Orally administered Odoribacter laneus improves glucose control and inflammatory profile in obese mice by depleting circulating succinate

Abstract

Background Succinate is produced by both human cells and by gut bacteria and couples metabolism to inflammation as an extracellular signaling transducer. Circulating succinate is elevated in patients with obesity and type 2 diabetes and is linked to numerous complications, yet no studies have specifically addressed the contribution of gut microbiota to systemic succinate or explored the consequences of reducing intestinal succinate levels in this setting. Results Using germ-free and microbiota-depleted mouse models, we show that the gut microbiota is a significant source of circulating succinate, which is elevated in obesity. We also show in vivo that therapeutic treatments with selected bacteria diminish the levels of circulating succinate in obese mice. Specifically, we demonstrate that Odoribacter laneus is a promising probiotic based on its ability to deplete succinate and improve glucose tolerance and the inflammatory profile in two independent models of obesity (db/db mice and diet-induced obese mice). Mechanistically, this is partly mediated by the succinate receptor 1. Supporting these preclinical findings, we demonstrate an inverse correlation between plasma and fecal levels of succinate in a cohort of patients with severe obesity. We also show that plasma succinate, which is associated with several components of metabolic syndrome including waist circumference, triglycerides, and uric acid, among others, is a primary determinant of insulin sensitivity evaluated by the euglycemic-hyperinsulinemic clamp. Conclusions Overall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation.

High-Resolution Taxonomic Characterization Reveals Novel Human Microbial Strains with Potential as Risk Factors and Probiotics for Prediabetes and Type 2 Diabetes

“…Odoribacter has been found to be negatively associated with the expression of intestinal epithelial tight junction proteins, suggesting a link with impairing mucosal barrier function in rats [ 39 ]. However, Huber-Ruano et al (2022) showed that one strain of O. laneus , DSM 22474 A, has beneficial anti-inflammatory and metabolic properties in obese mice [ 40 ]. Collectively, our results strongly suggest that the effects of this species may be strain-specific and indicate the need of comprehensive evaluation before pursuing Odoribacter strains for treating type 2 diabetes in humans.…”

Succinate aggravates intestinal injury in mice with necrotizing enterocolitis

“…Succinate is a cometabolite produced by both hosts and microbes, and it is typically identified at low levels in the intestinal lumen, likely due to its cross-feeding relationships ( Connors et al., 2018 ). Substantial evidence has indicated that succinate concentrations increase under conditions of hypoxia, stress, inflammation, and changes in intestinal microorganisms ( Nagao-Kitamoto et al., 2016 ; Macias-Ceja et al., 2019 ; Banerjee et al., 2020 ; Huber-Ruano et al., 2022 ). It has been widely reported in previous studies that changes in the intestinal flora are closely related to the development of NEC ( He et al., 2021 ; Liu et al., 2022a ; Samara et al., 2022 ).…”

The Role of Next-Generation Probiotics in Obesity and Obesity-Associated Disorders: Current Knowledge and Future Perspectives

“…Odoribacter laneus (O. laneus) is a Gram-negative anaerobe rod that was isolated from the human feces of a healthy Japanese adult donor in 2010 [ 125 ]. Very recently, in 2022, Hueber-Ruano et al characterized O. laneus as an NGP due to its ability to ameliorate insulin sensitivity and decrease inflammatory markers in a mouse model [ 126 ]. By administering O. laneus through oral gavage in obese mice, they documented a significant reduction in serum succinate levels.…”