IDDF2022-ABS-0053 GPR35 deficiency induces GUT microbial reconfiguration to increase colitis susceptibility

Background

Both host genetics and the gut microbiome have important impacts on health and disease, but how complex interactions between genetic and microbial factors contribute to the host phenotypes remains unclear. Here we aim to assess the impact of Gpr35 gene deficiency on the ecology of gut microbes and its causal role in colitis susceptibility.

Methods

DSS was established to induce acute colitis in male C57BL6/J mice (7 weeks). The severity of colitis in mice was evaluated by colon length, body weight change, DAI score and histological analysis. 16S rRNA sequencing was used to profile the composition of gut microbiome in Gpr35 gene-deficient (Gpr35^-/-) and wild-type (WT) mice. Fecal microbiome transplantation (FMT) to antibiotics-treated pseudo germ free (GF) mice and co-housing experiments were performed to verify the causal role of gut microbial remodeling in colitis susceptibility. Metabolomics analysis was performed on cecum contents and colon tissue of WT and Gpr35^-/- mice to profile potential regulatory metabolites.

Results

Gpr35^-/- mice were markedly susceptible to colitis, as evidenced by increased percent weight loss, DAI score, mucosal injury and inflammatory disturbance (IDDF2022-ABS-0053 Figure 1. Gpr35 loss increases the susceptibility to colitis). The fecal microbial structure in Gpr35^-/- mice was significantly different from that of WT mice, typically showing a dramatic depletion of Akkermansia muciniphila (IDDF2022-ABS-0053 Figure 2. Gpr35 deficiency is accompanied by gut microbial remodeling). Recipient mice with FMT from Gpr35^-/- donors showed increased susceptibility to colitis, and co-housing rendered WT mice more susceptible to colitis (IDDF2022-ABS-0053 Figure 3. Gpr35 loss associated microbial change contributes to colitis susceptibility). Metabolic profile difference in the colon tissue was remarkable between WT and Gpr35^-/- mice, with extensive alternation observed for tricarboxylic acid cycle and bile acid metabolism pathway metabolites (IDDF2022-ABS-0053 Figure 4. Gpr35 loss modulates the host microbe co metabolite profile).

Conclusions

Our results identify a causal role of Gpr35 gene deficiency-induced gut microbial remodeling in colitis susceptibility, and highlight the importance of combinatorial therapy targeting genetic and microbial signals for colitis treatment.