ClonalParabacteroidesfrom Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn’s Disease Complications

Abstract

Crohn’s disease (CD) has been traditionally viewed as a chronic inflammatory disease that cause gut wall thickening and complications, including fistulas, by mechanisms not understood. By focusing onParabacteroides distasonis(presumed modern succinate-producing commensal probiotic), recovered from intestinal microfistulous tracts (cavernous fistulous micropathologies CavFT proposed as intermediate between ‘mucosal fissures’ and ‘fistulas’) in two patients that required surgery to remove CD-damaged ilea, we demonstrate that such isolates exert pathogenic/pathobiont roles in mouse models of CD. Our isolates are clonally-related; potentially emerging as transmissible in the community and mice; proinflammatory and adapted to the ileum of germ-free mice prone to CD-like ileitis (SAMP1/YitFc) but not healthy mice (C57BL/6J), and cytotoxic/ATP-depleting to HoxB8-immortalized bone marrow derived myeloid cells from SAMP1/YitFc mice when concurrently exposed to succinate and extracts from CavFT-derivedE. coli, but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange withBacteroides fragilis-BGF539, evidence of international presence in primarily human metagenome databases, these CavFTPdisisolates could represent to a new opportunisticParabacteroidesspecies, or subspecies (‘cavitamuralis’) adapted to microfistulous niches in CD.

Rodent Gut Bacteria Coexisting with an Insect Gut Virus in Parasitic Cysts: Metagenomic Evidence of Microbial Translocation and Co-adaptation in Spatially-Confined Niches

“…DD2A (44.69%). The latter finding is of notoriety, since the DNA of fecal samples in this study did not reveal a large number of bacterial taxonomic units, as expected from other studies we have conducted in human colonoscopy content and in mice 7,22 , with the same methodology, or using 16S rRNA microbiome studies 23,24 . This finding could be attributed to completely different gut microbiome in these wild animals who inhabit subterraneous environments and have different diets.…”

“…This study provides a new perspective on the understanding of bacterial communities in migratory tapeworms and in dysbiosis associated with chronic intestinal diseases where spatially-restricted cavitating micro niches develop and could perpetuate inflammation through symbiotic mechanisms. Such a scenario is in Crohn’s disease, where recently we discovered that P. distasonis predisposes susceptible hosts to inflammation driven by succinate ( P. distasonis metabolite) 7 , which increases cytotoxicity of immune cells to co-habiting Escherichia coli . Our study could help identify revised strategies for the treatment of clinical cysticercosis and the potential benefits of adding antibiotics.…”

“…The interplay of microbial populations is critical in maintaining homeostasis and health in the mammalian gut ecology. Therefore, the study of these microbial communities could help us determine what influences these dynamic relationships in restricted ecological niches 3,4 , or the evasion of the host immunity in other confined biological niches, such as within gut wall-associated cavitating micropathologies in Crohn's disease 5,6 , which we found to have genomic evidence for niche specific genomic exchange that could favor silent commensalism and immune evasion [6][7][8][9] .…”

Genomes of Bacteroides ovatus , B. cellulosilyticus , B. uniformis , Phocaeicola vulgatus , and P. dorei isolated from gut cavernous fistulous tract micropathologies in Crohn's disease

“…Termed cavernous fistulous tract microlesions (CavFT) ( 4 ), intriguingly, such lesions harbor commensal bacteria. We previously reported the genome of two Parabacteroides distasonis strains ( 5 , 6 ) isolated from two CD-CavFT patients with ileitis ( 5 ), and showed via genome-rearrangement analysis that the two isolates are uniquely clonal and probably transmissible in the community ( 6 ). Experimentally, CavFT P. distasonis induced cell toxicity/inflammation via the interaction of succinate with other CavFT bacteria ( 7 , 8 ).…”

Antigenic operon fragmentation and diversification mechanism in Bacteroidota impacts gut metagenomics and pathobionts in Crohn's disease microlesions

“… 23 Of notoriety, CavFTs harbor cultivable bacteria, namely Bacteroidota and Enterobacteriaceae ( E. coli ). 5 , 24 , 25 Focused on CavFT, genomic analyses of consecutive Parabacteroides distasonis ( Bacteroidota ) isolates from two unrelated patients that underwent surgery for CD indicated for the first time that a novel lineage might have become adapted to CavFTs, swapping large fragments of DNA with Bacteroides , been likely transmissible in the community. 25 To classify P. distasonis and other Bacteroidota , and to facilitate the orderly study of such commensal/pathogenic dualism in the phylum, we recently proposed the use of the LPS/O-Antigen gene rfbA for the genotyping and classification of Bacteroidota .…”