MS Minute: Multiple Sclerosis & the Gut Microbiome

We have effectively coevolved with our microbiome (See Appendix at end of online article for definitions of bold terms),^1-6 a vast array of bacteria, archaea, viruses, and eukaryotes (eg, fungi) residing in and on us. The genetic load of the microbiome is an estimated 3 million genes, 150-fold larger than the human genome. Bacteria are the most commonly studied organisms in the human microbiome. Most (>90%) bacteria in the microbiome live in the gastrointestinal tract, primarily the colon.⁷ Typically, an individual hosts approximately 160 of around 1,000 different bacterial species found in the human gut.⁸ Gut microbiota play a fundamental role in human health, ranging from production of serotonin, vitamins (eg, K, B₁₂), amino acids (eg, tryptophan), and other beneficial metabolites (eg, short-chain fatty acids [SCFAs]) to immune-system regulation. It has been demonstrated that the microbiota can affect central nervous system (CNS) maturation and myelination.^9-13

The Human Microbiome in Multiple Sclerosis

Alterations in the gut microbiota have been suggested as influential in several neurologic diseases, including multiple sclerosis (MS).⁹ The presence of a chronic neurologic condition will also influence the microbiome (Figure),^14-21 such that the 2 could conceptually coevolve together across the lifespan. An important and ongoing first step in understanding this relationship is to describe the microbes present in persons with and without MS.²² Most studies in people with MS have focused on the gut bacteria, identified using 16S ribosomal RNA sequencing from stool-sample extracted DNA. Present on all bacteria and archaea, the 16S gene marker is a useful and cost-efficient method of describing which microbes are present. It is difficult, however, to use the 16S marker to identify microbes at lower taxonomic ranks, such as species- or strain-level. A few studies of people with MS have described the mycobiota (ie, fungi), which can be identified using an equivalent marker gene (eg, the internal transcribed spacer [ITS]).^23-25 Although functionality of identified microbes from marker gene sequencing can be inferred with validated algorithms,²⁶metagenomics, also termed ‘shotgun’ sequencing, is a more direct, but costlier approach. Computationally intense, metagenomic sequencing provides information about all genes in the microbiome, permitting a more detailed survey of the microbiome and their potential function.^15,22Metabolomics provides a direct measure of the actual products produced by the gut microbiome (eg, SCFAs),²⁷ and can be measured in various fluids (eg, serum, urine, or cerebrospinal fluid [CSF]).

Evidence From Animal Models of MS

Animal models of MS (eg, experimental autoimmune encephalomyelitis [EAE]) provide intriguing evidence that the presence, or specific composition, of the gut microbiome can trigger or worsen disease in mice. Mice raised in a germ-free vs conventional environment were less likely to develop EAE, and if EAE was triggered, the disease course was less severe.^28,29 Further, when stool was transferred from 8 people living with MS and 8 without MS into equal numbers of germ-free mice, more severe disease developed in the animals that received stool from people with MS.^30,31 Demonstrating similar causality in humans presents several key challenges (Box 1).^32-37

Evidence From Persons With MS

Direct or conclusive evidence that the (gut) microbiota contributes to MS onset or disease activity and progression is limited (Table 1, Questions 1 &2).^16,38 Specifically, no studies to date have acquired (stool) samples prior to clinical onset of MS, and few have gathered samples before specific outcomes (eg, relapses, disease activity, imaging biomarkers, or disability progression. Collection of (stool) samples prior to MS onset is particularly challenging, especially given the likely prolonged prodromal period (Box 1).³⁹

Despite challenges (Box 2),^40-42 there is some consistency across studies showing that microbiota in people with and without MS may differ, although typically, no large or statistically significant differences in the gut microbiota diversity (alpha or beta), has been found.^16,43,44 Small or modest differences may become apparent, however, as the number of individuals included in microbiome studies increases.

Findings may differ across studies, depending on the characteristics of the underlying population (Figure), especially if cases and controls differ for reasons other than MS itself. Nonetheless, taxa-level findings that have been observed in at least 2 or more studies have included a lower relative abundance of Prevotella, Faecalibacterium prausnitzii, Bacteroides coprophilus, Bacteroides fragilis, and higher abundance of Methanobrevibacter and Akkermansia muciniphila in MS cases vs controls.¹⁶ Even within a specific species (eg, A. muciniphila), however, there may be functionally distinct subspecies or strains,⁴⁵ which may differ between individuals, and hence across studies.¹⁶ Further, different microbes can have similar functions (eg, ability to produce SFCAs).²⁰ Thus, although individual taxa may be of relevance to MS, other gut microbiota features (eg, community structure, connectivity, and function) are also of interest.

Microbiota network analyses in both pediatric-onset and adult-onset MS suggest differential clustering and connectivity of microbes in the gut of people with MS vs those without MS or with other acquired demyelinating diseases.^15,46 Annotation of these taxa-level (genera) networks suggests overrepresentation of highly connected opportunistic pathogens and underrepresentation of SCFA-producing taxa in persons with MS.¹⁵ Emerging studies using metagenomic sequencing in people with pediatric- or adult-onset MS suggest a disturbed functional potential of the gut microbiota, including disruptions in pathways associated with SCFA production,^36,47 vitamin B₂ synthesis,³⁶ and lipopolysaccharides metabolism.^22,48 Others, by integrating metagenomics with other “-omics” point to a potentially disrupted immune-microbiome-blood metabolome network in adults with MS, including lower SCFA production in the gut and increased abundance of peripheral T helper 17 (Th17) cells.¹⁴

A very limited number of longitudinal studies examining whether the gut microbiota is associated with MS disease activity have been published (Table 1, Question 3). A relationship between the gut microbiota composition and future relapse risk or new/enlarging MRI lesions were observed in 2 studies, both of which were in people with pediatric-onset MS.^49,50 The larger, more recent of these followed 55 participants with pediatric-onset MS for a mean 2.5 years after obtaining a stool sample. There were 5 gut microbes associated with clinical and MRI relapse risk (hazard ratio), and inferred enrichment or clustering of species that produce SCFA and amino acids (eg, L-tryptophan) was associated with lower disease activity risk.⁴⁹

Manipulating the MS Microbiome

Despite limited evidence-based research, there is much interest and speculation regarding interventions to change the microbiota in people with MS. Interventions aimed at altering the microbiota have potential to directly affect MS course (eg, by reducing relapse risk), or could indirectly affect the person with MS via management of common comorbidities, such as bowel issues (eg, irritable bowel syndrome, constipation, or diarrhea), fatigue, depression and anxiety, or facilitating weight management.⁵¹ Establishing safety of any novel microbiome targeted intervention remains a priority.

Pre-, Pro-, and Postbiotics

Both novel and commercially available products, particularly pre- and probiotics, have been or are being trialed for potential treatment of MS (Table 2, Question 4). The size and scope of published studies remains rather limited, with relatively few (22-91) enrollees followed for short periods of time (2-24 weeks).^27,52 Potential favorable effects on biomarkers, such as change in peripheral blood mononuclear cell composition, were reported.^27,53 Ongoing studies will examine other biomarkers (eg, serum neurofilament light levels) as well as the safety and tolerability of pre-, pro-, and postbiotics.^a,b Challenges in this field include identifying and isolating the most functionally relevant (eg, strain-specific) microbes; determining if engraftment in the gut is possible or desirable, or if long-term use of these products is needed; and, intriguingly, understanding if a live product is actually needed at all, or if remnants of dead microbes are sufficient, or perhaps supplementation with a metabolite offer safer options (eg, propionic acid, an SCFA).^4-6,27,54

Dietary Interventions

Radical dietary changes can result in short-term shifts in the gut microbiota,⁵⁵ but evidence of any long-term meaningful impact are lacking, likely due, in part, to the resiliency of each person’s resident gut microbiota (Table 2, Question 5).⁵⁶ Failure of many individuals to respond to, or adhere to various diets long-term, combined with rebound weight gain, has lead to a targeted approach to dietary intervention-related research.⁵⁷ Emerging evidence suggests that how a person responds to specific foods (eg, measured with blood glucose levels) may depend on the person’s unique gut microbiota signature.⁵⁸ Whether this work will benefit people with MS remains to be determined.

Dietary patterns and specific macronutrients have been associated with MS risk and possibly disease activity.^58-62 Diets high in fiber or fermented foods have been shown, in healthy volunteers, to shift the host immune response towards a more anti-inflammatory profile.⁶³ Prospective studies are ongoing to examine the role of specific diets (eg, intermittent fasting and caloric restriction) on the gut microbiota composition, serum gut-derived metab-olites, and host immune profiles, among other measures in people with MS.^c,d

Fecal Microbial Transplants

Fecal microbial transplants (FMT) are an emerging treatment for recurrent, treatment-resistant Clostridium difficile infection. Best practice guidelines for FMT exist, but many recommendations are based on low-to-moderate evidence (Table 2, Question 6).⁶⁴ Beyond treating C. difficile, findings for the treatment of other diseases are promising, but mixed, and the procedure is not risk-free. The first FMT-related deaths were reported in 2019.⁶⁵ Studies evaluating safety of FMT for people with MS are ongoing. Despite this lack of evidence, medical tourism already exists, offering FMT to people with MS at resort-like locations.

Other Opportunities

Interventions being actively trialed for potential treatment of MS, in which affecting the gut microbiota is being examined as a study outcome, include transanal irrigation to treat constipation/incontinence⁶⁶ and melatonin as an add-on to ocrelizumab to target disease progression in primary progressive MS.^e,f Whether the gut microbiota can be targeted to reduce adverse effects of disease-modifying treatments (eg, GI-related issues associated with dimethyl fumarate) for MS, is being investigated.^g The use of bacteriophages, or “phage therapy” to modify the microbiota, and administration of synthetic microRNA that target specific microbes hold potential,^67,68 although studies in persons with MS are lacking. Topical bacteriophages are being trialed to treat pressure sores, which may have value in advanced MS.^h

Summary and Outlook

Advances in understanding how gut microbes may influence MS offer tantalizing research avenues, but much remains to be accomplished to establish causality between biome characteristics and disease processes. Many types of interventions such as prebiotics, probiotics, live biotherapeutics, phage therapy, or microRNA targeting could be considered. However, unraveling which microbes or networks of microbes contribute to MS activity and progression is a prerequisite condition to optimize the design of proof-of-concept trials.