Gut microbiota-based vaccination engages innate immunity to improve blood glucose control in obese mice

Abstract

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.

Postbiotics engage IRF4 in adipocytes to promote sex‐dependent changes in blood glucose during obesity

“…In contrast, other postbiotics such as under‐acylated LPS, NOD2 ligands, short chain fatty acids (SCFA), flavonoids, and flagellin have emerged as promotors of insulin sensitivity and glucose homeostasis (Anhê et al, 2021 ; Canfora et al, 2015 ; Cavallari et al, 2017 ; Cavallari et al, 2020 ; Kimura et al, 2013 ; Thaiss et al, 2016 ; Tran et al, 2019 ). Recent work showed that injection of crude extracts of intestinal luminal contents, containing a complex mixture of postbiotics, improves blood glucose control in HFD‐fed mice (Duggan et al, 2022 ; Pomié et al, 2016 ). The identity and interactions of the microbial factors responsible for glucose lowering remain unknown.…”

“…Postbiotics include microbial components or metabolites that do not require detection of live bacteria to influence host immunity and metabolism (Cavallari et al, 2017 ; Cavallari et al, 2020 ; Cicenia et al, 2014 ; Patel & Denning, 2013 ). For example, microbial components sensed by pattern recognition receptors (PRRs) of the innate immune system can alter host metabolism (Canfora et al, 2015 ; Cani et al, 2007 ; Duggan et al, 2022 ; Perry et al, 2016 ; Tran et al, 2019 ; Turnbaugh et al, 2006 ). Specific postbiotics, such as bacterial cell wall‐derived muramyl dipeptide (MDP), have been shown to mitigate metabolic inflammation and improve aspects of metabolic disease during bacterial and nutritional stress (Canfora et al, 2015 ; Cavallari et al, 2017 ; Cavallari et al, 2020 ; Tran et al, 2019 ).…”

Microbiota and Nod-like receptors balance inflammation and metabolism during obesity and diabetes

“…It was possible that injection of specific doses of a gut bacterial extract derived from specific gastrointestinal tract segments could improve blood glucose control. After optimization of the dose and extraction, sonication, sterilization of postbiotic factors from the mucosa and lumen of the gut, several groups have shown that a single subcutaneous injection of a diluted bacterial extract from the upper gut caused long-term lowering of blood glucose a month later in lean mice [ 97 , 98 ]. This was one of the first bacterial immunization strategies that can improve blood glucose during obesity.…”

“…This was one of the first bacterial immunization strategies that can improve blood glucose during obesity. This immunization required bacteria, since mucosal extracts prepared from germ-free mice did not lower glucose [ 97 , 98 ]. Bacterial vaccination required NOD2 to lower blood glucose.…”

“…Bacterial vaccination required NOD2 to lower blood glucose. MDP alone could not recapitulate the glucose lowering [ 97 ]. Thus, MDP-NOD2 is required, but not sufficient, for the bacterial vaccine lowering of blood glucose.…”