Functional Characterization of Inflammatory Bowel Disease–Associated Gut Dysbiosis in Gnotobiotic Mice

Abstract

Background & AimsGut dysbiosis is closely involved in the pathogenesis of inflammatory bowel disease (IBD). However, it remains unclear whether IBD-associated gut dysbiosis contributes to disease pathogenesis or is merely secondary to intestinal inflammation. We established a humanized gnotobiotic (hGB) mouse system to assess the functional role of gut dysbiosis associated with 2 types of IBD: Crohn's disease (CD) and ulcerative colitis (UC).MethodsGerm-free mice were colonized by the gut microbiota isolated from patients with CD and UC, and healthy controls. Microbiome analysis, bacterial functional gene analysis, luminal metabolome analysis, and host gene expression analysis were performed in hGB mice. Moreover, the colitogenic capacity of IBD-associated microbiota was evaluated by colonizing germ-free colitis-prone interleukin 10–deficient mice with dysbiotic patients' microbiota.ResultsAlthough the microbial composition seen in donor patients' microbiota was not completely reproduced in hGB mice, some dysbiotic features of the CD and UC microbiota (eg, decreased diversity, alteration of bacterial metabolic functions) were recapitulated in hGB mice, suggesting that microbial community alterations, characteristic for IBD, can be reproduced in hGB mice. In addition, colonization by the IBD-associated microbiota induced a proinflammatory gene expression profile in the gut that resembles the immunologic signatures found in CD patients. Furthermore, CD microbiota triggered more severe colitis than healthy control microbiota when colonized in germ-free interleukin 10–deficient mice.ConclusionsDysbiosis potentially contributes to the pathogenesis of IBD by augmenting host proinflammatory immune responses. Transcript profiling: GSE73882.

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

“…For pathogen-induced colitis, 6-to 8-wk-old mice were orally given 7.5 mg streptomycin per mouse and 24 h later were infected with 1 × 10 7 colony-forming units of S. Typhimurium SL1344. To establish the humanized gnotobiotic mouse colitis model, germfree IL10 −/− mice were inoculated with the gut microbiotas from a CD patient or HC subject and housed for 3 wk, as described previously (22). Humanized gnotobiotic mice were treated with or without 1 mg/mL DFP in the drinking water in last 2 wk.…”

“…S8). Moreover, to assess the role of mitochondrial iron dysregulation in a more clinically relevant model of colitis, we developed a novel microbiota humanized IL10 −/− model of chronic colitis that accurately reproduces the host-microbiota interaction observed in IBD patients (22) (Fig. 6E).…”

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…Ultimately, potential associations will need to be validated using animal or in vitro organoid models. For example, gnotobiotic animals future science group www.futuremedicine.com with a humanized gut microbiota have been used to test causal relationships between microbiota composition and disease states such as kwashiorkor [159] and inflammatory bowel disease [160]. This approach was recently applied to the phenomenon of oral vaccine failure by inoculating 24 newborn pigs with the fecal microbiota of a RotaTeq nonresponder with a high enteropathy score or a RotaTeq responder with a low enteropathy score (both from a study in Nicaragua) [161].…”

From the intestinal flora to the microbiome

“…Using this model, it has been shown that intestinal dysbiosis may potentially contribute to the pathogenesis of IBD, increasing the pro-inflammatory immune response of the host (41). The data from this study suggests that dysbiosis in patients with IBD is a key factor in the onset and maintenance of intestinal inflammation and not merely a secondary outcome.…”