Researchers uncover noncanonical clock regulators impact digestive diseases

The digestive system’s rhythms are controlled by body clock genes, as well as lesser-known regulators called noncanonical clock regulators. Researchers at Baylor College of Medicine aimed to understand how these additional regulators influence the way digestive organs handle stress. Their comprehensive review was published in Trends in Endocrinology and Metabolism.

Common habits such as shift work, jet lag or irregular mealtimes can throw off natural rhythms and trigger stress responses in the organs, leading to digestive disorders.

“By focusing on these overlooked clock factors, the paper integrates new findings into the bigger circadian (daily rhythm) picture and highlights how timing-based strategies, like eating or taking medicine at specific times of day (known as chronotherapy) might help keep our digestive health on track,” said Dr. Dongyin Guan, assistant professor of medicine-endocrinology at Baylor and author of the paper.

Chronic disruption of the natural daily rhythm has been linked to digestive problems, such as fatty liver disease, inflammatory bowel conditions and metabolic issues like diabetes. Maintaining regular habits like consistent mealtimes and sleep schedules is crucial for gut health.

The research team gathered results from previous studies on various stress conditions, such as a high-fat diet, changes in mealtime, exercise and aging, and how these factors can reshape the rhythmic patterns of genes and metabolism in digestive organs.

“By piecing together data from all these studies, we built and updated how these noncanonical clock regulators work alongside the core clock,” said Dishu Zhou, research assistant in the Dongyin Guan Lab at Baylor and corresponding author of the paper.

They noted that the biological clock is resilient and has built-in backups. Even when core clock genes (the usual master timekeepers) were disabled in lab experiments, most rhythmic genes still maintained their 24-hour cycles, implying that other players step in to keep time when the main clock falters. The noncanonical clock regulators connect the body’s timing system to various stress response pathways in the cells. The paper reveals that there is a whole network of other factors keeping time in the digestive organs. These factors kick in under stress or unusual conditions, ensuring that essential daily cycles stay in sync when lifestyle or environment tries to disrupt them.

The findings hint at new ways to treat or prevent digestive diseases. If the additional clock regulators are crucial in specific organs, they become active targets for new therapies. The review also reinforces that when people eat, sleep or take medicine could be as important as what food or medicine is consumed. Approaches like chrononutrition (eating at the right times of day) and chronopharmacology (taking medications at the optimal time) are simple, cost-effective ways to reduce stress on the digestive system.

“Doctors might be able to use these insights to advise patients on aligning meals and medication schedules with their natural body clocks,” Guan said. “Given how common circadian disruptions are, this timing-focused approach could become a powerful tool to boost digestive health and overall well-being.”

Future research will dive into questions such as, do differences in people’s genes or lifestyles change how these clock regulators work? Could a person’s unique genetic makeup affect their internal clock, making them more susceptible to digestive issues? The researchers also plan to develop tools (wearable sensors or advanced blood tests) to monitor a person’s internal clock in real time, which could allow providers to tailor nutrition plans or drug timing for individuals based on their own rhythm.

“The research is moving toward personalized medicine. By understanding each person’s internal clock, we can customize treatments and daily schedules to keep their digestive system and overall health in sync,” Guan said.

This is the first comprehensive review bringing together noncanonical clock regulators with digestive disease stress responses.

“By respecting that natural cycle, whether through smarter scheduling of eating and taking medicine or simply getting good sleep, we could vastly improve our digestive health and quality of life,” Guan said.

Other contributors to this work include Roberto E López-Valiente and Samer G. Mattar.

This work was supported by CPRIT Scholar in Cancer Research (RR210029), V Foundation (V2022-026), and NIH R37CA296577, DK056338, P30-CA125123, TRISH NNX16AO69A and H-NORC to D.G.