Validation studies for germ-freeSmad3^-/-mice as a bio-assay to test the causative role of fecal microbiomes in IBD

Abstract

While the association between microbiomes and inflammatory bowel disease (IBD) is well known, establishing causal relationships between the two is difficult in humans. Germ-free (GF) mice genetically susceptible to IBD can address this question. Smad3 -/mice with defective transforming growth factor ß signaling are a model of IBD and colon cancer. They develop IBD upon colonization with Helicobacter under specific pathogen-free conditions, suggesting a role of the microbiome in IBD in this model. Thus, we rederived Smad3 -/mice GF to determine the potential of using these mice for testing the causative role of microbiomes in IBD. We found that fecal microbiomes from mice with IBD cause more severe gut inflammation in GF Smad3 -/and wild type mice compared to microbiomes from healthy mice and that Helicobacter induces gut inflammation within the context of other microbiomes but not by itself. Unexpectedly, GF Smad3 +/+ and Smad3 +/mice given IBD microbiomes develop IBD despite their lack of disease in SPF conditions upon Helicobacter infection. This was not unique to the background strain of our Smad3 model ( 129); both wild type C57BL/6 and 129 strains developed IBD upon fecal transfer. However, wild type Swiss Webster stock was not susceptible, indicating that the genetic background of recipient mice influences the severity of IBD following fecal transfer. Our data suggest that the microbiome is an independent risk factor contributing to IBD development, and careful characterization of new GF models is needed to understand potential sources of confounding factors influencing microbiome studies in these mice.

Therapeutic Advances in Gut Microbiome Modulation in Patients with Inflammatory Bowel Disease from Pediatrics to Adulthood

“…The alarming rise in the incidence and prevalence of IBD in the industrialized world suggests that genetic factors only play a partial role in the development of IBD, and rapid changes in dietary and other environmental factors likely significantly contribute to this rise [9]. Moreover, under germ-free conditions (no microorganisms) animal models of IBD do not develop disease or the disease is significantly attenuated, suggesting that intestinal microbes are essential for the development of intestinal inflammation in IBD [10].…”

Changing epidemiology of inflammatory bowel disease in children and adolescents

“…High-income North America and high-income Asia Pacific showed the highest incidence and prevalence rates, which may be related to the risk factors of IBD. Although the pathogenesis of IBD is unclear, some studies have identified its risk factors [ 21 – 23 ]. For example, diet affects the development of IBD by altering the microbiota and modulating immune function [ 24 ].…”

Effect of gut microbiome regulated Taohong Siwu Decoction metabolism on glioma cell phenotype

“…This allows researchers to isolate the effects of the gut microbiota on host physiology. Thirdly, germ-free animals provide a standardized experimental model that is highly reproducible, which facilitates comparisons across different studies ( Paik et al., 2020 ). Also, germ-free animals have reduced animal-to-animal variability compared to animals with complex microbiota, which increases the statistical power of experiments ( Wu et al., 2021 ).…”