Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis

Abstract

Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date, no study has focused on the role of succinate on host metabolism. Here, we fed mice a fiber-rich diet and found that succinate was the most abundant carboxylic acid in the cecum. Dietary succinate was identified as a substrate for intestinal gluconeogenesis (IGN), a process that improves glucose homeostasis. Accordingly, dietary succinate improved glucose and insulin tolerance in wild-type mice, but those effects were absent in mice deficient in IGN. Conventional mice colonized with the succinate producer Prevotella copri exhibited metabolic benefits, which could be related to succinate-activated IGN. Thus, microbiota-produced succinate is a previously unsuspected bacterial metabolite improving glycemic control through activation of IGN.

Microbial modulation of cardiovascular disease

“…Interestingly, inhibition of the lactate receptor GRP81 was shown to protect against ischemic brain injury in mice 126 . As noted above, another emerging biologically active non-SCFA bacterial fermentation product is succinate 127–129 . Succinate is produced in large quantities in mammalian cells during the citric acid cycle, but it can also be generated by colonic microorganisms, including Prevotella 129 .…”

“…As noted above, another emerging biologically active non-SCFA bacterial fermentation product is succinate 127–129 . Succinate is produced in large quantities in mammalian cells during the citric acid cycle, but it can also be generated by colonic microorganisms, including Prevotella 129 . Prevotella -generated succinate is presumed responsible for the observed beneficial effect on mice intestinal glucose production following provision of Prevotella copri 129 .…”

“…Succinate is produced in large quantities in mammalian cells during the citric acid cycle, but it can also be generated by colonic microorganisms, including Prevotella 129 . Prevotella -generated succinate is presumed responsible for the observed beneficial effect on mice intestinal glucose production following provision of Prevotella copri 129 . Succinate can activate the host G protein-coupled receptor GPR91 127–1295 , which indicates a potential new gut microbial metabolite-host receptor interaction that is relevant to CVD pathogenesis.…”

Gut Microbiota and Host Metabolism: What Relationship

“…IGN indeed is a gut function initiating various metabolic benefits by generating a gut-brain nervous signal that positively interferes in energy homeostasis and glucose control [23]. Finally, Prevotella was shown to act positively in glucose control both by activating IGN as a substrate, but also via succinate-independent mechanisms, which remain to be deciphered [13,22].…”

“…Interestingly, P. copri is a succinate-producing bacterium. It was shown elsewhere that succinate is a major bacterial metabolite produced in response to fiber feeding in mice and provides metabolic benefits via its role as a substrate of intestinal gluconeogenesis (IGN) [22]. IGN indeed is a gut function initiating various metabolic benefits by generating a gut-brain nervous signal that positively interferes in energy homeostasis and glucose control [23].…”