Gut enterotype-dependent modulation of gut microbiota and their metabolism in response to xanthohumol supplementation in healthy adults

ABSTRACT

Xanthohumol (XN), a polyphenol found in the hop plant (Humulus lupulus), has antioxidant, anti-inflammatory, prebiotic, and anti-hyperlipidemic activity. Preclinical evidence suggests the gut microbiome is essential in mediating these bioactivities; however, relatively little is known about XN’s impact on human gut microbiota in vivo. We conducted a randomized, triple-blinded, placebo-controlled clinical trial (ClinicalTrials.gov NCT03735420) to determine safety and tolerability of XN in healthy adults. Thirty healthy participants were randomized to 24 mg/day XN or placebo for 8 weeks. As secondary outcomes, quantification of bacterial metabolites and 16S rRNA gene sequencing were utilized to explore the relationships between XN supplementation, gut microbiota, and biomarkers of gut health. Although XN did not significantly change gut microbiota composition, it did re-shape individual taxa in an enterotype-dependent manner. High levels of inter-individual variation in metabolic profiles and bioavailability of XN metabolites were observed. Moreover, reductions in microbiota-derived bile acid metabolism were observed, which were specific to Prevotella and Ruminococcus enterotypes. These results suggest interactions between XN and gut microbiota in healthy adults are highly inter-individualized and potentially indicate that XN elicits effects on gut health in an enterotype-dependent manner.

Keywords:

• Gut microbiota
• enterotypes
• phytochemical
• polyphenol
• microbial metabolism
• precision medicine

Acknowledgments

The authors would like to thank Gabriella Brown, as well as Jeff Morre and Liping Yang with the OSU Mass Spectrometry Center for their technical support and contributions to running experiments. The authors would also like to thank The Marion T. Tsefalas and Caron & Donald Reed Graduate Fellowship from the Linus Pauling Institute and The Center for Healthy Aging Research LIFE Scholars Summer Research Program for financial support.

Disclosure statement

The authors have no conflicts of interest to disclose.

Author contributions

Conceptualization, T.J.S., T.O.M., R.B., J.F.S.; Methodology, P.E.J., J.A.B., J.C., R.E.D., C.P.W., I.L.P., T.J.S., R.B., J.F.S.; Software, P.E.J.; Validation, P.E.J., J.C., C.P.W.; Formal analysis, P.E.J.; Investigation, P.E.J., E.B.S., J.C., C.P.W., I.L.P.; Resources, R.E.D., T.J.S., T.O.M., R.B., J.F.S.; Data Curation, P.E.J., T.J.S., R.B.; Writing – Original Draft, P.E.J.; Writing – Review & Editing, P.E.J, E.B.S., J.A.B, J.C., R.E.D., C.P.W., I.L.P., C.M., E.H., T.J.S., T.O.M., R.B., J.F.S.; Visualization, P.E.J.; Supervision, R.B., T.O.M., J.F.S.; Project administration, P.E.J., R.B., T.O.M., J.F.S.; Funding Acquisition, R.B., T.O.M., J.F.S. All authors have read and agreed to the published version of the manuscript.

Data availability statement

R code is available at github: https://github.com/jamiesop/Jamieson_XN_Microbiome. The targeted LC-MS/MS data obtained in this study has been submitted to the NIH Common Fund’s NMDR (supported by NIH grant, U01-DK097430) website, the Metabolomics Workbench, under study ID’s ST002941 (XN metabolites), ST002942 (short-chain fatty acids), and ST002943 (bile acids). The remaining individual participant data will be available from the corresponding author upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2315633

Additional information

Funding

This work was supported by the National Institutes of Health under Grants [R01AT010271, S10RR022589, S10OD026922].