The Role of the Intestinal Microbiome in Multiple Sclerosis-Lessons to Be Learned from Hippocrates

Abstract

Based on recent advances in research of chronic inflammatory conditions, there is a growing body of evidence that suggests a close correlation between the microbiota of the gastrointestinal tract and the physiologic activity of the immune system. This raises the idea that disturbances of the GI ecosystem contribute to the unfolding of chronic diseases including neurodegenerative pathologies. Here, we overview our current understanding on the putative interaction between the gut microbiota and the immune system from the aspect of multiple sclerosis, one of the autoimmune conditions accompanied by severe chronic neuroinflammation that affects millions of people worldwide.

Keywords: intestinal microbiome; macrophages; multiple sclerosis; regulatory T lymphocytes.

Figure 1

Pathological hallmark of multiple sclerosis. Multiple sclerosis is one of the demyelinating disorders with the leading pathological finding being the destruction of the myelin sheet around the axons (A). Oligodendrocytes can engage in apoptosis via the activation of multiple signaling pathways in response to the FAS ligand (FASL), Tumor necrosis factor alpha (TNFα) or Interferon gamma (IFNγ) (B). Created with BioRender.com.

Figure 2

Pro-inflammatory macrophages invade the CNS in the initial phase of neuroinflammation in multiple sclerosis. Autoreactive immune cells (AIC)-released (A) pro-inflammatory cytokines (PC) induce the expression of adhesion molecules in endothelial cells that trigger recruitment (B) of lymphocytes (Ly), first, via weak Selectin (C) and, then, via firm, integrin-mediated (D) cell–cell interactions. The latter ones initiate diapedesis (E) of activated lymphocytes (F) into the interstitial space of CNS where secretion of matrix metalloproteinases (MMPs) damage lamina basalis of the blood–brain barrier (BBB). This leads to inflammatory injury of the cellular components of the blood–brain barrier including the endothelium, peri- and astrocytes alike. The damaged blood–brain barrier then recruits (G) monocytes (M) and neutrophil granulocytes (N). Following their immigration into the CNS, monocytes differentiate into pro-inflammatory macrophages (ϕ) and, with neutrophil granulocytes (N), initiate neuroinflammation (H). Created with BioRender.com.

Figure 3

The gastrointestinal microbiome contributes to the functioning of the immune system. The gut microbiome and cellular elements of the intestinal epithelium have intricate interactions to maintain the barrier function of the gut lining. One of the critical components of this function is mediated by the tight junctions between enterocytes (E). Commensal germ metabolites, like short-chain fatty acids (SCFA), actively contribute to the upregulation of tight junction proteins. Parallel, enterocytes secrete cytokines that influence the immune cell population of the lamina propria including monocytes (M), antigen-producing cells (B) and helper (T_H) and regulatory (T_reg) T lymphocytes alike. Microbiota-derived antigens are also detected by enteroendocrine cells (EE), antigen presenting dendritic cells (DC) and enterocytes (E) by sampling the intestinal lumen directly. In return, enteroendocrine cells secrete bioactive peptide hormones (BPH), like serotonin, which, besides regulation of digestive functions of the enterocytes, affect B-, T_H- and dendritic cell activities as well. The latter ones (DC), in contrast, can penetrate the intercellular space of the enterocyte lining and uptake microbial antigens directly from the mucus for presentation to immunocompetent cells of the epithelium. In the case of segmented filamentous bacteria (SFB), enterocytes can also mediate antigens to IL-17-producing T lymphocytes (T_H17) contributing to the regulation of the functionally critical T_H17 pool of the intestines. For this effect, SFB need to contact enterocytes by penetrating the lower layers of the mucus. This physical barrier primarily consists of mucin produced by Goblet cells (G) which also sample the gut microbiota for antigens, e.g., the Helicobcter hepaticus (Hh), and delivers them to elements of innate immune cells of the lamina propria like the dendritic species (DC). Goblet cells are, at least in certain conditions, under the control of Tuft cells (T) that, in response to luminal antigens, for instance upon helminth invasion, produce IL-25. IL-25 activates type 2 innate lymphoid and T helper cells that, in response to IL-25, begin to produce IL-13. IL-13, in return, facilitates the commitment of epithelial stem cells (S) toward the production of Goblet- (G) and Tuft cells (T) [108]. The mucus also contains antimicrobial peptides (A) secreted by various elements of the epithelium including Paneth cells (P), which usually present in close vicinity of epithelial stem cells (S) and that, at least in part, are under the indirect control of dendritic cells via cytokines including IL-22 [109]. Created with BioRender.com.

Figure 4

Spatially diverse composition of the gastrointestinal microbiome along the GI tract. Although predominant phyla are the same, proportional changes in microbiome diversity have been observed along the gastrointestinal tract of which the most characteristic is the reciprocal alteration in the presence of Bacteroidetes/Firmucutes and Actino-/Proteobacteria phyla in a cranio-caudal manner [129]. Created with BioRender.com.

Figure 5

Dysbiosis of the gastrointestinal microbiome facilitates the proinflammatory state of multiple sclerosis. Alterations in the composition of the gastrointestinal microbiome influence the immunological status in multiple mechanisms in multiple sclerosis (MS). On one hand, MS-type microbiome directly facilitates differentiation and the expansion of T_H17 lymphocytes (T_H17) that play a central role in the maintenance of the inflammatory state of MS patients. Parallel, MS-type microbiome directly blocks the activity of anti-inflammatory species like the CCR9⁺ memory T cells (Tm) or tissue-resident dendritic cells (DC). Blockade of the latter results in the failure of differentiation of FOXP3⁺ regulatory T cells (T_reg) which results in the accumulation of pro-inflammatory cytokines and cellular species alike. On the other hand, the MS-type intestinal microbiome exerts pro-inflammatory effects via various microbial metabolites by blocking the physiologic metabolisms of compounds like the phytoestrogens, short-chain fatty acids (SCFA) or microbial lipids (Lipid 654). Created with BioRender.com.