Regulation of metabolic diseases by Clostridium immunis

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Visceral adiposity is a key risk factor for the development of type 2 diabetes and metabolic syndrome, owing to its role in promoting a chronic inflammatory state. While behavioral traits are a key driver for the accumulation of visceral adipose tissue (VAT), it is now well recognized that the microbiota is critically involved in regulating VAT development and remodeling.

However, there is a gap in knowledge regarding the specific mechanisms underlying this process. We recently identified Clostridium immunis, a new human commensal bacterium, that reduces serum triglycerides, body weight, and VAT in mice, and we have purified and characterized an exopolysaccharide (EPS) secreted by C. immunis that recapitulates these activities.

Moreover, we have demonstrated group 3 innate lymphoid cells (ILC3s) and IL-22 are both critically required for C. immunis and its exopolysaccharide to protect against metabolic diseases. Collectively, our preliminary data establish that C. immunis is the first human commensal bacterium that negatively regulates the development of VAT in an immune-dependent manner.

The overarching goal of this proposal is to determine the mechanism by which C. immunis EPS decreases VAT. We hypothesize the C. immunis EPS results in decreased VAT by reducing ILC3-derived IL-22, thereby increasing energy expenditure. In the first Aim, we will analyze energy balance under a range of relevant environmental conditions.

In the second Aim, we will determine the immunomodulatory effects of C. immunis EPS. Taken together, the proposed experiments will provide foundational insight into microbiome–immune–metabolism interactions. More broadly, these studies will highlight new microbiome-derived therapeutic opportunities for treating visceral adiposity and its associated complications.