Intestinal Barrier Dysfunction Develops at the Onset of Experimental Autoimmune Encephalomyelitis, and Can Be Induced by Adoptive Transfer of Auto-Reactive T Cells

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a pathogenesis involving a dysfunctional blood-brain barrier and myelin-specific, autoreactive T cells. Although the commensal microbiota seems to affect its pathogenesis, regulation of the interactions between luminal antigens and mucosal immune elements remains unclear. Herein, we investigated whether the intestinal mucosal barrier is also targeted in this disease. Experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS, was induced either by active immunization or by adoptive transfer of autoreactive T cells isolated from these mice. We show increased intestinal permeability, overexpression of the tight junction protein zonulin and alterations in intestinal morphology (increased crypt depth and thickness of the submucosa and muscularis layers). These intestinal manifestations were seen at 7 days (i.e., preceding the onset of neurological symptoms) and at 14 days (i.e., at the stage of paralysis) after immunization. We also demonstrate an increased infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T cell number in the gut lamina propria, Peyer's patches and mesenteric lymph nodes. Adoptive transfer to healthy mice of encephalitogenic T cells, isolated from EAE-diseased animals, led to intestinal changes similar to those resulting from the immunization procedure. Our findings show that disruption of intestinal homeostasis is an early and immune-mediated event in EAE. We propose that this intestinal dysfunction may act to support disease progression, and thus represent a potential therapeutic target in MS. In particular, an increased understanding of the regulation of tight junctions at the blood-brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.

The Second Brain: Is the Gut Microbiota a Link Between Obesity and Central Nervous System Disorders?

“…A recent work by Lavasani and colleagues describes that the induction of EAE promote significant increases in the small intestine permeability, an enhanced infiltration of IFN-γ + CD4 + (Th1) and IL-17 + IL-22 + CD4 + (Th17) cells, as well as enhanced frequencies of increased expression of IL-17 + γδ T cells in the small intestine gut mucosa and Peyer's patches. Antigen presenting cells isolated from the small intestine of EAE mice produced enhanced levels of pro-inflammatory IL-6 and TNF-α when compared to healthy animals [72]. Changes were observed as soon as 7 days post-EAE induction.…”

“…Thus, gut commensal microbes and metabolites are essential in regulating intestinal integrity and function, immune homeostasis in the gut and the periphery, and the recent experimental data discussed above suggest their relevance controlling BBB development and integrity. Also, CNS inflammation leads to changes in the intestinal integrity, as demonstrated by Lavasani and colleagues [72]. …”

The Microbiome and Neurologic Disease: Past and Future of a 2-Way Interaction

“…Similarly, treatment with antibiotics at early stages of disease (from day 0 to 14) resulted in reduced severity of disease, indicating the bidirectional association between disease and the microbiota [24]. The induction of EAE in mice has remarkable cellular and molecular effects on the intestinal barrier by promoting the induction of a Bleaky gut^and accumulation of proinflammatory Th17 and Th1 cells, concomitant with reductions in regulatory T cells in the intestinal mucosa [25]. The effects of MS in intestinal barrier disruption are reviewed by Buscarini et al [6].…”

Budowa bariery jelitowej

“…Udowodniono, że zaburzenia przepuszczalności bariery jelitowej odgrywają rolę w patogenezie nie tylko chorób przewodu pokarmowego, ale także układu nerwowego, immunologicznego czy rozrodczego [28,29,30,31].…”