Gut microbiome manipulation to improve efficacy and durability of anti-TNF treatments for inflammatory bowel disease

About This Grant

Project Summary/Abstract: This proposal addresses the significant challenge of limited treatment options in inflammatory bowel disease (IBD) and the loss of response to therapies that were previously effective. The long-term objective is to improve the clinical management of IBD by enhancing the initial response to therapy and extending the duration of remission, therein reducing the need for alternative medications or surgical interventions. Specifically, our study will investigate the role of the gut microbiome in modulating the initial effectiveness of anti-TNF therapies, as well as its ability to prevent anti-drug antibody (ADA) development, a common cause of subsequent treatment failure. In Aim 1, we will determine whether the response to anti-TNF therapy induction can be improved by transplanting the gut microbiome of known treatment responders into recipients planning to undergo therapy. Germ-free mice will be colonized with fecal inocula from human patients previously determined to have either responded, or not responded, to anti-TNF therapy. Following the development of intestinal inflammation, the mice will be treated with anti-TNF injections and evaluated for differential treatment response. To assess the robustness of our findings, we will utilize two germ-free IBD mouse models which have been previously demonstrated to be microbiome responsive: the IL-10 knockout and the adoptive T-cell transfer models. Furthermore, emerging studies have shown that exposure to different classes of antibiotics can alter the risk of ADA development among IBD patients treated with anti-TNF therapies. Therefore, our second Aim will be to evaluate if the durability of anti-TNF treatment can be enhanced by the ingestion of microbial communities shaped by antibiotic use. To parallel a future clinical scenario in which microbes may be delivered prophylactically, we will gavage conventional C57Bl/6 mice with microbiomes from mice that have been given various antibiotics. Recipient mice will then be treated with an anti-TNF and subsequently assessed for ADA development. The proposed research will integrate fecal metagenomic, transcriptomic, and metabolomic data to elucidate the molecular basis of the microbiome’s effects. The project endeavors to improve therapeutic strategies for IBD by optimizing the use of anti TNF-inhibitors which are already widely available, therefore offering a scalable approach that can be quickly implemented to address current challenges in IBD care, to guide antibiotic treatment decisions, and to help explain the heterogeneity of anti-TNF response, which has long been clinically recognized but incompletely understood.