title: Pomegranate ellagitannins stimulate the growth of Akkermansia muciniphila in vivo.
abstract: Results from our previous human pomegranate extract (POM extract) intervention study demonstrated that about seventy percent of participants were able to form urolithin A from ellagitannins in the intestine (urolithin A producers). Urolithin A formation was associated with a high proportion of Akkermansia muciniphila in fecal bacterial samples as determined by 16S rRNA sequencing. Here we investigated whether A. muciniphila counts increased in stool samples collected after the POM extract intervention compared to baseline stool samples using real-time PCR. In addition, we performed in vitro culture studies to determine the effect of POM extract and ellagic acid on the growth of A. muciniphila and to analyze ellagic acid metabolites formed in the culture broth by high-performance liquid chromatography. Supplementation of culture broth with 10 μM of ellagic acid did not change A. muciniphila growth while the addition of 0.18 mg/ml and 0.28 mg/ml of POM extract to the culture broth inhibited the growth of A. muciniphila significantly. Incubation of A. muciniphila with POM extract resulted in formation of ellagic acid and incubation of A. muciniphila with ellagic acid demonstrated hydrolysis of ellagic acid to metabolites different from urolithin A. The in vitro culture studies with A. muciniphila partially explain our in vivo findings that the presence of A. muciniphila was associated with breakdown of ellagic acid for further metabolism by other members of the microbiota. This is the first report of the role of A. muciniphila in ellagitannin hydrolysis. However, we conclude that enzymes from other bacteria must be involved in the formation of urolithin A in the human intestine.
authors.affiliation: Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Henning
authors.affiliation: VA Medical Center West Los Angeles, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA. Electronic address: carlsonph@aol.com.
authors.forename: Paula H
authors.initials: PH
authors.lastname: Summanen
authors.affiliation: Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ru-Po
authors.initials: RP
authors.lastname: Lee
authors.affiliation: Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jieping
authors.initials: J
authors.lastname: Yang
authors.affiliation: VA Medical Center West Los Angeles, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, CA 90095, USA; Department of Medicine, University of California Los Angeles, CA 90095, USA.
authors.forename: Sydney M
authors.initials: SM
authors.lastname: Finegold
authors.affiliation: Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Heber
authors.affiliation: Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; VA Medical Center West Los Angeles, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA; Department of Medicine, University of California Los Angeles, CA 90095, USA.
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Li
mesh_terms: D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development; D002851:Chromatography, High Pressure Liquid; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004275:DNA, Ribosomal / Q000737:chemistry / Q000235:genetics; D004610:Ellagic Acid / Q000378:metabolism / Q000494:pharmacology*; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome; D006801:Humans; D047348:Hydrolyzable Tannins / Q000378:metabolism / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D029561:Lythraceae / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D056692:Prebiotics; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D047348:Hydrolyzable Tannins; D010936:Plant Extracts; D056692:Prebiotics; D012336:RNA, Ribosomal, 16S; C013515:ellagitannin; D004610:Ellagic Acid
keywords: Akkermansia muciniphila; Ellagic acid; Ellagitannins; Intestinal bacteria; Pomegranate extract; Prebiotic; Urolithin A