Gut microbiota and fermentation-derived branched chain hydroxy acids mediate health benefits of yogurt consumption in obese mice

Abstract

Meta-analyses suggest that yogurt consumption reduces type 2 diabetes incidence in humans, but the molecular basis of these observations remains unknown. Here we show that dietary yogurt intake preserves whole-body glucose homeostasis and prevents hepatic insulin resistance and liver steatosis in a dietary mouse model of obesity-linked type 2 diabetes. Fecal microbiota transplantation studies reveal that these effects are partly linked to the gut microbiota. We further show that yogurt intake impacts the hepatic metabolome, notably maintaining the levels of branched chain hydroxy acids (BCHA) which correlate with improved metabolic parameters. These metabolites are generated upon milk fermentation and concentrated in yogurt. Remarkably, diet-induced obesity reduces plasma and tissue BCHA levels, and this is partly prevented by dietary yogurt intake. We further show that BCHA improve insulin action on glucose metabolism in liver and muscle cells, identifying BCHA as cell-autonomous metabolic regulators and potential mediators of yogurt’s health effects.

Dietary regulation in health and disease

“… 247 In addition, daily high-fibre supplementation combined with faecal microbiota transplantation (FMT) or yogurt consumption alleviates insulin resistance in cases with metabolic syndrome or severe obesity. 248 , 249 In similar, daily high-inulin supplementation combined with excise are able to reduce cholesterol level in plasma and liver, improve glucose tolerance and lead to weight loss through augmentation of inulin-degrading bacteria in gut. 250 In contrast, a CNOT6L inhibitor elevates hepatokine FGF21 and growth differentiation factor 15 (GDF15) levels by stabilizing their mRNAs and resulted in a remarkable improvement of overnutrition-induced metabolic syndrome.…”

Microbiome-based interventions to modulate gut ecology and the immune system

“…lactis ) in participants who also showed improved metabolic health characterised by reduced visceral fat 130 . Yoghurt contains concentrated milk fermentation metabolites such as branched chain hydroxy acids (BCHA) 131 . Recent studies in mice have noted that feeding the equivalent of 2 servings per day of yoghurt prevented insulin resistance and hepatic steatosis in diet-induced obesity.…”

“…Recent studies in mice have noted that feeding the equivalent of 2 servings per day of yoghurt prevented insulin resistance and hepatic steatosis in diet-induced obesity. This was partly driven by changes in gut microbiome composition and maintaining BCHA levels which are typically reduced in diet-induced obesity 131 .…”

Impact of Blueberry Consumption on the Human Fecal Bileacidome: A Pilot Study

“…A total of 19 BA species were extracted, separated and quantified using a previously reported liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method [20,21]. Briefly, fecal samples were lyophilized under nitrogen and resolubilized in a water: methanol (50:50) solution containing 0.1% formic acid.…”

“…The solution containing BAs then underwent a solid-phase extraction using Strata-X 60 mg columns (Phenomenex, Torrance, USA). As extensively reported [20,21], the LC-MS/MS system consisted in a Nexera ultra-high-pressure liquid chromatography (UHPLC) instrument (Shimadzu Scientific Instruments, Columbia, USA) coupled with an API6500 tandem mass spectrometer (Applied Biosystems, Concord, Canada).…”