Research Shows Promise to Alleviate Gut Health Issues Caused by a High-Sugar Diet

Consuming too much added sugar can increase the risk of chronic diseases such as Type 2 diabetes, heart disease, obesity, non-alcoholic fatty liver disease, high blood pressure, and some cancers, according to scientific research.

Now newly published research shows that a key regulatory enzyme inhibitor discovered in the laboratory of UC Davis distinguished professor Bruce Hammock can alleviate inflammation linked to health issues that are caused by a high-sugar diet.

The research paper, “Metabolomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for  High-Sucrose Diet-Mediated Gut Barrier Dysfunction,” appears in the current edition of Proceedings of the National Academy of Sciences. A 14-member international research team, including Hammock, authored the paper.

Lead author Jun-Yan Liu, a professor at Chongqing Medical University, China, and a former research scientist (7.5 years) in the Hammock lab, said a soluble epoxide hydrolase (sEH) inhibitor alleviated a gut barrier dysfunction caused by high-sucrose diet in a murine (mouse) model and shows promise in humans.

“Our research showed that a 16-week high sucrose diet in a murine model showed colon inflammation and a tight junction impairment,” said Liu, who specializes in  metabolomics, bio-analytical chemistry, molecular pharmacology, and natural medicinal chemistry.  “When we treated the mice with a chemical inhibitor of sEH, that reduced the colon inflammation and improved the tight junction impairment. That was further supported by the conditional knockout of sEH in intestinal epithelia.” 

Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, explained that “Such gut barrier dysfunctions allow microorganisms and deleterious inflammatory materials to cross the gut wall, leading to the increased risk of a variety of diseases and particularly those associated with intestinal disease.”

 “We know that a high-sugar diet can lead to multiple serious health problems, and can be a silent killer,” Hammock said. “We also know that underlying mechanisms and therapeutic strategies to alleviate the results of a high-sucrose diet remain largely unknown.  Our research shows that this inhibitor alleviates inflammation and is not acting as an anti-inflammatory compound.”

Hammock praised Liu for his work. “When Dr. Jun-Yan Liu was a postgraduate in my laboratory, he made many of the fundamental discoveries on how metabolites of polyunsaturated fatty acids regulate biology and how the soluble epoxide hydrolase inhibitors developed here can reduce inflammation and pain by altering this pathway.  His studies bring up that excessive amounts of the common dietary sugar sucrose can in fact increase deleterious inflammation in rodent models and that inflammation can be at least partly resolved by an inhibitor of the soluble epoxide hydrolase now in human clinical trials.  These data suggest that a lifestyle change or pharmaceutical could reduce this chronic inflammation problem associated with high sucrose consumption but also may provide a mechanism leading to its cause.”

Other co-authors include UC Davis organic chemist Sung Hee Hwang of the Hammock lab; and Liu’s colleagues, Zhi Lin, Xian Fu, Qing Jiang, Xue Zhou, Hou-Hua Yin, Kai-I Ni, Qing-Jin Pan, Xin He, Ling-Tong Zhang, Yi-Weng Meng and Ya-Nan Lia. The team thanked biochemist Christophe Morisseau, a research scientist in the Hammock lab for reviewing the research paper. 

Gastrointestinal pathologist  Guang-Yu Yang, a professor and physician at Feinberg School of Medicine,  Northwest University,  characterized the research as “a comprehensive experimental study on testing the effect of a high sucrose diet on inducing inflammatory damage and their related mechanisms, particularly focusing on sEH.” 

“Sugar consumption is not just associated with obesity and diabetes in humans –it is also associated with irritable bowel syndrome, inflammatory bowel disease, and autoimmune disease,” said  Robert Lustig, emeritus professor of pediatric endocrinology at the University of California, San Francisco, who specialized in neuroendocrinology and childhood obesity. “This paper (through rodent research) provides a window into causation. Sucrose consumption altered an intestinal enzyme system which led to gut inflammation, while removing the offending enzyme obviates the damage. This goes a long way in explaining why ultra-processed foods in general, and sugar in specific, is toxic to human health and provides a potential target for future therapeutics.”

Nutrition researcher Guodong Zhang, a member of the UC Davis Department of Nutrition faculty, and a former postdoctoral fellow in the Hammock lab with Liu, commented that the study “suggests that soluble epoxide hydrolase (sEH) plays an important role in regulating intestinal barrier functions. However, the molecular mechanisms leading to intestinal barrier dysfunction remain poorly understood, and there are few available therapeutic approaches to target barrier functions.”

 “I am so pleased that this pair of scientists (Zhang and Liu) are following how diet controls both the initiation and resolution of inflammation to improve human health,” Hammock commented.

“Human translation of this research could be rapid because the sEH inhibitors are currently being evaluated in human clinical trials for other disorders,” said Zhang, referring to EicOsis, a Davis-based clinical startup that Hammock co-founded in 2011 to alleviate chronic pain without the use of opioids. Its drug candidate, EC5026, has successfully completed Phase 1 human clinical trials, with no side effects.

Said Cindy McReynolds, CEO and co-founder of EicOsis: “The important work identified in this paper indicates potential future therapeutic targets for sEH inhibitors.” 

Liu and his team will next “investigate if blood and tissue levels of sEH and particularly the inflammation-resolving metabolites regulated by the sEH or its metabolites could be markers for HSD-mediated colon injury. If so, we will benefit from routine lab blood tests to get timely alerts on HSD-caused colon issues. Our research sheds light on the importance of dietary changes and/or intervention.”

Hammock, a member of the UC Davis faculty since 1980, and a fellow of the National Academy of Inventors and the U.S. National Academy of Sciences, has studied  sEH inhibitors for 50 years in research leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer’s disease, and cancer. Tracing the history of his enzyme research to his graduate student studies in the John Casida laboratory at UC Berkeley, he related that he colleague Sarjeet Gill, now a distinguished professor emeritus at UC Riverside, were  researching insect developmental biology and green insecticides when they co-discovered the target enzyme in mammals that regulates epoxy fatty acids.  “We were researching juvenile hormones, and how a caterpillar turns into a butterfly,” Hammock said. 

Scientists agree that obesity is a worldwide challenge, and it continues to be a complex and costly chronic disease. Research nutritionist Susan Raatz, with the USDA’s Agricultural Research Service at the Grand Forks Human Nutrition Research Center, expresses alarm about Americans’ sugar intake and the health risks.  “The average American eats (or drinks) 34 teaspoons of sugars a day, which is equal to 500-plus calories,” she recently wrote in a USDA publication. “This averages more than 100 pounds of sugars per person each year.  Sugar intake has drastically increased over the last century.  In 1822, the average American ate in 5 days the amount of sugar found in one of today’s 12-ounce sodas. Now, we eat that much every 7 hours!” (See https://tinyurl.com/4cmyamez) 

More than 70 percent of Americans are overweight, and 40 percent are obese, according to the Centers for Disease Control and Prevention, using the body mass index (BMI), a medical screening tool that measures the ratio of one’s height to weight. Worldwide, the country with the highest obesity rate is Tonga with 70.53 percent of adults obese, according to 2024 statistics from the World Health Organization. Nauru, Tuvalu, Samoa, and The Bahamas also rank in the top five.   

The research received financial support from five grants: the National Key Research and Development Program of China; the National Natural Science Foundation of China; two grants to Hammock from National Institutes of Health’s National Institute of Environmental Health Sciences (NIEHS);  and a NIEHS Superfund Grant. Hammock directed the NIEHS-UC Davis Superfund Research Program for nearly four decades.