Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity
Open accessAbstract
The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (Fxr(ΔIE)) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(ΔIE) mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.
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Tempol can alter the gut microbiome, leading to accumulation of intestinal T-βMCA, thereby inhibiting intestinal FXR signaling and decreasing obesity.
“Additionally, tempol, an antioxidant and protective agent against radiation, can alter the gut microbiome, leading to the accumulation of intestinal T-βMCA, thereby inhibiting intestinal FXR signaling and decreasing obesity (12).”
Tempol does not further reduce adiposity in intestinal FXR-null mice, which is consistent with changes in microbial bile acid metabolism and FXR signaling contributing to tempol's mechanism of action.
“Tempol does not further reduce adiposity in intestinal specific FXR-null mice85, consistent with the hypothesis that changes in microbial bile acid metabolism and subsequent signaling via the FXR pathway contribute to the mechanism of action of tempol.”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [85]
Tempol increases intestinal concentrations of multiple taurine-conjugated bile acids, including T-β-MCA, which is an antagonist of FXR.
“Consistent with these findings, tempol increases the intestinal concentration of multiple taurine-conjugated bile acids, including tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an antagonist of the farnesoid X receptor (FXR), a master regulator of lipid, glucose, and bile acid metabolism85, 87, 88.”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [85]
Tempol treatment in mice alters the relative abundance of distal gut bacterial phyla, increasing Bacteroidetes and decreasing Firmicutes, with the genus Lactobacillus significantly reduced.
“Treatment of mice with tempol altered the relative abundance of the two dominant bacterial phyla in the distal gut, increasing the abundance of Bacteroidetes and decreasing the abundance of Firmicutes85. Within the Firmicutes phylum, the genus Lactobacillus was significantly reduced (Fig. 3).”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [85]
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“Additionally, tempol, an antioxidant and protective agent against radiation, can alter the gut microbiome, leading to the accumulation of intestinal T- MCA, thereby inhibiting intestinal FXR signaling and decreasing obesity (12).”
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“TβMCA inhibited the FXR signaling pathway in the presence of FXR agonists TCA and TCDCA (Li et al., 2013).”
Background
- Authors
- Li, F., Jiang, C., Krausz, K. W., Li, Y., Albert, I., Hao, H., Fabre, K. M., Mitchell, J. B., Patterson, A. D., & Gonzalez, F. J.
- Affiliations
- National Institutes of Health (US)
- Pennsylvania State University (US)
- Corresponding author
- Gonzalez, Frank J.
- ORCID
- Venue
- Nature Communications
- Published
- 2013-09-24
- Volume
- 4
- Issue
- 1
- Pages
- 2384-2384
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6595219
- OpenAlex
- W2065147071
- Cited by
- 705
- References
- 45
- Citations by year
- 2026: 34 · 2025: 55 · 2024: 50 · 2023: 62 · 2022: 76 · 2021: 73 · 2020: 74 · 2019: 41 · 2018: 61 · 2017: 64 · 2016: 48 · 2015: 41 · 2014: 25 · 2013: 1
- FWCI
- 17.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Pennsylvania Department of Health
- University of Pennsylvania
- Wake Forest University
- Pennsylvania State University
- National Institutes of Health
- National Cancer Institute (ZIABC005708, ZIABC005562)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- tempol, gut microbiota, farnesoid X receptor, obesity, bile salt hydrolase, Lactobacillus, bile acids, high-fat diet, anti-obesity drugs, antioxidants
- MeSH terms
- Receptor, Farnesoid X-Activated, Amidohydrolases, Animals, Antioxidants, Bacterial Proteins, Cyclic N-Oxides, Gene Expression Regulation, Glucose, Intestinal Absorption, Intestinal Mucosa, Intestines, Lactobacillus, Male, Obesity, Spin Labels, Taurocholic Acid, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Anti-Obesity Agents, Lipid Metabolism, Mice, Diet, High-Fat, Microbiota
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