Develop a gut microbial sulfonolipid for inflammation modulation

About This Grant

Summary: Inflammation is a fundamental response that normally subsides when the triggering event is cleared. Non-resolving inflammation, however, results in continued immune activation, and plays a significant role in the pathogenesis of numerous health conditions including inflammatory bowel disease (IBD). The objective of our study is to establish the feasibility of developing sulfonolipid A (SoL A), a unique lipid produced by human gut microbiota, as an agent to modulate inflammation. We will use IBD as a prototype target disease of SoL A in this Phase I STTR project. IBD affects millions of people worldwide; current treatments either are insufficient to control disease progression or have severe side effects during long-term use; therefore, there is an urgent need for the development of more effective and safer preventive and therapeutic strategies. Microbial dysbiosis leads to persistent immune activation. It is well known that microbes biosynthesize and biotransform metabolites in the gut allowing them to interact with their host environments. While some pathogenic microbes produce toxins leading to increased inflammation, some other commensal microbes produce immunomodulatory metabolites that may protect against inflammation. Notably, Alistipes and Odoribacter are negatively associated with IBD, suggesting that they may protect against IBD-related inflammatory pathogenesis. We developed a unique biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites as potential molecular mechanisms in inflammatory diseases, such as IBD. We first directly connected the expression of gut microbial SoL biosynthetic enzymes to IBD in patients, revealing a negative correlation. This correlation was then corroborated by targeted metabolomics, indicating that SoL abundance is significantly decreased in IBD patients. We experimentally validated our analysis in a mouse model of IBD, showing that SoL production is indeed decreased in diseased mice. In support of this connection, we applied bioactive molecular networking to show that SoLs consistently contribute to the immunoregulatory activity of Alistipes and Odoribacter. We further revealed that SoLs A and B, two representative SoLs, primarily target TLR4 signaling to suppress LPS-induced inflammatory response in macrophages. Importantly, we developed a method to induce bacteria to overproduce SoLs and to purify them. Encouraged by these findings and considering that SoL A showed more potent anti-inflammatory activity than SoL B, we propose in this STTR Phase 1 project to test the feasibility of developing SoL A as treatment for IBD via two specific aims. SA1. To determine the toxicity of SoL A in cultured cells and its PK and safety in mice when it is administered orally or intravenously. SA2. To establish the effectiveness of SoL A in two well-established mouse models of IBD: piroxicam-accelerated colitis in C57BL/6 Il10-/- mice and DSS-induced colitis in BALB/c mice. This STTR Phase 1 project will provide proof-of-concept to use SoL A to treat inflammatory diseases such as IBD. The successful completion of these studies will serve as a milestone and the Go/No Go decision point for the further development effort.