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Polyphenol-Induced Improvements in Glucose Metabolism Are Associated Metabolism BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001386 on 7 August 2020. Downloaded from Open access Original research Polyphenol- induced improvements in glucose metabolism are associated with bile acid signaling to intestinal farnesoid X receptor Kevin M Tveter,1 Jose A Villa- Rodriguez ,1 Alrick J Cabales,1 Li Zhang,2 Fiona G Bawagan,1 Rocio M Duran,1 Diana E Roopchand 1 To cite: Tveter KM, ABSTRACT Villa- Rodriguez JA, Cabales AJ, Introduction Bile acid (BA) biotransformation by gut Significance of this study et al. Polyphenol- induced bacteria impacts BA profile and signaling to nuclear improvements in glucose receptors, such as the farnesoid X receptor (FXR) What is already known about this subject? metabolism are associated regulating glucose metabolism. Altered BA- FXR signaling ► Dietary polyphenols, such as proanthocyanidins, al- with bile acid signaling to ter the gut microbial community and are associated intestinal farnesoid X receptor. was therefore investigated as a potential mechanism linking polyphenol- induced gut bacterial changes and with improved metabolic resilience in humans and BMJ Open Diab Res Care mice. 2020;8:e001386. doi:10.1136/ improved glucose metabolism. Bile acids (BAs) signal to farnesoid X receptor (FXR), bmjdrc-2020-001386 Research design and methods Diabetic db/db were ► fed low-fa t diet (LFD) or LFD supplemented with a a nuclear transcription factor that regulates hepatic proanthocyanidin-rich extract of grape polyphenols (LFD- BA synthesis and glucose metabolism. ► Additional material is GP) for 4 weeks. Metabolic phenotypes, serum BAs, gut What are the new findings? published online only. To view microbiota composition, and gene expression markers ► Grape polyphenol (GP) supplementation decreased please visit the journal online relevant to gut barrier and glucose metabolism were (http:// dx. doi. org/ 10. 1136/ abundances of gut bacterial taxa associated with assessed. Gut organoids were used to investigate effects bmjdrc- 2020- 001386). secondary BA (SBA) production concomitant with of individual BAs on ileal FXR activity. depletion of SBAs and increased primary BAs (PBAs) Results Compared with LFD- fed controls, GP in murine serum. KMT and JAV- R contributed supplemented db/db mice showed improved glucose GP supplementation suppressed expression of FXR- equally. metabolism, decreased relative abundance of gut bacteria ► regulated genes Fgf15, Fabp6, and Shp, an inhib- associated with production of secondary BAs (SBAs), itor of PBA synthesis, which was consistent with Received 24 March 2020 and depleted serum levels of SBAs taurohyodeoxycholic Revised 2 June 2020 increased serum PBAs. acid (THDCA), ω-muricholic acid (ωMCA), and tauro- http://drc.bmj.com/ Accepted 22 June 2020 GP- induced FXR inhibition was associated with de- ω-muricholic acid (TωMCA). Serum levels of primary ► creased expression of genes required for biosynthe- BAs (PBAs) increased, consistent with higher gene sis of ceramides, which impair glucose homeostasis. expression of PBA synthesis enzyme Cyp7a1. GP- induced BA changes associated with FXR inhibition as evidenced ► The SBAs depleted in GP- treated mice were revealed by reduced expression of FXR- responsive genes Shp, as FXR agonists in ileal gut organoids. Fgf15, and Fabp6 in ileum tissue as well as hepatic Shp, How might these results change the focus of which negatively regulates PBA synthesis. GP treatment research or clinical practice? on September 25, 2021 by guest. Protected copyright. did not affect expression of hepatic Fxr or expression of © Author(s) (or their ► This study highlights BA-FXR signaling pathways as , , and genes controlling BA transport. employer(s)) 2020. Re- use Abcb11 Slc51b Obp2a an important mechanism for further investigation in permitted under CC BY-NC. No Ceramide biosynthesis genes Smpd3, Sptlc2, and Cers4 human intervention studies of dietary polyphenols commercial re- use. See rights were decreased in liver and intestine suggesting lower and metabolic health. and permissions. Published tissue ceramides levels may contribute to improved by BMJ. glucose metabolism. THDCA, ωMCA, and TωMCA behaved 1Food Science, Rutgers, The as FXR agonists in ileal organoid experiments; therefore, State University of New Jersey, their depletion in serum of GP-supplemented db/db and mice and humans.1–3 Improved glucose metab- New Brunswick, New Jersey, wild type (WT) mice was consistent with FXR inhibition. USA Conclusion These data suggest that by altering the gut olism in mice supplemented with berry/ 2Key Laboratory of Genomic microbiota, GPs modify BA- FXR signaling pathways to fruit extracts was related to a proanthocyan- and Precision Medicine, Beijing promote glucoregulation. Institute of Genomics, Chinese idin (PAC)-induced bloom of Akkermansia 1 2 4 Academy of Sciences, Beijing muciniphila, a microbe shown to attenuate Branch, Beijing, China symptoms of metabolic syndrome (MetS) INTRODUCTION and type-2 diabetes (T2D) in obese mice and Correspondence to 5 6 Dr Diana E Roopchand; Dietary polyphenols in plant- based foods humans. We hypothesized that metabolic roopchand@ sebs. rutgers. edu contribute to improved glycemic control in improvements also result from changes in BMJ Open Diab Res Care 2020;8:e001386. doi:10.1136/bmjdrc-2020-001386 1 BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001386 on 7 August 2020. Downloaded from Metabolism host- derived bacterial metabolites regulating host energy for acclimation. Mice were randomized to receive LFD metabolism. (n=7) or LFD- GP (n=7) for 28 days. Metabolic phenotyping Bile acids (BAs) are signaling molecules linking the gut included food intake, body weight, body composition microbiota to host energy metabolism. Primary BAs (PBAs) (EchoMRI 3- in-1 system; Echo Medical Systems, Houston, synthesized in the liver are conjugated with taurine (mice) Texas, USA), and oral glucose tolerance tests, as previously 7 1 4 or glycine (humans). Bacterial- derived bile salt hydro- described. On day 29, mice were euthanized by CO2 lases deconjugate taurine or glycine from the sterol core inhalation, followed by cardiac puncture and collection of of PBAs followed by bacterial transformations, such as 7 tissues, as previously described.1 4 Fecal and cecal samples α/β-dehydroxylation, dehydrogenation, and epimeriza- were collected for microbial community profiling. Wild tion, which generate secondary BAs (SBAs).7 PBAs and type C57BL/6J mice (n=10) aged 5 weeks were acclimated SBAs signal to key regulators of energy metabolism, such on LFD for 1 week and randomly divided into two groups as nuclear transcription factor farnesoid X receptor (FXR) and fed HFD or HFD- GP (n=5 per group) for 10 weeks 7 −/− and Takeda G protein- coupled receptor 5 (TGR5). Fxr after which mice were euthanized by CO2 inhalation. mice were protected from high-fat diet (HFD)-induced obesity and had altered BA and gut microbiota (higher Tissue gene expression analysis Bacteroidetes, less Firmicutes) profiles compared with RNA was extracted from ileum, jejunum, colon, and liver wild type (WT) mice.8 Transfer of cecal microbiota from (30–60 mg) with RNeasy Plus Universal Mini Kit (QIAGEN) HFD- fed Fxr−/− mice to germ free WT mice resulted in less followed by RNA cleanup (Machery- Nagel, RNA purifi- adiposity and improved glucose metabolism compared cation kit). RNA (5 µg) was reverse transcribed to cDNA with mice that received microbiota from HFD- fed WT and qPCR was performed using TaqMan primers (online 4 mice, suggesting the altered gut microbial and BA profiles supplementary table 4) as previously described. Data were -ΔCT in FXR deficient mice contributed to metabolic improve- analyzed using 2 method using hydroxymethylbilane ments.8 Studies using tissue-specific FXR knockout mice synthase (HMBS) as housekeeping gene. showed that intestinal FXR activity was required to mediate qPCR of A. muciniphila in fecal and cecal samples was 1 4 HFD- induced metabolic dysfunctions.9 10 Pharmacolog- performed as previously described. Briefly, gDNA ical inhibition of intestinal FXR using tempol, antibiotics, extracted from fecal/cecal samples was diluted to 2.5 ng/ metformin, or glycine-β-muricholic acid (Gly-MCA) led to µL for quantification of A. muciniphila abundance relative gut microbial remodeling and improved glucose and lipid to total bacteria and archaea by qPCR using A. muciniphila 1 4 homeostasis.9–12 (AM1, AM2) and universal primer (U341F, U515R) sets. In addition to the A. muciniphila bloom, mice fed HFD- 16S rRNA gene sequencing supplemented with PAC- rich grape polyphenols (GPs) Genomic DNA was extracted from 84 fecal and 14 cecal showed other profound bacterial community changes samples collected from db/db mice. Illumina protocols were raising the possibility that altered BA profile and signaling used to prepare V4 amplicons of the 16S rRNA gene for could contribute to observed improvement in glucose sequencing on a MiSeq system, resulting in >1.099×107 homeostasis.1 4 The present study provides compelling reads. Denoising and clustering were conducted using http://drc.bmj.com/ evidence in support of this hypothesis. DADA2 algorithm to differentiate sequences into amplicon sequence variants (ASVs) for downstream analysis using QIIME 2.0.14 15 Details are available in online supplemen- RESEARCH DESIGN AND METHODS tary materials. Diets A complex of 10% grape polyphenols and soy protein isolate Serum biochemistry 1 4 13 on September 25, 2021 by guest. Protected copyright. (GP-SPI) was
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