Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota

Abstract

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe–microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk.

Detection of Early Disease Risk Factors Associated with Metabolic Syndrome: A New Era with the NMR Metabolomics Assessment

“…Succinate, a metabolite produced in the human body but also by the gut microbiota, is described as the major intermediary in the citric acid cycle, where it stands between succinyl-CoA and fumarate in the carbohydrate metabolism but the gut-microbiota produced succinate is classically described as an intermediate of the propionate synthesis [57]. Succinate has been increased in hypertension, ischemic heart disease, and T2D, but also in obesity, which is associated with elevated plasma levels of succinate concomitant with impaired glucose metabolism [227] Alterations in circulating succinate levels were associated with specific metagenomics signatures linked to energy production and carbohydrate metabolism [64]. It has been related with an antilipolytic action in adipose tissue through the succinate receptor 1 (SUCNR1), inhibiting the release of fatty acid from adipocytes.…”

A thermodynamic atlas of carbon redox chemical space

“…The recently elucidated signalling functions 32,33 . Interestingly, succinate accumulation occurs in a number of different organisms, including bacteria such as Escherichia coli 34 , Mycobacterium tuberculosis 35 , as well as several bacterial members of the human gut microbiome [36][37][38][39] and the bovine rumen 40,41 ; fungi such as the yeast Saccharomyces cerevisiae 42 and members of the genus Penicillium 43 ; green algae 44 ; parasitic helminths 45 ; the sleeping sickness-causing parasite Trypanosoma brucei 46 ; marine invertebrates 47 ; and humans [48][49][50][51] . More specifically, our observations are consistent with the behavior of the TCA cycle under anaerobiosis and hypoxia [52][53][54][55] .…”

Gut microbiota and obesity: An opportunity to alter obesity through faecal microbiota transplant (FMT)

“…Increase in another metabolite, succinate, has been observed in human subjects with metabolic syndrome . The elevated circulating succinate in these subjects is associated with an increase in succinate‐producing bacteria ( Prevotellaceae and Veillonellaceae ) and a decrease in succinate‐consuming bacteria ( Odoribacteraceae and Clostridiaceae ) .…”

“…49 Body weight loss led to a reversal of the bacterial family proportions along with a decrease in circulating succinate. 49 These findings by Serena et al suggest that metabolites produced by the gut microbiota can serve as important biomarkers for the development of metabolic syndrome, especially for determining the efficacy of therapies, and broaden the target gut microbiota families that may be linked to obesity.…”