Horizontal gene transfer shapes pathogenic bacteria in multiple sclerosis

Abstract Multiple sclerosis (MS) is an autoimmune demyelinating disease influenced by environmental factors. Except during relapses, baseline neurological status is generally stable in the early stage, whereas progressive deterioration may occur silently. The progressive disease form (secondary progressive MS; SPMS) characterised by both neuroinflammation and neurodegeneration differs significantly from the non-progressive form in microbiome profiles1 2 3. After confirming an increased abundance of gut bacterium “Tyzzerella nexilis” in SPMS, the role of T.nexilis in progressive MS was studied. The strain-level analysis based on long-read metagenomics identified a distinct cluster of T.nexilis highly enriched in SPMS. T.nexilis strains in this novel cluster were characterised by an incredible number of mobile genetic elements (MGEs) and the absence of defence systems against MGEs. Mono-colonisation with this MGEs-enriched T.nexilis strain made germ-free mice more susceptible to induction of experimental autoimmune encephalomyelitis. The pathogenicity of this strain was mediated by TLR5 stimulation by flagella encoded on MGEs. Moreover, this T.nexilis strain was thought to have potentials of causing neurodegeneration, because of its ability to produce reduced sulphur compounds encoded on MGEs. Such a horizontal gene transfer, causing functional diversity beyond existing bacterial taxonomy, may have causal implications in chronic disorders influenced by gut microbiome.