, François J. Roman 2, Benjamin Lelouvier 3, Céline Ribière 3, Jacques Touchon 41 REGEnLIFE, 75008 Paris, France
2 FRconsulting, 34800 Clermont l’Hérault, France
3 Vaiomer, 31670 Labège, France
4 Faculty of Medicine, University of Montpellier, 34000, Montpellier, France
Abstract
The evidence of brain–gut interconnections in Alzheimer’s disease (AD) opens novel avenues for the treatment of a pathology for which no definitive treatment exists. Gut microbiota and bacterial translocation may produce peripheral inflammation and immune modulation, contributing to brain amyloidosis, neurodegeneration, and cognitive deficits in AD. The gut microbiota can be used as a potential therapeutic target in AD. In particular, photobiomodulation (PBM) can affect the interaction between the microbiota and the immune system, providing a potential explanation for its restorative properties in AD-associated dysbiosis. PBM is a safe, non-invasive, non-ionizing, and non-thermal therapy that uses red or near-infrared light to stimulate the cytochrome c oxidase (CCO, complex IV), the terminal enzyme of the mitochondrial electron transport chain, resulting in adenosine triphosphate synthesis. The association of the direct application of PBM to the head with an abscopal and a systemic treatment through simultaneous application to the abdomen provides an innovative therapeutic approach to AD by targeting various components of this highly complex pathology. As a hypothesis, PBM might have a significant role in the therapeutic options available for the treatment of AD.
Keywords
- Alzheimer's disease
- neurodegeneration
- neuroinflammation
- brain–gut axis
- microbiota
- microbiome
- photobiomodulation
- low-level laser therapy (LLLT)
- oxidative stress
- mitochondria
Recent treatments such as Food and Drug Administration (FDA)-approved
anti-amyloid-
In AD, patients display altered microbial diversity and composition, as indicated by fecal analysis compared with controls [7]. The observed shifts in the composition of the microbiome may lead to an inflammatory condition in the intestine that degrades the epithelial barrier [8]. This could result in an increased translocation of proinflammatory products and bacterial molecules triggering autoimmunity, such as liposaccharides, amyloids, DNA, proteins, and polysaccharides. The systemic inflammation leads to microglia activation, neuroinflammation, and blood–brain barrier impairment [9]. Photobiomodulation (PBM) allows simultaneous transcranial and abdominal application, reaching several important targets for the treatment of such a complex pathology. Transcranial PBM, acting via the cytochrome c oxidase (CCO), could increase adenosine triphosphate (ATP) and influence downstream cellular signaling to reduce oxidative stress and neuroinflammation as well as upregulate synaptogenesis and neurogenesis [10]. Abdominal PBM application could restore mitochondrial normal function in gut neurons. Its potential restorative effects on the gut–microbiome–brain axis may have a significant effect on immune modulation through a reduction of oxidative stress, a decrease in proinflammatory cytokines, and changes in macrophage phenotype [11]. The local effect of PBM on inflammatory pathways most likely has systemic consequences. Circulating immune cells (mast cells, macrophages, etc.), stimulated by PBM [12, 13, 14, 15], could transduce protective signals from distal tissues such as the gut to sites in need of protection such as the brain.
The mechanisms considered in this opinion paper are involved in brain–gut interconnections, evidencing PBM as a potential treatment of AD and allowing synergies through multitarget approaches to this multifactorial disease.
There is increasing evidence for the contribution of gut microbiota (GM) to the pathogenesis of AD, and it has already been found that AD patients have altered microbiota diversity [16]. Furthermore, GM have been demonstrated as an important player in insulin resistance and type 2 diabetes mellitus [17, 18], which are known to be more frequent in AD patients [19].
Bacterial byproducts such as short-chain fatty acids (SCFAs) exert numerous
neuromodulation effects and act directly on gastrointestinal cells, stimulating
the synthesis of hormones such as leptin, ghrelin, and glucagon-like peptide 1,
peptide YY [20]. These hormones have been shown to exhibit neuroprotective
effects [21]. The microbiome has a role in tryptophan metabolism, producing
tryptophan catabolites and also other metabolites including neurotransmitters and
hormones able to leave the gut lumen and be detected in the circulation to serve
as signaling molecules such as catecholamines, serotonin, gamma aminobutyric
acid, dopamine, acetylcholine
As the source of a large amount of bacterial product, GM may contribute through the disruption of physiological barriers to systemic inflammation and autoimmunity [26]. Bacteria or their products can translocate from the gastrointestinal tract to the CNS. Bacterial amyloids [27] may act as prion protein cross-seeding of misfolding and enhance native amyloid aggregation. Moreover, GM products may prime microglia, enhancing the inflammatory response in the CNS, which, in turn, results in pathologic microglial function, increased neurotoxicity, and impaired amyloid clearance [28].
GM may promote brain inflammation in AD brains and be responsible for the
inflammatory reaction featured around amyloid plaques. The possible role of GM
was investigated in cognitively impaired AD patients by studying the association
of brain amyloidosis, GM taxa with pro-inflammatory or anti-inflammatory
properties, and peripheral inflammation [29]. Cognitively impaired patients with
amyloidosis revealed higher expression levels of blood pro-inflammatory cytokines
such as interleukine-6 (IL-6), chemokine ligand 2 (CXCL2), nucleotide oligomerization domain (NOD)-like receptor
protein 3 (NLRP3), and interleukin-1
Modifying the gut microbiome exhibits promise in treating AD and other neurological conditions [30, 31]. While interventions like diet, probiotics, and fecal microbiota transplantation (FMT) have had some success, they may not be sufficient for a complete treatment. Recently, it has been demonstrated in aged rats that the mixture VSL#3 containing eight strains of probiotics modulates the expression of several genes in the brain cortex, with positive inflammatory and neuronal consequences [6]. A recent clinical phase-3 trial [32] has shown that GV-971, a sodium oligomannate that is able to remodel gut microbiota, suppressing gut dysbiosis and the associated phenylalanine/isoleucine accumulation, reverses cognition impairment in patients with mild cognitive impairment due to AD [33]. FMT, approved for certain intestinal diseases including recurrent Clostridium difficile infection [34], is being explored for neurodegenerative diseases such as Parkinson’s and other non-intestinal disorders [35]. Studies suggest FMT can improve cognitive symptoms in AD patients [36, 37]. Achieving a healthy microbiome seems crucial for balancing key compounds and influencing the progression of neurodegenerative diseases. However, clinical trials are still lacking and are essential for more conclusive results.
The mechanisms involved in PBM exposure to produce its positive effects on AD symptoms are not fully understood. Transcranial PBM for stimulation of the brain in AD patients has shown improvement of cognitive functions [38, 39, 40], quality of life and patient independence [41], and enhancement of prefrontal oxygenation [39, 42].
However, the exact mechanism by which light interacts with the microbiome
remains to be elucidated. Beyond the chromophores located in mammalian cells,
which could respond to PBM, there is also a diverse range of bacterial species
(both Gram-positive and Gram-negative) and fungal (including yeast) cells that
have been demonstrated to respond to PBM [43, 44]. In general,
an increased proliferation of the microbial cells was observed, but at higher
doses, inhibition was also seen, resulting from a biphasic dose-response curve of
the PBM [45, 46]. In vitro study [47] has indicated that PBM inhibits
the growth of Pseudomonas aeruginosa and Escherichia coli, two
Gram-negative bacteria that infect skin ulcers. However, the changes in the
microbiome composition observed in the mouse experiments [48] may be due to other
effects of PBM on the murine inflammatory system. Indeed, PBM has well-known
anti-inflammatory and redox signaling effects, thus reducing the level of
pro-inflammatory cytokines such as IL-6, tumor necrosis factor-
It has been posited that PBM delivered to the abdomen of healthy mice can
significantly modify the gut microbiome composition [51]. Recent data has
signified that an Amyloid
During the last several years, more evidence has been accumulated demonstrating the involvement of microbiota in various diseases such as cancer [58], diabetes [59], neurological disorders, and gastrointestinal disorders [60]. Furthermore, the manipulation of the microbiota in the human body can be a strategy for disease treatment. In view of the complexity of AD, the discovery of a single, unique molecule with an unambiguous mechanism of action able to prevent or cure this pathology as found in other cases of drug discovery becomes increasingly elusive. As a result, novel clinical trials are being designed by combining the action of several pathways to obtain stronger effects with fewer side effects [61], and this type of drug development is promoted by the US FDA [62]. In this context, PBM emerges as a therapeutic opportunity because it can target the CNS through transcranial application concomitantly with abscopal effects through abdominal application.
The direct effect of PBM on mitochondria to activate CCO is of importance as a possibility of information exchange exists between the GM and neural mitochondria [18, 63]. Furthermore, there is an increasing amount of data demonstrating the involvement of an aberrant metabolism and defective mitochondrial bioenergetics [64, 65, 66, 67, 68] in AD onset and progression. These mitochondrial dysfunctions trigger impaired synaptic activities in AD such as calcium signaling, synaptic energy, and neurotransmission [69, 70]. Maintaining optimal neuronal and synaptic function is crucial in AD and is closely linked to mitochondria [67, 69, 70].Thus, the suggestion emerges that targeting mitochondria could be a promising approach for developing new treatments. As PBM is strongly hypothesized to target mitochondria function, it may be considered as a novel promising therapeutic tool for treating AD.
Preclinical data obtained in mice in the A
Transcranial PBM is emerging as a potential treatment and cognitive enhancement method for various neurodegenerative pathologies. It has also been shown to help increase the potential of pharmacological therapies by modulating the blood–brain barrier permeability, opening innovative avenues for non-invasive therapeutic interventions in the CNS [75]. The evidence that abdominal PBM is able to activate mechanisms of brain neuronal rescue by means of the brain–microbiome–gut axis confirms the interest in associating transcranial to abdominal PBM in clinical practice.
PBM appears to be a promising non-invasive, non-pharmacological therapeutic strategy for AD, able to mobilize multiple mechanisms in synergy through the association of transcranial and transabdominal application for optimal treatment efficacy. Due to its affordability, safety profile, and ability to be administered both at home and in hospitals, brain–gut PBM has the potential to become widely accessible and integrated into the treatment of AD.
FJR and GB performed the literature searches, designed and wrote the paper and contributed to the editorial changes in the manuscript. BL, CR, and JT contributed to its analysis, its critical review, and its final version approval. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Not applicable.
Not applicable.
This research received no external funding.
GB is an employee of REGEnLIFE and owns equity in the company. FJR is the director of FR Consulting. BL and CR are employees of Vaiomer. BL is a shareholder of Vaiomer. The authors declare no conflict of interest and the writing is not influenced by this relationship.
References
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