IMR Press / FBE / Volume 16 / Issue 2 / DOI: 10.31083/j.fbe1602013
Open Access Review
Inflammatory Bowel Diseases and the Efficacy of Probiotics as Functional Foods
Luis Vitetta1,2,*,†Debbie Oldfield2,†Avni Sali2,†
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1 Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
2 Research Department, National Institute of Integrative Medicine, Hawthorn, VIC 3122, Australia
*Correspondence: luis.vitetta@sydney.edu.au (Luis Vitetta)
These authors contributed equally.
Front. Biosci. (Elite Ed) 2024, 16(2), 13; https://doi.org/10.31083/j.fbe1602013
Submitted: 10 February 2024 | Revised: 22 March 2024 | Accepted: 28 March 2024 | Published: 8 May 2024
Copyright: © 2024 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Adverse intestinal microbiome profiles described as a dysbiotic gut are a complicit etiological operative factor that can progress and maintain inflammatory sequelae in the intestines. The disruption of the gut microbiome that ensues with intestinal dysbiosis is, for example, posited by decreases in the alpha-diversity of the gut microbiome, which is characterized by significant reductions in the abundance of bacterial members from the Bacteroidetes and Firmicutes phyla. Proteobacteria have often been recognized as gut microbial signatures of disease. For example, this happens with observed increases in abundance of the phyla Proteobacteria and Gammaproteobacteria, such as the adherent-invasive Escherichia coli strain, which has been significantly linked with maintaining inflammatory bowel diseases. Research on the administration of probiotics, often identified as gut-functional foods, has demonstrated safety, tolerability, and efficacy issues in treating inflammatory bowel diseases (IBDs). In this narrative review, we explore the efficacy of probiotics in treating IBDs with bacterial strain- and dose-specific characteristics and the association with multi-strain administration.

Keywords
inflammatory bowel disease
ulcerative colitis
Crohn's disease
intestinal dysbiosis
gut microbiome
probiotics
prebiotics
functional foods
1. Introduction

Inflammatory bowel diseases (IBDs) have been described as diseases of chronic intestinal inflammation with the progression of damage to colonocytes that are subject to multiple etiologic factors, including genetic, epigenetic, environmental insults and gut microbiota dysregulation, which have been attributed as linked to the causes of IBDs [1, 2]. IBDs include ulcerative colitis (UC) and Crohn’s disease (CD), which are common and complex conditions that are difficult to cure [2].

UC often begins in the rectum and continuously extends to part or the whole colon alongside intestinal mucosal damage; clinical manifestations are normally bloody diarrhea, abdominal discomfort, and pain [3]. In comparison, CD is characterized by transmural intestinal damage, which is described as an immune-related abnormality that could arise in any part of the gastrointestinal tract [4, 5]. The main characteristic of IBDs is the chronic inflammation that ensues with increased levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL-12, IL-17, IL-23, IL-1β, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Concomitantly, there are also decreased levels of anti-inflammatory cytokines, such as IL-10 and TGF-β [1]. In IBD, activated macrophage cells are stimulated to secret pro-inflammatory cytokines, which in turn activate pro-inflammatory immune cells type 1 T helper cells (Th1) and Th17 cells, thus skewing the equilibrium of anti-inflammatory/pro-inflammatory actions toward an increased inhibition of anti-inflammatory, immune Th2 cells and regulatory T cells.

The administration of probiotics has recently been reviewed and further promoted as targeting the intestinal microbiome to ameliorate IBD symptomatology [6]. Dysregulation of the gut bacterial cohort has been consistently demonstrated in metabolic disorders (e.g., type 2 diabetes mellitus). Compositional alterations include a reduced abundance of putatively beneficial taxa (e.g., Akkermansia muciniphila and Faecalibacterium prausnitzii) and a higher abundance of putative pathogenic taxa (e.g., Escherichia coli and certain Enterobacteriaceae) as reported across multiple conditions [7, 8]. Meanwhile, functional alterations associated with the disease include a general reduction in short-chain fatty acid (SCFA)-producing bacteria, which appear to be particularly pronounced in conditions with severe intestinal inflammation, such as certain cancers and diabetes [8, 9, 10].

Recently, functional foods have been defined as those formulated to contain substances or live microorganisms with a possible health-enhancing or disease-preventing value, such as probiotics, which can achieve the intended benefit at a safe and sufficiently high concentration [11]. Probiotics have long been associated with improving the non-hematological intestinal interface by engaging intestinal bacteria with multiple beneficial effects [12]. Mechanistically, these non-hematological effects have included (i) reinforcing the integrity of the gut epithelial cell wall cooperatively with the scaffold of tight junction proteins and (ii) concomitant increases in mucin production and turnover by Goblet cells [13]. In addition, probiotics have been reported to induce various immune tissue-related effects [14]. Specifically, probiotics enhance hematological effects, attenuating pro-inflammatory outcomes in the intestines [15] through (i) inhibition of pathobiont growth and (ii) increased intestinal antimicrobial activity from Paneth cells [15]. Such biochemical and physiological influences provide a credible hypothesis that administering probiotics can attenuate inflammatory symptoms in IBDs [16].

Furthermore, we have previously reported that decreased levels of SCFAs, such as butyrate, from keystone commensal gut species (e.g., Roseburia spp., Clostridiales spp.) [17] can progress gut dysbiosis and exacerbate IBD symptomatology. The consumption of probiotics can affect the modulation of SCFA production by the intestinal microbiome [18], as reported following the administration of Bifidobacterium species providing SCFAs (e.g., acetate) in cross-feeding reactions, for example, for Ruminococcus spp. commensals in the gut that increase butyrate [17, 18]. Intestinal dysbiosis can progress in IBDs by decreased beneficial bacteria and increased pathobionts and aberrant bile acid metabolism [19], given that gut commensals provide critical metabolic reactions of bile salts in the gut. Moreover, microbiota-derived succinate, a by-product of primary cross-consumed metabolite between gut-dwelling microbes, also provides specific functions in outward tissues that control host nutrient metabolism that maintains a healthy microbiome [20]. In a study with type 1 diabetic patients, it was reported that regulating tryptophan metabolism with probiotic intake (i.e., Lactobacillus rhamnosus GG) resulted in reduced inflammatory profiles [21]. The authors further concluded that the immune regulatory catabolites from tryptophan metabolism occurred in the gut, underpinning the decreased inflammatory cytokines observed.

In the intestines, multiple axes are present, including microbiota–intestinal epithelium and intestinal immune system connections that establish the health status of the host. Moreover, perturbations in one or more parts can disrupt the gut microbiome and progress inflammatory responses as a function of gut dysbiosis, which happens in IBDs [22]. In this clinical research-driven review, we further posit the importance of the clinical and voluntary administration of probiotics and functional foods to ameliorate IBD symptomatology. The scientific evidence presented is compelling and worthy of progress, and additional robust clinical studies are being conducted to elucidate effective formulations and doses that could be administered for IBDs. Probiotics and/or prebiotics could be prescribed as stand-alone medicines or in conjunction with standard anti-inflammatory medications to patients diagnosed with IBD.

2. Intestinal Dysbiosis and IBD

Intestinal dysbiosis usually describes an unevenness in the gut microbiota [23]. Intestinal dysbiosis has been posited as a major cause of IBD pathogenesis [23], even though research cites gut dysbiosis observed in IBD patients as either being a risk factor or an effect of the inflammatory disease. Nevertheless, the ecosystem that is present in the intestines, along with the microbiota that resides in the colon (i.e., with the densest concentration of bacteria), can be subject to disruption affecting the intestinal barrier (Fig. 1) and with a consequent disproportionate effect on the host immune and metabolic systems. Multiple overlapping mechanisms have been reported that can adversely influence the integrity of the colonic epithelia. For example, the integrity of the intestinal wall can be compromised by consuming alcohol [24]. Moreover, exogenous or endogenous ethanol in the gut can produce microbiota-elaborated acetaldehyde, progressing intestinal dysbiosis [24]. Furthermore, effects on the host metabolic system, especially the overconsumption of glucose and fats, adversely affect gut metabolism. Changes in bile acid composition [25] can be mediated by the manufacturing of short-chain fatty acids (SCFAs) from dietary fiber, conversion of choline to trimethylamine (TMA), and others [26]. An early study investigated increased mucus-associated bacteria in IBD [27]. Png and colleagues [27] reported and confirmed the increased total mucosa-associated bacteria gene in macroscopically and histologically normal intestinal epithelia of CD and UC patients, indicating a direct mucolytic mechanism in the gut. In addition, they also report disproportionate increases in some mucolytic bacteria, such as R. gnavus and R. torques, which can possibly explain the increased total mucosa-associated bacteria present in patients diagnosed with IBD [27].

Fig. 1.

Colonic intestinal dysbiosis in IBDs. Decreased abundance and diversity of keystone intestinal microbiota species (e.g., F prauznitzii, A.muciniphila) that fail to provide colonization resistance to increased pathobiont bacteria (e.g., E. coli) characterized by low butyrate production that progresses pro-inflammatory activity. Mechanism of action of probiotics as functional foods. (The figure was constructed from BioRender templates (biorender.com); see the Acknowledgement section at the end of the manuscript for the provided publication license). IBD, inflammatory bowel disease; LPS, lipopolysaccharide; SCFA, short-chain fatty acid; COLON, the longest part of the large intestine; LUMEN, in the intestines the lumen is the opening inside of the intestines; LAMINA PROPRIA, is a connective tissue found under the thin layer of tissues covering a mucous membrane in the intestines. NOD, nucleotide-binding oligomerization domain.

An important and most commonly reviewed mechanism is the effect on the host immune system that is modulated by microbiota-derived molecules via inflammasome signaling through Toll-like receptors (TLRs) [28] and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) [29]. The initial act of defense from an insult displayed by the innate immune system against microbial pathobionts is constantly surveilling the host’s internal environment, as the innate immune response identifies an invading and foreign pathobiont. This initial detection step involves specific interactions between microbial structural motifs and host receptors [30].

Recent studies have reported that the innate immune system has a high degree of specificity and can discriminate between an invading pathobiont and self [31]. A group of evolutionary conserved receptors termed pattern-recognition molecules (PRMs) can recognize a limited but highly conserved set of molecular structures produced specifically by microorganisms and are absent from the host cell. A first family of PRMs, the TLRs comprise membrane-anchored proteins that detect a variety of extracellular (or intravesicular) MAMPs (microbial-associated molecular patterns) or DAMPs (danger-associated molecular patterns) [32]. In addition, recent studies in mammalian systems have indicated the presence of intracellular PRMs called NLRs (NOD (nucleotide-binding oligomerization domain)-like receptors) that, as for TLRs, sense and respond to MAMPs or DAMPs in the cytosol [33, 34, 35].

The glycolipid component of the endogenous toxin lipopolysaccharide (LPS) is embedded in Gram-negative bacterial outer membranes (e.g., Escherichia coli) [36, 37]. This structure maintains the structural integrity of the bacterium. Structural studies of Gram-negative bacteria have reported that LPS includes three major biochemical domains. Firstly, the structure contains an O-specific chain that is a repetitive glycan polymer that projects outside of the outer membrane onto the surface of the bacterium. The importance of the O-specific chain is that it contributes to the antigenicity, morphological appearance, and antibiotic sensitivity of Gram-negative bacteria [38, 39]. Secondly, the core domain is a phosphorylated oligosaccharide that links the O-specific chain to the lipid A moiety, which importantly maintains structural viability [39, 40]. Thirdly, lipid A is a heat-stable phosphorylated glucosamine disaccharide with multiple fatty acid side chains that anchor the LPS molecule into the lipid bilayer of the bacterium’s outer membrane [39]. Gram-negative bacteria proliferation and death are caused, for example, by the release of lipid A into the local intestinal environment, which occurs because of a disruption to the microbial outer membrane [39]. Oliveira and Reygaert [39] report that LPS is a heterogeneous bacterial complex in various intestinal bacterial groups [39]. In some bacterial groups, this antigen is manifested weakly due to possibly epigenetic variations that TLRs do not identify. There are, though, bacterial Gram-negative groups that can produce such a reaction of a large magnitude. LPS, hence, can prompt the innate immune response through TLR4 activation, which is present in various immune cells such as monocytes, macrophages, dendritic cells, and neutrophils (Fig. 1). Subsequent activation of innate immune cell reactions mediated by LPS binding to TLR4 receptors leads to an exacerbated response that is skewed towards increased pro-inflammatory levels of cytokines, chemokines, and interferons and the suppression of anti-inflammatory cytokines.

Furthermore, the NOD proteins NOD1 and NOD2 are the established members of the NOD-like receptor family of intracellular pattern recognition receptors [41]. This family of receptors senses conserved motifs in bacterial peptidoglycan and induces pro-inflammatory and anti-microbial responses [41]. These proteins have been reported to be correlated with the regulation of increased inflammatory pathways in response to bacterial insults through the induction of signaling pathways, which occurs with nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) [30]. Furthermore, it has also been reported that the NOD proteins act autonomously from that of the TLR cascade. Notwithstanding, NOD strongly synergizes with TLR receptor activities to trigger innate immune responses to the gut microbiota [30]. In addition, mutations in NOD2 have been shown to confer susceptibility to several chronic inflammatory disorders, including CD [30]. These adjunctive mechanisms operate to progress a shift in the balance between regulatory and pro-inflammatory immune cell-developed immunological factors (Fig. 1).

Foods that can be defined as functional for well-being have beneficial and constructive effects on one or more physiological outcomes on health beyond that of basic nutrition, promoting health and assisting with reducing the risk of disease (Figs. 1,2) [42]. Probiotic formulations predominantly with Lactobacillus, Bifidobacterium, and Streptococcus species and novel entities such as Escherichia coli strains, and a new generation of probiotics, including Bacteroides thetaiotaomicron and Akkermansia muciniphila, have been shown to progress numerous actions in the gut [43, 44]. Hence, probiotics, as functional foods, can beneficially affect numerous physiological structures in the gut. Functional food probiotics include activities that enhance the development of the gut epithelial wall, increased adhesion to the intestinal mucosa, simultaneous inhibition of pathogen adhesion, competitive prohibition of pathogenic microorganisms, production of anti-microbial substances, and immune system modification [45]. Specifically, there are multiple beneficial implementations that the oral administration of probiotics can achieve. The mechanisms involved include enhancement of intestinal homeostasis, host immunity, intestinal barrier functional integrity, intestinal microbiome, and metabolome modulations [43].

Fig. 2.

Diagrammatic representation of the effects of probiotics on the intestinal epithelium barrier and junction, intestinal microbiome, and mucosal immunity. (The figure was constructed from BioRender templates; see the Acknowledgement section at the end of the manuscript for the provided publication license).

The mechanism of action of probiotics is conducive to the structure of the intestinal barrier, which presents simple columnar epithelial cells, enterocytes, as the major cell type in the intestines, with important functions in nutrient absorption (i.e., ions, water, sugar, peptides, and lipids) and the secretion of immunoglobulins [46]. The reported interactions between probiotics and the gut barrier are important [47]. The epithelial barrier also consists of 10% Goblet cells that secrete mucus, lubricating the passage of food through the intestines while protecting the intestinal wall from digestive enzyme actions [48]. Additionally, Paneth cells located only in the small intestine, predominantly in the ileum [49], synthesize and secrete antimicrobial peptides and proteins.

Probiotics have been reported to have the capacity to block the effects of pathogenic bacteria by processing bactericidal substances and competing with pathogens and other toxins for adherence to the intestinal epithelia [50]. Hence, probiotic bacteria can improve the gut cell wall equilibrium by enhancing intestinal epithelial cell survival and gut barrier function [51, 52] and stimulating the protective responses from intestinal epithelial cells [53]. Paneth cells can directly sense enteric bacteria via cell-autonomous MyD88-dependent Toll-like receptor activation, triggering the expression of multiple antimicrobial factors [54]. The epithelial barrier also consists of a dense mucus layer containing secretory IgA, antimicrobial peptides, and dynamic junctional complexes that regulate cell permeability [52].

Probiotics express various immune-stimulatory surface components, including flagella, pili, surface layer proteins, capsular polysaccharide, lipoteichoic acid, lipopolysaccharide, and peptidoglycan, comprising microbial-associated molecular patterns (MAMPs) that can specifically bind to pattern recognition receptors (PRRs), such as NOD-like receptors (NLRs) and toll-like receptors (TLRs) [44, 55] as well as nucleic acids. In addition, probiotic bacteria also contain muramyl dipeptide units that function as Nod-like receptor ligands [55]. Consequently, probiotic surface components are ligands for receptors on the intestinal epithelia, as reported, for example, with pili (TLR4), flagellin (TLR5), and capsular polysaccharide (TLR5) [44]. Specific intracellular biochemical reactions that are elicited regulate adapter molecules such as MyD88, which in turn activate nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), peroxisome proliferator-activated receptor gamma, and response genes that lead to the activation of signaling pathways in intestinal epithelial cells [44]. Probiotic bacteria can regulate innate and adaptive immunity processes through TLRs and dendritic/macrophage cell recognition. Naïve T cells can then promote T cell differentiation and Th2 and Th1 interconversion, leading to the modulation of cytokine levels (e.g., IL-10, IL-22, and TNF-α) [43]. Specifically, the upregulation of the expression of tight junction proteins enhances intestinal barrier integrity and reduces permeability, in addition to inducing the secretion of cytokines, such as IL-10 and IL-12, to alleviate intestinal inflammatory responses.

Furthermore, probiotics increase metabolites such as indole, secreted extracellular proteins, extracellular vesicles, SCFAs (e.g., acetate, butyrate, propionate), and bacteriocins that protect the intestinal epithelial barrier by interacting with some receptors or directly promoting mucus secretion by goblet cells, increasing the secretion of antimicrobial peptides, or enhancing the expression of tight junction proteins building the barrier scaffold [44, 56].

3. Short-Chain Fatty Acids (SCFAs)

SCFAs are an important class of by-product molecules from the fermentation metabolism of non-digestible carbohydrates in the intestines [44]. SCFAs have an essential role in gut physiology and intestinal microbiota composition [57] (Fig. 2). Importantly, these molecules, especially butyrate, comprise the preferential source of energy for colonic epithelial cells [58]. Various probiotic and commensal intestinal bacteria have been reported to increase SCFAs (Table 1, Ref. [18, 59, 60, 61, 62, 63]). The SCFA butyrate is sensed by specific membrane-bound receptors such as free fatty acid receptor 2 (FFA2), free fatty acid receptor 3 (FFA3), G protein-coupled receptor 109a (GPR109a), GPR43, and GPR41 [64, 65], whereas olfactory G protein-coupled receptor 78 modulates the inflammatory response in colitis [66]. These receptors are expressed uniquely throughout the intestines and signal through distinct mechanisms [67], which are reported to regulate aspects of gut motility, hormone secretion, intestinal epithelial barrier integrity maintenance, and immune cell function [66, 67]. Specifically, the increase in IL-18 by immune cells expressing the GPR109a receptor is of physiological importance in maintaining intestinal barrier equilibrium [68]. Butyrate achieves this action by improving intestinal epithelial barrier function by activating AMP-activated protein kinase [68].

Table 1.Probiotic and commensal/intestinal bacteria that increase SCFAs (adapted from multiple published sources [18, 59, 60, 61, 62, 63]).
Types of bacteria SCFAs increased
Commensal intestinal bacteria spp.
Roseburia spp. Propionate
Salmonella spp.
Veillonella spp.
Anaerostipes spp. Butyrate
Clostridium spp. Acetate | Butyrate | Propionate
Ruminococcus spp.
Specific commensal bacteria
Dalister succinatiphilus Propionate
E. halli
Megasphaera elsdenii
Phascolarctobacterium succinatutens
Coprococcus catus Butyrate | Propionate
Roseburia inulinivorans
Eubacterium halli
Coprococcus comes Butyrate
Coprococcus eutactus
Clostridium symbiosum
Eubacterium rectale
Roseburia intestinalis
Probiotics
Bifidobacterium spp. Acetate | Lactate
Bifidobacterium longum Acetate | Lactate | Propionate
Bifidobacterium bifidum
Lactobacillus rhamnosus GG (LGG) Lactate | Propionate
Lactobacillus gasseri
Lactobacillus acidophilus Acetate | Butyrate | Lactate | Propionate
Novel probiotics
Faecalibacterium prausnitzii Butyrate

SCFAs, short-chain fatty acids.

Low concentrations of luminal butyrate have also been reported to augment the MUC2 mRNA level that promotes AP-1 binding to the MUC2 promoter, which protects the epithelial barrier [69]. Butyrate augments the acetylation of the most highly conserved histones (i.e., H3 and H4) and the methylation of H3 on the MUC2 promoter. This biochemical signaling protects the epithelial barrier [69]. Butyrate also inhibits permeability-promoted claudin-2 tight junction protein expression [70], though a mechanism dependent on IL-10 receptor subunit alpha inhibits the synthesis of pro-inflammatory cytokines. In addition, the production of cathelicidin, such as LL-37 (i.e., an antimicrobial), has also been specifically linked to butyrate [71]. Butyrate can also influence the consumption of O2 by the intestinal epithelium that progresses hypoxia-inducible factor stability while increasing the expression of barrier-protective hypoxia-inducible factor target genes that link gut microbes and the intestinal epithelial barrier.

Gut bacterial fermentation of dietary fibers and resistant starch have been reported to be key in mediating the relationship between the intestines and DNA methylation [72, 73]. This is indicative of the SCFAs (i.e., specifically by butyrate) signaling-associated inhibition of histone deacetylases (HDACs), which regulate gene expression, where the inhibition of HDACs has a vast array of downstream consequences [74]. Furthermore, when inspecting the genomes of species from the Bifidobacterium genera isolated from the human gut, there is a high occurrence of genes concerned with the metabolism of complex oligosaccharides [75]. Bacteria such as Lactobacilli, Bacteroides, and other butyrate producers encountered in the gut can also enable the degradation of inulin-type fructan substances (Table 1).

The cross-feeding mechanisms of bacteria inhabiting the gut and, more specifically, the colon are intricately involved in the increase in butyrate, a purposeful, distinctive characteristic of numerous colon-resident bacteria. Moreover, the specific utilization of polysaccharides by the microbiota in the colon could determine changes in the gut microbiota that are diet-induced and, consequently, produce favorable metabolic effects [76]. Indubitably, supplementation with polysaccharides of plant origin that remain undigested in the gut is an important consequence for enriching the intestinal cohort of bacteria with Lactobacillus and Bifidobacterium species. Bacterial members from these genera can ferment plant-origin polysaccharide compounds into SCFAs [18, 77]. Research has described that SCFAs, such as butyrate, can progress epigenetic effects in the gut [78]. While the mechanisms of action of butyrate are centered on diverse actions, epigenetic regulation of gene expression does occur through the inhibition of histone deacetylase biochemical reactions [78]. Consequently, the stream of continuous concentrated investigations on fatty acids has indicated that there are important functional characteristics that fats may have on the neurometabolic pathophysiology of psychiatric disorders [79]. Further, investigations on brain phospholipid content metabolism and membrane fluidity have been linked to mood disorders [80]. A murine model that employed the forced swim test described that dietary supplementation with omega-3 fatty acids reduced the levels of immobility when administered for 30 days [80]. A review of the data reported that butyrate [81] and beta-hydroxy-butyrate [82] were inhibitors of the catalytic activity of Zn2+-dependent HDACs, highlighting a probable mechanism of activity. Such inhibition was robustly shown to elicit anti-inflammatory effects in cell culture and rodent model studies. Specifically, SCFA inhibition of HDACs improved neurocognitive and mood disorders. The class I HDAC inhibitor MS-275 prevented depression-like behavior in mice when subjected to a social stress model [82].

4. The Intestinal Microbiome and IBD

The adult human gut microbiota has been reported to comprise several species of microorganisms, including bacteria, yeast, and viruses [83]. The intestine harbors several major divisions of bacteria and presents a dense concentration of microorganisms [84]. The Firmicutes and Bacteroidetes phyla comprise the most dominant groups of bacteria, representing approximately 90% of the gut cohort of bacteria [84]. Furthermore, the gut microbiota is supplemented with less dominant bacteria groups, including Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia phyla [85].

Reports have commonly cited an association between IBD and three major pathobiont bacteria that inhabit the gut, giving rise to the ‘one-microbe-one disease’ concept. The mentioned pathobionts include adherent-invasive Escherichia coli and Mycobacterium avium paratuberculosis, which historically were thought to be potential pathobiont agents associated with the development of CD disease [86]. These pathobionts have been frequently found in patients diagnosed with acute/active phases of IBD that have advanced to progress an increased inflammatory response in the intestines [86]. In addition, Clostridium difficile has also been suggested to be associated with IBD; specifically, this bacterium was detected in patients diagnosed with UC relapse as well as remission [87]. Clinical studies have demonstrated a plausible increase in comorbidity with these infectious bacteria for IBD. Additional results have indicated that these outcomes were inconsistent [88, 89]. The clinical results are contentious as there is still no direct evidence that these bacteria are the sole cause of IBD. The clinical environment, though, has shifted toward the concept that IBD may be caused by a disparity in the commensal microbiome potentially associated with more complex interactions between the host and the entire small and large bowel cohort of bacteria [90].

In patients diagnosed with IBD compared to healthy individuals, reports show changes in the gut microbiome composition and the diversity of the microbiome populations [91]. Santana and colleagues [91] have reported bacterial species associated increases with Clostridioides difficile and Listeria monocytogenes from the Firmicutes phylum; Eggerthella lenta and Mycobacterium avium from the Verrucomicrobia phylum; E. coli, Campylobacter spp., Eikenella corrodens, and Haemophilus parainfluenzae from the Proteobacteria phylum; Fusobacterium nucleatum from the Fusobacteria phylum; Bacteroides spp. from the Bacteroidetes phylum, in patients diagnosed with IBD when compared to healthy controls. Moreover, Santana and colleagues [91] also showed a decrease in numerous bacterial species, such as F. prausnitzii, Eubacterium spp., Ruminococus albus, A. muciniphila, and Bifidobacterium bifidum. Given the reduced changes reported in key butyrate-producing species (i.e., F. prausnitzii, Ruminococcus spp., Eubacterium spp.), it is plausible to posit that adverse shifts in intestinal microbiome profiles with reductions in the abundance of bacteria such as F. prauznitzii, A. muciniphila, Roseburia species, and Bifidobacterium species may promote inflammatory sequelae in the gut important to the pathogenesis of IBD. We have previously reported that important net effects of decreases in the levels of luminal SCFAs (e.g., butyrate) by key commensal species can progress gut dysbiosis [17]. Alternatively, with the increased microbial elaboration of butyrate by key commensal species, energy carbon sources are provided for the intestinal microbiome in cross-feeding activities that occur with Bifidobacterium species. Hence, there is a simultaneous improvement in intestinal dysbiosis with improved intestinal gut barrier integrity, resulting in an overall attenuation of inflammatory sequelae [17], encouraging effects that can improve IBD symptomatology. Observations have been made that non-digested oligosaccharide chains within the mucus environment of the intestinal epithelial barrier become available for a broad range of intestinal microbes. Following the degradation and liberation of sugars by the species A. muciniphila, microbial synthesis of vitamin B12, 1,2-propanediol, propionate, and butyrate is increased, which benefits the microbial ecosystem and host epithelial cells [92].

5. Probiotics and Inflammatory Bowel Diseases

Probiotics have been extensively investigated and reported to have humoral, cellular, and non-specific immunity modulation effects and promote the integrity of the immunological barrier. A common mechanistic view of probiotics in IBD is that their administration can confer important immunological protection to the host in terms of regulation, stimulation, and modulation of the host’s immune responses [93].

A recent critical review has reported on various in vitro (laboratory-based cell culture investigations) and in vivo studies (i.e., animal models and humans) on the overall benefit that probiotics can provide to the inflammatory conditions of IBD [94]. The review investigated the value of different probiotic bacteria, especially those from the Bifidobacterium spp., in various considerations that could have possibly been involved in the etiology of IBD [94]. The authors investigated and reported probiotic modulatory properties amid different study models (i.e., cell lines, animal models of colitis, clinical studies) and reported on the usefulness of administration in relation to the treatment, prevention, and remission of IBD diseases. The authors concluded that the administration of probiotics was posited as a very promising therapeutic strategy and that the most benefit to reduce inflammatory sequelae in IBD was hypothesized to be the administration of gut bacteria-based therapy in combination mixtures of probiotic bacteria and postbiotic components (e.g., SCFAs). Furthermore, a recent Cochrane review concluded that the available evidence cast doubt on the efficacy or safety of probiotics when compared with a placebo for inducing remission in CD [95].

Notwithstanding, a recent interesting study with a murine model reported that the probiotic Lactiplantibacillus plantarum D13 exhibited anti-staphylococcal and anti-listerial activity, thought to increase the production of a presumptive bacteriocin with antibiofilm capacity [96]. The study concluded that the probiotic strain D13 modulated the intestinal microbiota of the DDS-induced colitis of the mice. Mechanistically, this resulted in increasing the abundance of beneficial bacteria (e.g., Allobaculum, Barnesiella) with a concomitant decrease in the richness of inflammatory-producing bacteria (e.g., Candidatus Saccharimonas) [96]. In conclusion, the probiotic strain D13 beneficially restored the gut microbiota after DSS-induced colitis, indicating its potential as a probiotic strain for the prevention and treatment of colitis [96].

We, herein, report only on numerous human clinical trials demonstrating that probiotics offer safety and efficacy in various matrix configurations (i.e., as single- or multi-strain formulations or as adjuvants to medications at various doses and administration times) in attenuating inflammation responses in UC and CD with outcomes that provide an overall glaring view of the mechanisms involved (Table 2, Ref. [97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135]). In addition, a systematic review of fecal microbiota transplantation (FMT) concluded that for adults diagnosed with mild to moderate UC, a 1-week treatment with anaerobically prepared donor FMT compared to autologous FMT resulted in a higher likelihood of remission at 8 weeks [136]. Moreover, a methodical-based review and meta-analysis reported that when comparing the analyses, it was demonstrated that frozen fecal material from universal donors could be related to a higher rate of clinical remission in patients diagnosed with CD [136].

Table 2.Human studies of the safe and efficacious administration of probiotics/prebiotics-functional foods/FMT on IBD.
IBD and probiotic/functional food formulations Clinical study including doses and duration of treatment Outcomes
(n = patients)
[Reference]
Ulcerative colitis
(Yakult Co., Ltd. Japan) *PCRCT Sustained remission phase:
Bifidobacterium breve strain, Yakult —mild to moderate active UC. clinical activity index score.
Bifidobacterium bifidum strain, Yakult —supplemented 100 mL/day (10B cells). histological scores.
Lactobacillus acidophilus strain, Yakult —12 weeks.
(n = 20)
[97]
(Lacteol Fort: Rameda Egypt) Two-group assignment trial IL-6 level.
Lactobacillus fermentum —mild to moderate UC. TNF-α level.
Lactobacillus delbruekii —assessed Mayo score. regulation of NF-κB.
(n = 30) —supplemented with 1 × 1010 CFU probiotic cells powder dissolved in 50 mL of water.
[98]
—8 weeks.
Bifidobacterium infantis 35624 PCRCT levels CRP.
(n = 22) —mild to moderate active UC. TNF-α.
[99] (based on a clinical activity index). —gastrointestinal.
—supplemented 1 × 1010 CFUs. —non-gastrointestinal.
Viable probiotic cells. —inflammatory disorders but do not particularly affect UC disease.
—6–8 weeks.
Bifidobacterium breve strain, Yakult Two-group assignment trial endoscopic scores.
(n = 41) —active and inactive UC. MPO level.
[100] —supplemented 1 g of the freeze-dried powder containing a probiotic at 109 CFU/g. —modulation of luminal environmental factors | intestinal microflora | pH.
—52 weeks.
(Yakult fermented milk (Mil–Mil)) DBPCRCT —no result.
Bifidobacterium breve strain, Yakult —UC in remission.
Lactobacillus acidophilus strain, Yakult —supplemented 100 mL/day.
(n = 195) —10B cells of Bifidobacterium and 1B of cells of Lactobacillus) of fermented milk.
[101]
—52 weeks.
(Probio-Tec AB25) DBPCRCT —maintaining remission in colitis.
Lactobacillus acidophilus strain LA-5 —UC in remission.
Bifidobacterium animalis subsp. lactis BB12 —supplemented 1.5 × 1011 CFU.
(n = 32) (2 capsules t.d.s.)
[102] —52 weeks.
(Morinaga Milk Industry Co. Ltd, Tokyo, Japan) Multi-center DBPCRCT disease activity index.
—mild to moderate UC (based on disease activity index). rectal bleeding.
Bifidobacterium longum 536 clinical remission.
(n = 39) —supplemented with 2–3 × 1011 CFUs in freeze-dried viable probiotic capsules.
[103]
—3 times daily.
—8 weeks.
(Acronelle®Bromatech SRL, Milan Italy) Clinical study recovery time weaker disease activity.
Lactobacillus salivarius —moderate to severe UC (based on disease activity index).
Lactobacillus acidophilus endoscopic picture.
Bifidobacterium bifidum strain BGN4 —supplemented with probiotic blend.
(n = 60) —104 weeks.
[104]
VSL#3 RCT rectal bleeding.
(L. paracasei, L. plantarum, L. acidophilus, L. delbrueckii subspecies bulgaricus, B. longum, B. breve, B. infantis, Streptococcus thermophilus) —mild to moderate active UC (based on activity index). stool frequency.
mucosal appearance.
—supplemented with the probiotic mixture. overall physician’s evaluation.
—twice daily.
(n = 147) —12 weeks.
[105]
VSL#3 Multi-center DBPCRCT parallel study UCDAI scores.
(L. paracasei, L. plantarum, L. acidophilus, L. delbrueckii subspecies bulgaricus, B. longum, B. breve, B. infantis, Streptococcus thermophilus) —mild to moderate active UC (based on activity index). frequency rectal bleeding.
—no differences in parameters such as the physician’s rate of disease activity or endoscopic scores.
—supplemented with a probiotic mixture.
—8 weeks + standard therapy.
(n = 144)
[106]
VSL#3 Open label study —remission colitis.
(L. paracasei, L. plantarum, L. acidophilus, L. delbrueckii subspecies bulgaricus, B. longum, B. breve, B. infantis, Streptococcus thermophilus) —children mild to moderately active UC (based on activity index). —improvement in microbiota composition.
—supplemented probiotic b.d. levels of IFN-γ | TNF-α | CRP | ESR.
—dose of probiotic based on age (from one 0.5 to 2.5 sachets).
(n = 13)
[107] —8 weeks.
Late night enema L. reuteri ATCC 55730. Prospective RCT —effective rectal infusion of L. reuteri.
(n = 40) —children mild–moderate active distal UC.
[108] —enema solution containing 1010 CFUs of L. reuteri ATCC 55730 vs. placebo. improving mucosal inflammation and changing mucosal expression levels of some cytokines.
—8 weeks.
( ss IL-10 | ss IL-1b | TNF-α | IL-8) involved in the mechanisms of IBD.
Single-center DBPCRCT in a four-group assignment —no benefit in the use of E. coli Nissle as an add-on treatment to conventional therapies for active UC.
Ciprofloxacin and probiotic Escherichia coli Nissle add-on treatment in active UC. —colitis activity index score 6.
—ciprofloxacin (500 mg × 2 daily) or placebo 1-week followed by Escherichia coli Nissle 1917 (100 mg × 1/4 days followed by 100 mg × 2 daily/3 days) or placebo for 7 weeks.
(100)
[109]
Multi-center Mutaflor, BL&H Co. Ltd., Seoul, Korea Mutaflor (E. Nissle 1917) on 5-aminosalicylic acid therapy in patients with UC. DBPCRCT in two-goup assignment —no sig. differences between groups in primary endpoint.
—primary endpoint IBD questionnaire scores.
—sig. difference (p = 0.04) in clinical response at 4 weeks.
—secondary endpoint clinical remission and response rates.
(118) —sig. difference (p = 0.03) in endoscopic remission at 8 weeks.
[110] —dose E. coli Nissle 1017 2.5 × 109 CFUs daily and 1 cap/day on days 1–4 and 2 cap/day from day 5.
—8 weeks.
Multi-center, phase-II dose-finding study of E. coli Nissle 1917 in acute distal UC. DBPCRCT in four-parallel-group assignment —rectal administration of E. coli Nissle 1917, well-tolerated treatment in moderate distal UC.
(90) —administered 10, 20, 40 mL enemas or placebo, daily.
[111]
—dose 108 CFU/mL.
—2 weeks.
FMT from multi-donor. Multi-center DBPCRCT —intensive dosing, multi-donor, fecal microbiota transplantation, induced clinical remission, and endoscopic improvement.
Active UC. —active UC (Mayo score 4–10).
(81) —primary outcome steroid-free clinical remission with endoscopic remission or response (Mayo score 2, all sub-scores 1, and 1 point reduction in endoscopy sub-scores) at week 8.
[112]
—associated with distinct microbial changes related to outcome.
—a colonoscopy infusion followed by enemas 5 days/week.
—8 weeks.
FMT and FMPT. FMT and FMTP groups random allocation —pectin decreased the Mayo score by preserving the diversity of the gut microbiota following FMT for UC.
Active UC. —UC (Mayo score 2–20 at enrolment).
(20) —FMT via colonoscopy.
[113] —FMTP oral doses of pectin (20 g/d, 50% wt/wt) for 5 consecutive days.
—12 weeks.
FMT FMT RCT —no significant difference between treatment groups.
UC —1° endpoint clinical remission UC (simple clinical colitis activity index scores 2) combined with 1-point decrease in the Mayo endoscopic score at 12 weeks.
FMT with feces from healthy donors vs. autologous FMT (control) administered via nasoduodenal tube at baseline and 3 weeks.
(50) —2° endpoint safety and microbiota composition by phylogenetic microarray.
[114]
—12 weeks.
FMT FMT parallel RCT —FMT induces remission in a significantly greater percentage of patients with active UC than placebo.
UC —1° outcome clinical remission UC.
FMT 50 mL, via enema, from healthy anonymous donors vs. 50 mL water enema (placebo). —defined as a Mayo score 2 with an endoscopic Mayo score of 0, at week 7.
—7 weeks.
(75)
[115]
FMT Multi-center DBPCRCT —preliminary study adults with mild to moderate UC.
Mild to moderately active UC. —1° outcome steroid-free remission defined by total Mayo score of 2 with an endoscopic Mayo score of 1 or less at week 8.
FMT anaerobically prepared pooled donor or autologous FMT via colonoscopy followed by 2 enemas over 7 days. —1-week treatment with anaerobically prepared donor FMT over autologous FMT resulted in a higher likelihood of remission at 8 weeks.
—Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease).
(73)
[116] —52 weeks follow-up.
FMT Prospective DBPCRCT —FMT engraftment after active FMT was observed only in a single patient.
Antibiotic dependent pouchitis proof of concept study—evaluating safety, efficacy, and donor microbial engraftment of an intensified FMT. —endpoints were safety, clinical remission without need for antibiotics during 16 weeks of follow-up.
—low donor FMT engraftment resulted in low clinical efficacy of FMT in patients with antibiotic dependent pouchitis.
—quantitative changes in fecal calprotectin and engraftment of donor FMT.
(20)
[117]
FMT in maintenance of remission in UC. PPCRCT —maintenance FMT in patients in clinical remission may help sustain clinical, endoscopic, and histological remission.
—clinical remission achieved after multi- session FMT were randomly allocated to either maintenance FMT or placebo colonoscopy infusion every 8 weeks for 48 weeks. —1° endpoint steroid-free remission defined by total Mayo score of 2, all sub-scores 1 at 48 weeks.
—2° endpoint achievement of endoscopic remission (endoscopic Mayo score 0) and histological remission (Nancy grades 0, 1) at 48 weeks.
(61)
[118]
FMT Open label study —FMT appears to be highly effective and safe in patients with IBD and rCDI.
Patients enrolled with C. difficile infection received sequential FMT either for pseudomembranous colitis or failure of single fecal infusion. —patients with IBD and rCDI received FMT administered via colonoscopy.
—1° outcome negative C. difficile toxin 8 weeks after FMT.
(8) —8 weeks.
[119]
FMT Single-center prospective PRCT —data suggest that daily encapsulated cFMT may extend the durability of index FMT-induced changes in gut bacterial community structure.
Feasibility study of long-term FMT in patients with mild to moderate UC using frozen, encapsulated oral FMT. —randomization 1:1.
—FMT induction by colonoscopy, followed by 12 weeks of daily oral administration of frozen encapsulated cFMT or sham therapy.
(120)
[120] —12 weeks. —an association between MAIT cell cytokine production and clinical response to FMT may exist in UC populations.
FMT Open label prospective study —FMT after washed preparation appears to be a safe and effective adjunct therapy for moderate to severely active UC during a short-term follow-up.
Moderate to severe UC. —random allocation to undergo FMT thrice on days 1, 3, and 5 by a naso-jejunal tube or transendoscopic enteral tube.
Evaluated the short-term efficacy and safety.
(90)
[121] —1° outcome clinical response at week 2 post-FMT.
—2° outcome clinical and endoscopic remission at week 12 post-FMT, safety and disease progression.
—12 weeks.
FMT Prospective, open-label pilot study —high-diversity, two-donor FMP delivery by colonoscopy seems safe and effective in increasing fecal microbial diversity in patients with active UC; donor composition correlated with clinical response.
Single FMT delivery by colonoscopy for active UC. —assessment of safety and clinical endpoints for response, remission, and mucosal healing
(20) —4 weeks.
[122]
Crohn’s disease
(Floratil®) RCT remission time and bowel sealing.
Saccharomyces boulardii —CD in remission (based on CD activity index).
(n = 34)
[123] —supplemented S. boulardii 4 × 108 cells every 8 h as an oral capsule formulation.
—12 weeks.
(Symprove™, Symprove Ltd, Farnham, United Kingdom) DBPCRCT —no significant changes were seen in CD.
—primary measure IBD QoL changes.
VSL#3 —secondary measure fecal calprotectin changes.
(n = 142)
[124] —4 weeks.
(Orafti, Tienen, Belgium Synbiotic–Bifidobacterium longum and Synergy 1) DBPCRCT —significant in clinical status improvement in active CD.
—clinical status primary measure IBD changes in mucosal TNF-α.
—significant in TNF-α only at 12 weeks.
(n = 35) —secondary outcome number of patients in remission.
[125]
—2 × 1011 freeze-dried viable B. longum gelatin capsule + sachet containing 6 g of Synergy I. b.d.s.
—12 and 24 weeks.
All patients started on oral antibiotic (ciprofloxacin 500 mg b.d.s. metronidazole 250 mg t.d.s.) for 2 weeks. RCT —study could not demonstrate benefit for inducing or maintaining medically induced remission in CD.
—patients with moderate to active CD.
—primary endpoint was sustained remission.
(CAG Functional Foods, Omaha, NE Lacto-bacillus GG). —2 × 109 CFU/day Lactobacillus GG.
—24 weeks.
(n = 11)
[126]
Prospective study. Primary outcome —no beneficial effects for patients with CD in remission after steroid or salicylate therapies.
Saccharomyces boulardii—probiotic yeast. —percentage of patients in remission at week 52.
(n = 165)
[127] —dose 1 g/day.
—52 weeks.
FMT by gastroscopy or colonoscopy Two-group allocation RCT —FMT was safe and effective in this cohort of patients with CD.
determining the efficacy and safety of different methods of FMT in CD. —assessed by clinical evaluation and serum testing (at weeks 1, 2, 4, 6, and 8) and endoscopy (8 weeks after FMT).
—no significant differences in clinical remission rate and adverse events between gastroscopy and colonoscopy groups.
(27)
[128]
FMT PRCT —the primary endpoint was no reached for any patient.
Patients enrolled while in flare received oral corticosteroid. —FMT or sham transplantation during a colonoscopy.
—in this pilot study, higher colonization by donor microbiota was associated with maintenance of remission.
Patients in clinical remission randomized to receive either FMT or sham transplantation during a colonoscopy. —Crohn’s Disease Endoscopic Index of Severity.
—1° endpoint was the implantation of the donor microbiota at week 6 (Sorensen index >0.6).
(17)
[129]
—6 weeks.
Probiotic yogurt DBPCRCT —patients with remission course of IBD.
Lactobacillus acidophilus La-5 Bifidobac terium BB-12. —dose 106 CFU/g of yogurt at 250 mg/day.
—8 weeks. stool concentration of Lactobacil-lus and Bifidobacterium.
(n = 120)
[130] stool concentration of Bac-teroides.
Probiotic formulation. Pilot study—PCRCT —overall improvements in health following probiotics.
(n = 40) —patients diagnosed with IBD.
[131] —assessments at 4 and 12 weeks.
Probiotic kefir Open-label—randomized control single-center prospective trial. —patients with CD.
(n = 45) inflammatory markers (i.e., ESR, C-reactive protein) (p < 0.05).
[132] —2.0 × 1010 CFU/mL viable Lactobacillus bacteria to IBD patients.
—dose 400 mL/day kefir b.d.s.
—4 weeks.
Probiotic formulation ± Pentasa (mesalazine extended action, 1–2 tablets). Open-label—randomized control single-center prospective trial to patients with IBD inflammatory markers with combination treatment.
(n = 40) —Bifico 2 probiotic tablets.
[133] —(no doses or probiotic information provided).
Probotic yoghurt Open-label—single-center blinded trial to patients with IBD (15 CD | 5 UC) —probiotic yogurt intake was associated with significant anti-inflammatory effects and paralleled the expansion of peripheral pool of putative Treg cells in IBD patients.
(n = 40)
[134] Lactobacillus rhamnosus GR-1 L. reuteri RC-14 supplemented 125 g yoghurt.
—30 days.
—primary outcome parameters changes in prevalence of putative Treg cells (CD4+ CD25high) | TNF-α | IL-12-producing monocytes and DC in peripheral blood during treatment.
—secondary outcome parameters changes in the presence of T cell surface activation markers, serum and fecal cytokine concentrations and ex vivo proliferative responses of PBMCs.
Exploratory study as control
—un-supplemented yogurt to 6 CD and 2 UC patients.
Lactococcus lactis (LL-Thy12) Uncontrolled placebo trial —first human trial with a genetically engineered, therapeutic bacterium.
(n = 10) —dose 10 capsules with 1 × 1010 CFUs of LL-Thy12 b.d.s.
[135]
—1 week. —results indicated the strategy was safe for the patient as well as biologically contained.
—during study period to improve LL-Thy12 variability administered.
—4 g of cholate acid binder b.d.s. (Questran; Zambon, Amersfoort, The Netherlands).
—40 mg of PPI once daily (Pantozol; Altana Pharma BV, Hoofddorp, The Netherlands).

*PCRCT, placebo-controlled randomized clinical trial; DBPCRCT, double-blind placebo-controlled randomized clinical trial; RCT, randomized clinical trial; PRCT, pilot randomized clinical trial; PPCRCT, pilot placebo-controlled randomized clinical study; UCDAI, UC disease activity index; CFUs, colony forming units; b.d.s., twice per day; t.d.s. three times per day; , decreased; , increased; PBMCs, peripheral blood mononuclear cells; ss, statistically significant; PPI, proton pump inhibitor; IL, interleukin; TNF-α, tumor necrosis factor-alpha; FMT, fecal microbiota transplantation; FMTP, fecal microbiota transplantation + pectin; rCDI, recurrent Clostridium difficile infection; cFMT, encapsulated oral FMT; MAIT, mucosal associated invariant T cells.

Notwithstanding the clinical benefits of bone health, avoiding dairy products has been related to possible detrimental effects on health. This is especially true in those with various health conditions such as weight management, lactose intolerance, osteoarthritis, and rheumatoid arthritis or those who have decided to avoid milk products to reduce the risk of cardiovascular disease progression and its metabolic complications [137]. Moreover, enduring abstention from dairy and its products because of lactose malabsorption or lactose intolerance may lead to malnutrition and skeletal disorders [137, 138]. Epidemiological studies on lactose intolerance have reported that approximately 70% of the global population can be affected by lactose malabsorption, with prevalence rates as high as 95% to 100% in some Asian and African regions [139].

Lactose is biochemically hydrolyzed into glucose and galactose and is used as an energy source, which is highest at birth and declines after weaning. Lactose digestion occurs through the action of β-gal, an enzyme from the intestinal–brush border. The predominant intolerance to lactose is generally caused by primary lactose malabsorption [140]. Undigested lactose is metabolized by intestinal commensal bacteria and converted into varying concentrations of SCFAs (i.e., acetate, propionate, butyrate, lactate, and formate), and gases (i.e., hydrogen, methane, and carbon dioxide), which can cause gastrointestinal discomforts, such as diarrhea, bloating, and abdominal pain [141]. Probiotic bacteria and the yeast Saccharomyces boulardii have been posited to improve tolerance to lactose [140, 142]. Functional foods such as milk products (e.g., yogurts) formulated with probiotics are more useful for digesting lactose in lactose maldigestion than milk alone [143]. It has been reported that the enzyme lactase is present in probiotics, which is predominantly why probiotic bacteria can ferment milk [143].

During digestion in the intestines, probiotic cell membranes are subject to disruption by bile acids in the small intestine, releasing lactase that can metabolize lactose [143]. Marteau and colleagues [144] also reported that probiotics can transfer lactases outside cell membranes, demonstrating increased activity in the intestines. Hence, bile-sensitive probiotics can be utilized for the transport of lactase or other active components to the intestines [145]. Mechanistically, probiotics that reach the digestive tract and act as a source of β-gal in the intestines [146] can increase the overall hydrolytic capacity and colonic fermentation [147]. In addition, probiotic bacteria can exert antagonistic effects on hetero-fermentative bacteria that produce gas and secrete antibiotic-like substances [148]. Investigations also show that probiotic bacteria competitively attach to the mucus membrane and improve colonic compensation, leading to the regulation of intestinal cell barrier permeability [149, 150]. In a related report, Kwak and colleagues [151] demonstrated that lactose can act as a calcium absorption enhancer and that the calcium present in milk can be absorbed and transferred to bones during the digestion of lactose. Therefore, it was posited that the administration of probiotics can relieve lactose intolerance and promote calcium absorption from milk [151].

Commensal intestinal bacteria are in continuous equilibrium with innate immune cells in a mutual environment that maintains healthy immune activities [152]. Probiotics as functional foods have been shown to modulate the immune system and are the most credible mechanism underlying the beneficial effects of probiotics on human health [53, 152]. Moreover, probiotic bacteria have been reported to elaborate numerous immunological factors in conjunction with cooperative activities with commensal bacteria [14]. Probiotics have been postulated to have immunomodulating capabilities by influencing the intestinal microbial cohort and dampening the activity of pathobiont intestinal microbes [14].

6. Discussion

Milk products produced from fermentation have a long history of use, exemplified by portrayals in Egyptian hieroglyphs [153]. Moreover, fermented yak milk was traditionally used by Tibetan nomads to preserve milk during their long nomadic journeys [154]. It was not till 1905 that Elie Metchnikoff, who had studied under Pasteur in the 1860s, was credited with linking longevity among Bulgarians to lactobacilli (i.e., later postulated to be L. bulgaricus). Metchnikoff linked the presence of these bacteria in the colon to a longevity factor rather than the yogurt they consumed [155]. In 1906, Tissier isolated Bifidobacterium from an infant and postulated that these genera of bacteria could displace intestinal resident pathobionts [156]. These seminal discoveries helped conceptualize research into the health-promoting effects of probiotics in disease prevention.

Early studies with human participants that employed Lactobacillus acidophilus (i.e., 30 patients) to treat chronic constipation, diarrhea, or eczema showed plausible improvements for all three conditions [157]. It was not until 1932 that a clinical study confirmed the effect of L. acidophilus in patients diagnosed with constipation and mental disease [158].

The occurrence of IBD has been postulated as causal for a genetically predisposed individual due to an aberrant immune response to intestinal pathobionts or commensal gut bacteria [159]. It is generally well-accepted that there is an interaction between prescribed non-antibiotic medications and the gut microbiome [160]. Some medications include proton pump inhibitors, metformin, selective serotonin reuptake inhibitors, and laxatives, which can significantly adversely influence the intestinal microbiome in composition and function [160].

Two classes of biological agents are used to control IBD symptoms: Monoclonal antibodies that target and oppress specific cytokines, such as TNF-α, IL-12/IL-23, or those that prevent lymphocyte migration to the intestine by blocking α4-integrin or α4β7-integrin. These medications are often administered long-term, sometimes alongside immunomodulators [161] and steroids, 5-aminosalicylic acid, antibiotics, antispasmodics, and analgesics. Furthermore, patients can also be prescribed vitamins and minerals, given that patients diagnosed with IBD can often have vitamin and mineral deficiencies.

The idea that antibiotics could be considered for the management of IBD and specifically UC was due to the hypothesis that the antimicrobial properties of antibiotics could target the intestinal bacteria potentially linked to inflammation [159]. Notwithstanding, a recent systematic review reported that there was clinical relevance, and there may be a greater proportion of patients who achieve clinical remission and perhaps a greater percentage who achieve clinical responses with antibiotics when compared with a placebo after 12 months of antibiotic administration [162]. The downside is that significant health-related risks could ensue. Prescribed medications for IBD, especially antibiotics, can induce changes in gut microbial composition that can then have multiple negative impacts on host health [162]. Reduced gut microbial diversity, changes in functional attributes of the gut microbiota, formation, and selection of antibiotic-resistant strains could also debilitate patients with increased susceptibilities to infections by pathogens such as Clostridium difficile [162]. A recent systematic review reported that there was no credible evidence that probiotics could help manage CD. However, the authors concluded that combining standard treatments with probiotics could be a plausible option to achieve remission in active UC patients [163].

The use of probiotics has a long clinical history of efficacy, as viewed from a literature review report [164]. From 1977 to 2014, 420 randomized controlled trials were published that demonstrated efficacy for some of the most common indications for probiotic administration. These included the prevention of antibiotic-associated diarrhea (17%), treatment of pediatric acute diarrhea (16%), treatment of Helicobacter pylori infections (16%), the prevention of allergies (12%), treatment of chronic irritable bowel disease (10%) or inflammatory bowel disease (7%), and the treatment of vaginitis and bacterial vaginosis (6%) [164]. In addition, the less common reported effects were for the prevention of necrotizing enterocolitis in newborns (3%), the prevention of traveler’s diarrhea (3%), the treatment of adult acute diarrhea (3%), the treatment of constipation (3%), and the treatment of Clostridium difficile infections (3%) [164]. Rarely were probiotics reported to be effective for the management of sepsis (1%), dental infections (1%), and obesity (1%) [164].

Extensive clinical investigations during the past two decades have reported that the clinical efficacy of probiotics can vary significantly depending on the probiotic bacterial strain included in the formulations, the type of indication [164], the doses used, and the duration of the administered dose. In this context, relative to IBD, probiotic formulations should ensure that the strains used can increase tight junction (TJ) barrier function (reducing permeability) and increased gut cell tight junction reliability, with concomitant increased secretion of mucus, antimicrobial peptides, and sIgA production, competitive adherence for pathobionts (Fig. 2). In other gut-related conditions, such as pouchitis the prevention and treatment of pouchitis after restorative proctocolectomy with ileal pouch-anal anastomosis (IPPA), the authors reported that probiotics were effective in preventing pouchitis after IPAA [165].

The initial introduction to potential allergen foods for normal infants or probiotics for infants at high risk of allergies may protect against the development of allergic diseases [166]. The disruption in the intestinal microbiome can have adverse effects on cancer treatments. Present-day evidence suggests that the use of antibiotics, PPIs, steroids, and opioids negatively impacts the efficacy of immune checkpoint inhibitor medications (ICIs) [167]. However, this effect was reported to vary depending on the type of tumor, the timing of exposure, and the intended application, where weak evidence suggested that statins and probiotics could enhance the efficacy of ICIs.

Recent systematic reviews and meta-analyses have further expanded the thoughtful appreciation of the efficacy of probiotic administration for managing non-IBD-related diseases. A systematic review of six studies encompassing 642 patients from evidence derived from randomized clinical trials (RCTs) indicated a survival benefit associated with using probiotics among COVID-19 patients [168]. The significance of probiotics in lowering plasma lipids was more obvious in hyperlipidemia participants than those from a healthy population cohort [169].

Moreover, probiotic supplementation can enhance cognitive symptomatology in older adults with cognitive impairment. Notwithstanding, psychological symptoms did not improve. Thus, additional research is needed to determine the effects of probiotic formulations on gastrointestinal symptoms and sleep quality in this population cohort [170].

An additional systematic review of moderate- to high-certainty evidence demonstrated an association between multi-strain probiotics in combination formulations with prebiotics and lactoferrin for reductions in all-cause mortality [171]. These clinical interventions were also associated with the greatest effectiveness for other key outcomes. The authors concluded that combination formulations that included single- and multiple-strains of probiotics combined with prebiotics or lactoferrin were associated with the largest reduction in morbidity and mortality [171].

7. Conclusions and Future Directions

The Human Microbiome Project has allowed the characterization of the human microbiome network to analyze the role of the microbiota in human health and disease. The microbiome comprises a collection of microbes, namely bacteria, viruses, and single-cell eukaryotes, which inhabit the human host [172].

The long history of fermented milk products for health and the discoveries of lactic acid bacteria propelled the plausible science of using probiotics for managing and treating diseases. Probiotics do not constitute a panacea for alleviating all diseases, yet they are a treatment modality that may have useful sequelae in, for example, infirm patients diagnosed with IBDs, as reported and observed in clinical studies of UC.

Probiotics have properties that can improve intestinal barrier function by attenuating intestinal epithelial barrier permeability with increased TJ integrity of intestinal epithelial cells. In addition, it has increased intestinal mucus secretions, antimicrobial peptides, sIgA production, and competitive adherence for pathobionts. Probiotic bacteria elaborate SCFAs, predominantly acetate and propionate [173], which can act as cross-feeding activities with commensal gut bacteria that elaborate butyrate (e.g., F. prauznitzii) and progress anti-inflammatory activities in the gut.

The future direction of managing intestinal inflammation due to diseases such as CD and UC has progressed to developing novel probiotic formulations that may enhance the increase in beneficial probiotics. Recent investigations have focused on genetically engineered reprogramming of a probiotic (i.e., E. coli Nissle 1917) to abrogate reactive oxygen species, specifically at the site of inflammation in IBDs [174]. This hypothesis relates to upregulating the expression of antioxidant enzymes, such as catalase and superoxide dismutase, intracellular enzymes that have evolved to control the steady state of redox potential cellular signaling [175]. In addition, in support of Zhou et al. [174] have adopted the suppression strategy of reactive oxygen species (ROS) to control intestinal inflammation without due consideration of disrupting the redox steady state. This is cited in the in vitro studies of the bacterium Corynebacterium glutamicum [176]. In our view, this is an untenable opinion, given that the role of ROS and reactive nitrogen species (RNS) constitute regulated pro-oxidant second messenger systems [175, 177]. ROS and RNS have precise sub-cellular production locales and are essential for normal metabolome and physiological function—the biochemical function of the second messengers in regulating the metabolome express radical formation. ROS and RNS are critical contributors to the physiologically normal regulation of sub-cellular bioenergy systems, such as proteolysis regulation, transcription activation, enzyme activation, mitochondrial DNA changes, and redox regulation of metabolism and cell differentiation [175, 177]. Other studies with genetically engineered E. coli Nissle 1917, which elaborate fibrous matrices and promote intestinal epithelial integrity in situ [178], provide a viable foundation for delivering therapeutic protein matrices that can enhance anti-inflammatory activity in the gut by restoring intestinal epithelial cell integrity.

Preparations of paraprobiotics that include inanimate microorganisms (i.e., heat-inactivated probiotics or gut commensal bacteria) and/or their workings and postbiotics (i.e., products of bacterial metabolism or from endogenously produced) present robust plausible strategies that may confer health benefits and improve immunological responses to gut inflammation [179, 180]. The clinical administration of probiotics for ameliorating IBD symptomatology warrants further robust clinical studies. Hence, it is important to elucidate effective formulations and doses to be prescribed to patients diagnosed with IBDs. This, then, is to accept further clinically and judiciously the plausible posit that there is clinical benefit in the co-administration of probiotics/prebiotics or FMT with standard pharmaceuticals for treating IBDs.

Author Contributions

Conceptualization, LV; writing—original draft preparation, LV, AS, DO; writing—review and editing, AS, DO, and LV; interpretation of the clinical trial data in Tables 1,2—AS, DO, LV; All authors have read and agreed to the published version of the manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Figures were adapted from BioRender templates, namely “Gut Epithelial Barrier” 1 and 2 with the author of the manuscript adding content [BioRender.com (2020)].

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

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