Succinate-derived microbial metabolites as a novel treatment for non-alcoholic steatohepatitis by reprogramming immunometabolism

Following the so-called obesity epidemic the incidence of non-alcoholic steatohepatitis (NASH) is steeply increasing.

An improved mechanistic understanding, particularly of inter-organ crosstalk, is required to develop new therapeutic approaches.

The overall purpose of this project is to provide novel insights how succinate-derived bacterial metabolites reprogram hepatic metabolism and inflammation to decrease NASH via a gut-liver signaling axis.

Specifically, subproject 1 characterizes how dietary succinate improves NASH in a mouse model independent of the succinate receptor 1 but dependent on the presence of the intestinal microbiota.

In subproject 2 the respective bacterial metabolites of succinate underlying this biological effect as well as the responsible microbial communities are identified.

The metabolites are further characterized using organotypical 3D liver cultures, including a system derived from NASH patients.

Subproject 3 is then testing, if the identified microbiota-derived metabolites of succinate are sufficient to fully reproduce the beneficial biological effects on NASH in mouse models.

Further, specific cellular uptake transporters as well as cellular signaling receptors that mediate these effects will be investigated.

As perspective, our results will have the potential to provide novel oral therapeutic intervention strategies against NASH that will be easy to administer and have limited foreseeable side effects.