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Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health.

ABSTRACT: We previously showed that C57BL/6J mice fed high-fat diet (HFD) supplemented with 1% grape polyphenols (GP) for 12 weeks developed a bloom of Akkermansia muciniphila with attenuated metabolic syndrome symptoms. Here we investigated early timing of GP-induced effects and the responsible class of grape polyphenols. Mice were fed HFD, low-fat diet (LFD) or formulations supplemented with GP (HFD-GP, LFD-GP) for 14 days. Mice fed HFD-GP, but not LFD-GP, showed improved oral glucose tolerance compared to controls. A. muciniphila bloom occurred earlier in mice fed LFD-GP than HFD-GP; however, timing was dependent on baseline A. muciniphila levels rather than dietary fat. Mice gavaged for 10 days with GP extract (GPE) or grape proanthocyanidins (PACs), each delivering 360 mg PACs/kg body weight, induced a bloom of fecal and cecal A. muciniphila, the rate of which depended on initial A. muciniphila abundance. Grape PACs were sufficient to induce a bloom of A. muciniphila independent of specific intestinal gene expression changes. Gut microbial community analysis and in vitro inhibition of A. muciniphila by GPE or PACs suggest that the A. muciniphila bloom in vivo occurs via indirect mechanisms.

SUBMITTER: Zhang L

PROVIDER: S-EPMC5971143 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health.

Zhang Li L Carmody Rachel N RN Kalariya Hetal M HM Duran Rocio M RM Moskal Kristin K Poulev Alexander A Kuhn Peter P Tveter Kevin M KM Turnbaugh Peter J PJ Raskin Ilya I Roopchand Diana E DE

The Journal of nutritional biochemistry 20180215

We previously showed that C57BL/6J mice fed high-fat diet (HFD) supplemented with 1% grape polyphenols (GP) for 12 weeks developed a bloom of Akkermansia muciniphila with attenuated metabolic syndrome symptoms. Here we investigated early timing of GP-induced effects and the responsible class of grape polyphenols. Mice were fed HFD, low-fat diet (LFD) or formulations supplemented with GP (HFD-GP, LFD-GP) for 14 days. Mice fed HFD-GP, but not LFD-GP, showed improved oral glucose tolerance compared ...[more]

PMID: 29571008

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Project description:Traumatic brain injury (TBI) initiates not only complex neurovascular and glial changes within the brain but also pathophysiological responses that extend beyond the central nervous system. The peripheral response to TBI has become an intensive area of research, as these systemic perturbations can induce dysfunction in multiple organ systems. As there are no approved therapeutics for TBI, it is imperative that we investigate the peripheral response to TBI to identify targets for future intervention. Of particular interest is the gastrointestinal (GI) system. Even in the absence of polytrauma, brain-injured individuals are at increased risk of suffering from GI-related morbidity and mortality. Symptoms such as intestinal dysmotility, inflammation, ulceration, and fecal incontinence can drastically diminish quality of life. The GI tract is inhabited by trillions of microbes that have been implicated as modulators of many neurological disorders. Clinical and preclinical studies implicate gut dysbiosis, a pathological imbalance in the normally symbiotic microbiota, as both a consequence of TBI as well as a contributing factor to brain damage. However, our understanding of this interplay is still limited. While relatively little is known about the effects of TBI on the structure and function of the GI tract, prior studies report that experimental TBI induces intestinal barrier dysfunction and morphological changes. To confirm these findings in the current model of TBI, male C57BL/6J mice underwent a sham control or a controlled cortical impact (CCI) procedure to induce a contusive brain injury, and intestinal permeability was assessed at 4 h, 8 h, 1 d, and 3 d post-injury. An acute, transient increase in permeability was observed at 4 h after CCI. Histological analyses of the ileum and colon at multiple time points from 4 h to 4 wks revealed no overt morphological changes, suggesting that CCI induced a short-lived physiologic dysfunction without major structural alterations to the GI tract. As the microbiome is a modulator of GI physiology, we performed 16s gene sequencing on fecal samples collected prior to and over the first month after CCI or sham injury. Microbial community diversity was assessed using common metrics of alpha and beta diversity. Alpha diversity was lower in the CCI injury group and beta diversity differed among groups, although these effects were not observed in all metrics. Subsequent differential abundance analysis revealed that the phylum Verrucamicrobiota was increased in CCI mice at 1, 2, and 3 d post-injury when compared to sham mice. Subsequent qPCR identified the Verrucamicrobiota species as Akkermansia Muciniphila, an obligate anaerobe that resides in and helps regulate the intestinal mucus layer and barrier. To determine whether TBI promotes changes to the GI tract favorable for the proliferation of A. muciniphila, mucus-producing goblet cells and the level of GI hypoxia were evaluated. Goblet cell density in the medial colon was significantly increased at 1 d, while colon hypoxia was significantly increased at 3 d. Taken together, these studies show that CCI induces transient intestinal barrier dysfunction followed by increased goblet cell density and hypoxia in the colon with a concomitant increase in A. muciniphila that may suggest a compensatory response to systemic stress after TBI.

Project description:ObjectivePolyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown.MethodsHigh-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice.ResultsThe administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis.ConclusionsOur study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.

Project description:A healthy gastrointestinal tract functions as a highly selective barrier, allowing the absorption of nutrients and metabolites while preventing gut bacteria and other xenobiotic compounds from entering host circulation and tissues. The intestinal epithelium and intestinal mucus provide a physical first line of defense against resident microbes, pathogens and xenotoxic compounds. Prior studies have indicated that the gut microbe Akkermansia muciniphila, a mucin-metabolizer, can stimulate intestinal mucin thickness to improve gut barrier integrity. Grape polyphenol (GP) extracts rich in B-type proanthocyanidin (PAC) compounds have been found to increase the relative abundance of A. muciniphila, suggesting that PACs alter the gut microbiota to support a healthy gut barrier. To further investigate the effect of GPs on the gut barrier and A. muciniphila, male C57BL/6 mice were fed a high-fat diet (HFD) or low-fat diet (LFD) with or without 1% GPs (HFD-GP, LFD-GP) for 12 weeks. Compared to the mice fed unsupplemented diets, GP-supplemented mice showed increased relative abundance of fecal and cecal A. muciniphila, a reduction in total bacteria, a diminished colon mucus layer and increased fecal mucus content. GP supplementation also reduced the presence of goblet cells regardless of dietary fat. Compared to the HFD group, ileal gene expression of lipopolysaccharide (LPS)-binding protein (Lbp), an acute-phase protein that promotes pro-inflammatory cytokine expression, was reduced in the HFD-GP group, suggesting reduced LPS in circulation. Despite depletion of the colonic mucus layer, markers of inflammation (Ifng, Il1b, Tnfa, and Nos2) were similar among the four groups, with the exception that ileal Il6 mRNA levels were lower in the LFD-GP group compared to the LFD group. Our findings suggest that the GP-induced increase in A. muciniphila promotes redistribution of the intestinal mucus layer to the intestinal lumen, and that the GP-induced decrease in total bacteria results in a less inflammatory intestinal milieu.

Dataset Information

Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health.

Publications

Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health.

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