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. 2024 Jul 1;19(7):1480-1488.
doi: 10.4103/1673-5374.387974. Epub 2023 Nov 13.

Gut flora in multiple sclerosis: implications for pathogenesis and treatment

Weiwei Zhang  1 , Ying Wang  1 , Mingqin Zhu  1 , Kangding Liu  1 , Hong-Liang Zhang  2
Affiliations

Gut flora in multiple sclerosis: implications for pathogenesis and treatment

Weiwei Zhang et al. Neural Regen Res. .

Abstract

Multiple sclerosis is an inflammatory disorder characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Although current first-line therapies can help manage symptoms and slow down disease progression, there is no cure for multiple sclerosis. The gut-brain axis refers to complex communications between the gut flora and the immune, nervous, and endocrine systems, which bridges the functions of the gut and the brain. Disruptions in the gut flora, termed dysbiosis, can lead to systemic inflammation, leaky gut syndrome, and increased susceptibility to infections. The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors, and gut flora may play a pivotal role in regulating immune responses related to multiple sclerosis. To develop more effective therapies for multiple sclerosis, we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis. This review provides an overview of the role of the gut flora in multiple sclerosis.

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Conflict of interest statement

Conflicts of interest: HLZ is affiliated with the National Natural Science Foundation of China. The views expressed are his own and do not necessarily represent the views of the National Natural Science Foundation of China or the Chinese government. Other authors declare that they have no conflicts of interests.

Figures

Figure 1
Figure 1
Pathophysiological mechanisms of MS. MS is a central autoimmune, inflammatory disease. The pathological mechanisms underlying MS are thought to begin when foreign antigens enter the peripheral nervous system. APCs identify foreign antigens as they circulate in the bloodstream. Th1 cells detect the foreign antigens, become activated, excite an immune reaction against them, and then generate inflammation cytokines, for example, INF-γ, TNF-α and IL-12, which enhance the immune cascade by generating extra Th1 cells and inducing the upregulation of adhesion cytokines (ICAM-1 and VCAM-1) next to the BBB surface. Th1 cells attach to the surface of BBB endothelial cells, where they induce MMP-3/-9 production. Metalloproteinases upregulate BBB permeability, while activated Th1 cells can transverse the BBB into the CNS, and are excited upon exposure to myelin. They continue to generate inflammatory cytokines which facilitate the production of additional inflammatory mediators that damage neuromyelin. Created with Figdraw. APCs: Antigen presenting cells; BBB: blood-brain barrier; CNS: central nervous system; GPR: G protein-coupled receptor; HDAC: histone deacetylase; HPA: hypothalamic-pituitary-adrenal; ICAM-1: intercellular cell adhesion molecule-1; IL-12: interleukin-12; INF-γ: interferon-gamma; MAMPs: microbial-associated molecular patterns; MMP-3: matrix metalloproteinase-3; MMP-9: matrix metalloproteinase-9; MS: multiple sclerosis; NF-κB: nuclear factor kappa-B; SCFA: short-chain fatty acid; TGF-β: transforming growth factor-β; Th1: T helper 1; TNF: tumor necrosis factor; Treg: regulatory T cells; VCAM-1: vascular cell adhesion molecule-1.
Figure 2
Figure 2
Communication between the brain and the microbiota. There are multiple pathways, both direct and indirect, through which the brain communicates with the microbiota. For example, the vagus nerve and SCFAs produced by gut microbiota participate actively in the regulation of the brain-gut axis. These pathways encompass the neuroactive route, immune route, gut microbial metabolites, vagus nervous pathway, HPA axis, and the endocrine route. The gut microbiota plays a crucial role in generating local neurotransmitters in the intestine, which serves as a key communication mechanism. Neuroactive substances and other dietary metabolites produced by gut microbiota can influence intestinal barrier function, stimulate the production of hormones by enteroendocrine cells, and modulate immune function by affecting dendritic cells. These processes have significant implications for the understanding of neurological disorders. Created with Figdraw. BBB: Blood-brain barrier; HPA: hypothalamic-pituitary-adrenal; SCFAs: short-chain fatty acids.
Figure 3
Figure 3
Disruption of the gut microbiota and its impact on BBB integrity in MS. The BBB plays a crucial role in maintaining the homeostasis of the CNS and preventing the entry of foreign antigens into brain tissue. In individuals without MS, the gut microbiota produces beneficial substances, such as SCFAs, which are important for maintaining BBB integrity. However, alterations in the composition of the gut microbiota can lead to a decrease in the levels of these beneficial metabolites, ultimately resulting in BBB damage. Additionally, changes in the gut microbiota can trigger systemic inflammation, leading to the production of cytokines by immune cells, further promoting the demyelination of the CNS in MS. Created with Figdraw. BBB: Blood-brain barrier; CNS: central nervous system; ICAM-1: intercellular cell adhesion molecule-1; IFN-γ: interferon-gamma; IL-12: interleukin 12; MMP-3: matrix metalloproteinase-3; MMP-9: matrix metalloproteinase-9; MS: multiple sclerosis; SCFAs: short-chain fatty acids; Th1: T-helper 1; TNF-α: tumor necrosis factor-alpha; VCAM-1: vascular cell adhesion molecule-1.
Figure 4
Figure 4
The hygiene hypothesis regarding the occurrence of MS. In healthy individuals, PAMPs derived from the gut microbiome have minimal systemic circulation and interact with pattern recognition receptors, such as TLR2, on immune cells. This interaction induces TLR tolerance, which helps regulate subsequent immune responses. This level of tolerance is crucial in minimizing excessive stimulation, controlling the expression of DAMPs, and reducing the risk of autoimmunity. It maintains an appropriate proinflammatory response to increased ligand levels resulting from infectious factors. In individuals with MS, there is a deficiency in PAMPs derived from the gut microbiome, leading to inadequate innate immune tolerance. The reduced TLR tolerance allows for an exaggerated proinflammatory response, as DAMP stimulation is no longer properly controlled. This dysregulation contributes to an increased risk of neuroimmune disorders, such as MS. Furthermore, heightened TLR2 responses are associated with impaired myelin regeneration. Created with Figdraw. DAMP: Damage-associated molecular patterns; MS: multiple sclerosis; PAMPs: pathogen-associated molecular patterns; TLR: Toll-like receptor.
Figure 5
Figure 5
Multiple lines of evidence support the role of the gut-brain axis in MS pathogenesis. Experimental and clinical studies provide compelling evidence linking the gut microbiota to the development of MS. Probiotics have shown promising results in reducing incidence, delaying disease onset, and attenuating symptoms in EAE, an animal model of MS. FMT has also demonstrated the ability to delay disease onset and alleviate clinical symptoms in EAE. Moreover, oral administration of broad-spectrum antibiotics has been found to decrease the severity of EAE. Additionally, DMTs have shown effectiveness in management and prevention of clinical disease activity in MS. These findings suggest that targeting the gut microbiota could be a potential therapeutic approach for MS. Created with Figdraw. DMTs: Disease-modifying treatments; EAE: experimental autoimmune encephalomyelitis; FMT: fecal microbiota transplantation; GF: germ-free; IBD: inflammatory bowel disease; MS: multiple sclerosis.
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