39: 150–161.
[285]
Hirose K, Hartsock JJ, Johnson S, Santi P, Salt AN. Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. Journal of the Association for Research in Otolaryngology. 2014; 15: 707–719.
[286]
Hirose K, Li S. The role of monocytes and macrophages in the dynamic permeability of the blood-perilymph barrier. Hearing Research. 2019; 374: 49–57.
[287]
Hirose K, Discolo CM, Keasler JR, Ransohoff R. Mononuclear phagocytes migrate into the murine cochlea after acoustic trauma. The Journal of Comparative Neurology. 2005; 489: 180–194.
[288]
Weiwei H, Jintao Y, Yu S, Weijia K. Macrophages in Noise-Exposed Cochlea: Changes, Regulation and the Potential Role. Aging and Disease. 2020; 11: 191.
[289]
Zhu J, Li Z, Ji Z, Wu Y, He Y, Liu K, et al. Glycocalyx is critical for blood‐brain barrier integrity by suppressing caveolin1‐dependent endothelial transcytosis following ischemic stroke. Brain Pathology. 2021; 32: e13006.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Share
Back to top