Microbiota-Driven Mechanisms in Multiple Sclerosis: Pathogenesis, Therapeutic Strategies, and Biomarker Potential

Abstract

Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut-brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut-brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management.

Keywords: dysbiosis; gut microbiota; immune modulation; multiple sclerosis; therapeutic interventions.

Figure 1

Different combinations of gut commensal bacteria can generate signals that induce the differentiation of various T-cell subtypes. Some of these bacteria cause dendritic cells to generate cytokines, including IL-1β, IL-6, and IL-23, which in turn causes Th17 cells to differentiate. Others can promote the production of Treg cells and affect the Th1/Th2 ratio, altering the composition of the intestinal T-cell population and establishing a balance between inflammatory and anti-inflammatory states in the gut. Bacterial metabolites and antigens present in the gut can influence naïve B cells, prompting their differentiation into Breg cells. These Breg cells produce anti-inflammatory cytokines such as IL-10, thereby inducing an anti-inflammatory environment within the gut. These bacteria also influence gut humoral immunity by inducing plasma cells to produce IgA antibodies, which play a crucial role in maintaining the homeostasis of gut bacteria.

Figure 2

Some food-derived metabolites that can influence the immune and nervous systems include short-chain fatty acids (SCFAs), the amino acid tryptophan, urolithins, and polyamines. These compounds can inhibit inflammatory macrophages (M1) and astrocytes, preventing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and CCL2. Conversely, by inducing the production of Treg cells and subsequently increasing anti-inflammatory cytokines like IL-10 and TGF-β, they contribute to the establishment of an anti-inflammatory environment. These metabolites, through the aryl hydrocarbon receptor (AhR), can reduce the production of the pro-inflammatory cytokine IL-17. On the other hand, according to the findings of some studies, these metabolites restore claudin and occludin proteins, thereby strengthening tight junctions and contributing to the maintenance of the blood–brain barrier’s integrity.

Figure 3

Interaction between gut microbiota and genetics, epigenetics, and environmental agents in multiple sclerosis (MS). Through a variety of mechanisms, the gut microbiota’s makeup can affect MS outcomes. As a significant environmental risk factor, obesity can alter the composition of the gut microbiome, leading to increased inflammation and disease aggravation. Different antibiotics and diets may also influence the gut microbiota, which can then affect the immune system and result in various outcomes for MS. The gut microorganisms of MS patients likewise are significantly influenced by host genetics. In particular, this association has been noted between the gut microbiota of these individuals and polymorphisms in the HLA class II gene. Additionally, a number of researchers have demonstrated the difference between the intestinal microbiomes of EAE-susceptible C57BL/6J mice and mice models that are resistant to the illness. The use of beneficial probiotics in the diet has also been associated with a lowering trend in the expression of genes linked to inflammation, such as NLRP-1 and NLRP-3. Gut bacteria’s production of short-chain fatty acids (SCFAs) might influence epigenetic modifications such as increased histone acetylation, which can promote the growth of Treg cells and preserve the blood–brain barrier.