RIKEN IMS AnnualReport 2020
8/98

In the autoimmune disease multiple sclerosis (MS), the 2LactobacillusErysipelotrichaceaesmall intestinemyelin-mimicry antigenactivation and proliferationmyelin-specific T cellsTh17 differentiationdemyelinationimmune system attacks the myelin sheath insulating the central nervous system. Damage to the myelin sheath disrupts nerve signaling, impairing communication be-tween the brain and the body. Patients with MS experience numbness, slurred speech, and difficulty walking, among other symptoms. Although the gut microbiome has been linked to MS, how microbes in the gut affect the central nervous system remained a mystery. Using a mouse model of MS, researchers led by Hiroshi Ohno at the RIKEN Cen-ter for Integrative Medical Sciences revealed an important clue: two species of gut bacteria trick the immune system into attacking myelin.As described in their recent publication in Nature, the researchers began by investigating connections between gut bacteria and disease symptoms, using antibiotics to selectively remove gut bacteria. They noticed that mice treated with ampicillin showed weaker symptoms and less demyelination. The mice were only protected against demyelination when they were fed ampicillin, not when it was injected, so it was clear that an intestinal microbe was exacerbating disease progression.Microbiome analysis of these mice revealed that ampi-cillin almost completely deleted one microbe in particular: a novel species called OTU0002 of family Erysipelotrix-haceae. To test their hypothesis that this microbe was caus-ing the autoimmune reaction, the team orally administered germ-free mice with OTU0002 alone. These mice still showed demyelination, but their symptoms were milder than those of the original mice, indicating that more than one microbe must be involved.Applying a clue from another study− that proteins of some gut bacteria mimic host proteins, thereby trigger-ing autoreactive T cells to proliferate− the team used in silico analysis to search the mouse gut microbiome for myelin-mimic proteins. They found them in Lactobacillus reuteri. When mice were infected with both L. reuteri and OTU0002, they showed full-strength symptoms. Further research showed that L. reuteri induces myelin-specific T cells to proliferate. OTU0002 then stimulates these T cells to differentiate into inflammatory Th17 cells, leading to devastating demyelination.This is the first time that a mechanism like this− where two commensal bacteria synergistically trigger a host au-toimmune reaction− has been reported. Next steps include determining how the Th17 cells migrate from the intestine to infiltrate and attack the central nervous system and investigating whether a similar mechanism occurs in hu-mans. Dr. Ohno says “Our findings could be extended to the pathogenesis of other autoimmune diseases, including rheumatoid arthritis, type 1 diabetes mellitus, and systemic lupus erythematosus, and even to diseases such as obesity and type 2 diabetes mellitus− wherever systemic chronic inflammation is involved in the pathogenesis.”Figure: Two gut bacteria trigger the autoimmune reaction char-acteristic of MS. One species presents a myelin-mimic antigen that induces T cell proliferation and the other acts as an adjuvant to promote differentiation into inflammatory Th17 cells.Original paper:Miyauchi E, Kim S-W, Suda W, Kawasumi M, Onawa S, Taguchi-Atarashi N, Morita H, Taylor T D, Hattori M, Ohno H. Gut microbes act in concert to exacerbate inflammation in spinal cords. Nature 585, 102-106 (2020)Hiroshi OhnoSignals from two gut bacteria trick the body into attacking its own central nervous system

元のページ  ../index.html#8

このブックを見る