Orally administered Odoribacter laneus improves glucose control and inflammatory profile in obese mice by depleting circulating succinate29 agosto 2022
BackgroundSuccinate 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.
ResultsUsing 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.
ConclusionsOverall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation.
IntroductionObesity is an increasing global public health challenge and a major risk factor for developing pathologies such as type 2 diabetes, cardiovascular disease, and metabolic syndrome . While a number of genetic and environmental factors contribute to the etiology of obesity, gut microbiota disturbances have recently emerged as an important determinant [2,3,4]. Indeed, microbial metabolites (e.g., short-chain fatty acids (SCFAs)) are now recognized as central messengers between the microbiota and the host, and their dysregulation is involved in the development of metabolic diseases .
The Krebs cycle intermediate succinate has the distinction of being produced by both the microbiota and the host . In the context of microbiota metabolism, succinate has been traditionally considered as a cross-feeding intermediary metabolite in the microbial synthesis of the SCFA propionate . While succinate has been long been perceived as an overall pro-inflammatory factor, even in the gut , it can also have beneficial effects on intestinal gluconeogenesis , and some authors have suggested the use of dietary succinate and bacterial succinate-producing species to improve glucose tolerance . Indeed, a recent report revealed that succinate administration reduces chronic intestinal inflammation by modulating tuft cell expansion , which illustrates the complexity of host-microbiota metabolic interactions. Succinate is typically found in low concentrations in the gut lumen, likely related to its cross-feeding relationships, but some studies have suggested a link between the accumulation of luminal succinate and gut microbiota alterations associated with inflammatory bowel disease (IBD) or antibiotic treatment . Along this line, we recently showed that obesity-related perturbations of gut microbiota are characterized by an increase in the abundance of bacterial succinate producers (Prevotellaceae and Veillonellaceae), concomitant with a reduction in succinate consumers (Odoribacteraceae and Clostridaceae) . This specific microbiota signature was strongly associated with the higher circulating succinate observed in obesity. Nonetheless, no study has yet determined the origin of circulating succinate under steady-state or pathological conditions.
Beyond its role as a fuel metabolite, succinate is a signaling molecule responsible for many complex and often conflicting effects derived from its intracellular and extracellular actions, with the latter being particularly important in the regulation of the immune response. Accordingly, although succinate triggers divergent responses in a context- and tissue-dependent manner , it now appears fairly certain that the succinate/succinate receptor 1 (SUCNR1) axis fine-tunes immune cell biology to induce appropriate inflammatory responses . Indeed, we recently demonstrated that SUCNR1 signaling in adipose tissue-resident macrophages is key for the resolution of acute inflammation––a physiological process that is inoperative in human obesity . This may represent a novel mechanism underlying the chronic low-grade systemic inflammation evident in obesity. Notably, similar to what is seen with other hormones including insulin and leptin , obesity and type 2 diabetes are associated with higher circulating levels of succinate [12, 17] in a background of impaired SUCNR1 signaling (at least in terms of inflammation), which we have termed a “succinate-resistant” state. Whether this condition could be effectively counteracted by lowering circulating succinate levels as recently demonstrated for leptin  is unknown.
We sought to address the role of intestinal succinate in the context of obesity. To do this, we (i) explored the contribution of gut microbiota to systemic succinate, (ii) screened for non-pathogenic bacteria that could consume succinate in the human gut, (iii) tested whether oral treatment with such bacteria could effectively reduce circulating succinate and improve the metabolic and inflammatory status of obese mice, (iv) assessed circulating and fecal succinate in a cohort of patients with severe obesity, and (v) undertook metagenomic studies to identify specific associations between succinate and bacterial functions. Overall, our approach sets the stage for a new microbiota-mediated therapeutic strategy to reduce circulating succinate in patients with obesity and type 2 diabetes.