Objective

Obesity and diabetes increase circulating levels of microbial components derived from the gut microbiota. Individual bacterial factors (i.e., postbiotics) can have opposing effects on blood glucose.

Methods

We tested the net effect of gut bacterial extracts on blood glucose in mice using a microbiota-based vaccination strategy.

Results

Male and female mice had improved glucose and insulin tolerance five weeks after a single subcutaneous injection of a specific dose of a bacterial extract obtained from the luminal contents of the upper small intestine (SI), lower SI, or cecum. Injection of mice with intestinal extracts from germ-free mice revealed that bacteria were required for a microbiota-based vaccination to improve blood glucose control. Vaccination of Nod1^−/−, Nod2^−/−, and Ripk2^−/− mice showed that each of these innate immune proteins was required for bacterial extract injection to improve blood glucose control. A microbiota-based vaccination promoted an immunoglobulin-G (IgG) response directed against bacterial extract antigens, where subcutaneous injection of mice with the luminal contents of the lower SI elicited a bacterial extract-specific IgG response that is compartmentalized to the lower SI of vaccinated mice. A microbiota-based vaccination was associated with an altered microbiota composition in the lower SI and colon of mice. Lean mice only required a single injection of small intestinal-derived bacterial extract, but high fat diet(HFD)-fed, obese mice required prime-boost bacterial extract injections for improvements in blood glucose control.

Conclusions

Subversion of the gut barrier by vaccination with a microbiota-based extract engages innate immunity to promote long-lasting improvements in blood glucose control in a dose-dependent manner.