SUMMARY Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b−/−. Reducing Treg cell numbers, or reconstitution of TCRβ−/− mice with CD8+ T cells from Wnt10b−/− mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8+ T cell Wnt10b production.

Highlights d The gut microbiome induces the Nrf2 antioxidant response pathway in the liver d Gut-resident Lactobacilli induce hepatic Nrf2 in both Drosophila and mice d Oral delivery of Lactobacillus rhamnosus GG protects against oxidative liver injury d Lactobacilli-derived 5-methoxyindoleacetic acid activates Nrf2

Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome. However, the causality of changes in the microbiome-host interaction affecting energy metabolism remains controversial. Here, we show the microbiome-derived metabolite δ-valerobetaine (VB) is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans. VB is absent in germ-free mice and their mitochondria but present in ex-GF conventionalized mice and their mitochondria. Mechanistic studies in vivo and in vitro show VB is produced by diverse bacterial species and inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine and mitochondrial long-chain acyl-CoAs. VB administration to germ-free and conventional mice increases visceral fat mass and exacerbates hepatic steatosis with Western diet but not control diet. Thus, VB provides a molecular target to understand and potentially manage microbiome-host symbiosis/dysbiosis in diet-dependent obesity.

A high sugar and high‐fat diet Western‐style diet can result in significant dyslipidemia, often leading to non‐alcoholic fatty liver disease (NAFLD), with females particularly affected by this diet irrespective of total caloric intake. Dietary supplementation with beneficial bacteria has been advocated as therapeutic intervention to modulate liver adiposity resulting from a Western‐style diet. Here, we assess the activity of beneficial bacteria on modulating the impact of a Western‐style diet in female mice. Of those tested, we show that a previously uncharacterized beneficial bacterium, namely Lactococcus lactis sp. cremoris significantly protected against Western style diet‐induced hepatic steatosis, elevated cholesterol levels, glucose intolerance, increased body mass index (BMI), and adiposity. Due to these effects, we propose the use of L. lactis sp. cremoris as a therapeutic modality to promote metabolic health in individuals suffering adverse health events resulting from a Western style diet. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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