Author:
Gray Simon M.,Moss Anh D.,Herzog Jeremy W.,Kashiwagi Saori,Liu Bo,Young Jacqueline B.,Sun Shan,Bhatt Aadra P.,Fodor Anthony A.,Balfour Sartor R.
Abstract
Abstract
Background
Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis.
Results
Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10−/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10−/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10−/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10−/− mice than the distinct microbiota reassembled in non-inflamed WT hosts.
Conclusions
Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.
Funder
NIH/NIDDK
UNC Physician Scientist Training Program Fellowship Award
Crohn’s & Colitis Foundation Career Development Award
The Engineering Research Centers Program of the National Science Foundation
Crohn’s & Colitis Foundation
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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