Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflanunatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (ft-10), TLR4 KO (T4), and IL-10/T4 double KC) mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SE!, remain empty. In WI mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and htunan UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD) and for identification of targets for novel preventative and therapeutic interventions31011G973G988United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); Leona and Harry Helmsley Trust (SHARE); Gastrointestinal Research Foundation of Chicago; Peter and Carol Goldman Family Research gran

Genomic encyclopedia of bacteria and archaea: sequencing a myriad of type strains.

Microbes hold the key to life. They hold the secrets to our past (as the descendants of the earliest forms of life) and the prospects for our future (as we mine their genes for solutions to some of the planet's most pressing problems, from global warming to antibiotic resistance). However, the piecemeal approach that has defined efforts to study microbial genetic diversity for over 20 years and in over 30,000 genome projects risks squandering that promise. These efforts have covered less than 20% of the diversity of the cultured archaeal and bacterial species, which represent just 15% of the overall known prokaryotic diversity. Here we call for the funding of a systematic effort to produce a comprehensive genomic catalog of all cultured Bacteria and Archaea by sequencing, where available, the type strain of each species with a validly published name (currently∼11,000). This effort will provide an unprecedented level of coverage of our planet's genetic diversity, allow for the large-scale discovery of novel genes and functions, and lead to an improved understanding of microbial evolution and function in the environment

Genomic encyclopedia of bacteria and archaea: sequencing a myriad of type strains.

Microbes hold the key to life. They hold the secrets to our past (as the descendants of the earliest forms of life) and the prospects for our future (as we mine their genes for solutions to some of the planet\u27s most pressing problems, from global warming to antibiotic resistance). However, the piecemeal approach that has defined efforts to study microbial genetic diversity for over 20 years and in over 30,000 genome projects risks squandering that promise. These efforts have covered less than 20% of the diversity of the cultured archaeal and bacterial species, which represent just 15% of the overall known prokaryotic diversity. Here we call for the funding of a systematic effort to produce a comprehensive genomic catalog of all cultured Bacteria and Archaea by sequencing, where available, the type strain of each species with a validly published name (currently∼11,000). This effort will provide an unprecedented level of coverage of our planet\u27s genetic diversity, allow for the large-scale discovery of novel genes and functions, and lead to an improved understanding of microbial evolution and function in the environment. PLoS Biol 2014 Aug 5; 12(8):e1001920

Numbers of Archaea and Bacteria.

1<p><a href="http://www.arb-silva.de" target="_blank">http://www.arb-silva.de</a>;</p>2<p><a href="http://wdcm.org" target="_blank">http://wdcm.org</a>;</p>3<p><a href="http://services.namesforlife.com/home" target="_blank">http://services.namesforlife.com/home</a>;</p>4<p><a href="http://www.bacterio.cict.fr" target="_blank">http://www.bacterio.cict.fr</a>;</p>5<p><a href="http://genomesonline.org/" target="_blank">http://genomesonline.org/</a>.</p

Interactive map based on the NamesforLife (N4L) taxonomic information of the type strains.

<p>Each leaf represents a type strain. Colors denote strains with or without genome projects. Lighter colored nodes denote higher taxonomic ranks. Branch lengths are not meaningful.</p

Genome project coverage of bacterial and archaeal type strains.

<p>From a total of approximately 11,000 bacterial and archaeal type strains, 3,285 (30%) have a publicly known genome project.</p