Linus Pauling Institute

Collaborative Study Investigates Inflammatory Bowel Disease Therapies

The National Institutes of Health, through the National Center for Complementary and Integrative Health (NCCIH), awarded $1.6 million to the Linus Pauling Institute at Oregon State University (OSU); the Helfgott Research Institute at the National University of Natural Medicine (NUNM); and the Pacific Northwest National Laboratory (PNNL), a U.S. Department of Energy research laboratory in Richland, Washington, for a collaborative integrative clinical research study investigating the potential of a diet-derived therapeutic to target inflammatory bowel disease (IBD) and the microbial imbalance contributing to the inflammation in IBD.

The NCCIH four-year R01 research project aims to understand how a compound called xanthohumol, from the flowers of the hop plant (Humulus lupulus), may reduce the severity of inflammation in IBD. Hops, more commonly associated as a flavoring ingredient in beer, are also used in botanical medicine.

IBD is increasing worldwide and has become a global emergence disease, most prevalent in developing countries. It includes Crohn’s disease and ulcerative colitis.[1] According to the Centers for Disease Control and Prevention (CDC), an estimated three million people (1.3% of U.S. adults) were diagnosed with IBD in 2015, a large increase from 1999.[2] This increase is especially notable because IBD increases risks of colorectal cancer. IBD is also affecting more and more children, and between 2000 and 2009 the number of children hospitalized due to IBD grew by 64%[3].

Current therapies for IBD are very limited and often include steroids and other anti-inflammatories that have systemic side effects. These limitations underscore the need for new therapeutic modalities that both target the inflamed gut and the microbial imbalance causing the inflammation.

LPI Principal Investigator and Project Lead Fred Stevens, Ph.D., has studied the chemistry and biological activity of xanthohumol and related hop compounds since 1995. In preclinical studies conducted in the Stevens, Gombart, and Maier labs at LPI and OSU, xanthohumol appears to improve obesity-related dysfunctional glucose- and lipid metabolism. Ongoing and published investigations into the compound’s mechanism of action have identified the farnesoid X receptor (FXR) as a molecular target of xanthohumol. FXR is a master regulator of cholesterol metabolism and the synthesis of glucose and fatty acids in the liver.

Besides acting as an FXR modulator, xanthohumol reduces inflammation in various preclinical models of disease and it alters the gut microbiota composition in obese mice. The combined findings gave Dr. Stevens the idea to study the effects of xanthohumol in Crohn’s Disease, because microbial imbalance-driven chronic inflammation of the gut’s ileum, where FXR is highly expressed, exacerbates the disease.

The investigators’ preliminary studies show that mouse and human gut microbiota extensively metabolize xanthohumol. Overall, there is strong support for a mitigating impact of xanthohumol (and its gut microbiota-derived metabolites) on gut inflammation. The researchers hypothesize that they can identify a biological signature of xanthohumol and observe a reliable effect on inflammation in Crohn’s disease.  

LPI/OSU investigators Stevens, Maier, Ho, Sharpton, Gombart, and Bobe are focusing on the metabolic, biochemical, and gut microbial aspects of the project. They are collaborating with Dr. Bradley’s team of investigators at the NUNM who are leading the clinical trials with healthy volunteers and Crohn’s Disease patients. Dr. Metz’s team at PNNL will be studying how xanthohumol interacts with the gut microbiome’s proteins by using an activity-based proteomics approach. The PNNL team will also assemble and annotate metagenomes (the microbial genetic material in the sample), and integrate the data to obtain a functional understanding of the role of xanthohumol and its metabolites in ameliorating gut inflammation.

Dr. Stevens partners with Hopsteiner Inc., New York NY, and Metagenics Inc., Gig Harbor WA, for the development of a nutraceutical formulation of xanthohumol and for quality control of the xanthohumol-containing test product.