Rhythmic microbiome in the small intestine prevents obesity and type 2 diabetes

There are an estimated 500 to 1,000 bacterial species in each person’s gut, perhaps 100,000 trillion microorganisms. In a new article, published on July 5, 2022 in Mobile ReportsResearchers at the University of California San Diego School of Medicine used mouse models to examine how diet and feeding patterns affect these gut microbes — and the health of the hosts, particularly in obesity and type 2 diabetes.

In both mice and men, the ileum is the last part of the small intestine, which connects to the cecum, the first part of the large intestine. In the ileum, nutrients are taken from liquid food; in the cecum, which also marks the beginning of the large intestine, the process of extracting water begins.

Both processes are complex, dynamic and heavily influenced by factors ranging from the type of food consumed and when, to the microbial inhabitants of the gut, whose presence and behavior help dictate digestion, nutrient absorption, vitamin synthesis and immune system development.

“It’s important to realize that the gut microbiome is constantly changing, not just based on what we eat, but also based on the time of day,” said senior study author Amir Zarrinpar, MD, PhD, assistant professor of medicine at the UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health.

“Most researchers get snapshots of this constantly changing environment, which makes it difficult to understand what’s happening in the gut. With this study, we’re trying to take multiple snapshots throughout the day, almost like a movie, to better understand how food and the microbiome interact to influence weight gain and diabetes.

“And what we’ve learned is that cyclical changes in the gut microbiome are very important for health, because they help with the circadian clock, and thus the regulation and control of glucose, cholesterol and fatty acids — and overall metabolic health.”

In their latest work, Zarrinpar and colleagues further elucidate the impact and interplay of these factors, particularly in terms of the ileum and its unique functions related to digestion and absorption. In particular, they looked at how diet-induced obesity (DIO) and time-restricted nutrition (TRF) alter the composition of the ileal microbiome and transcriptome (the protein-coding part of an organism’s genome) in mouse models.

The researchers found that DIO and the absence of TRF (mice could eat as much as they wanted when they wanted) in mouse models resulted in disruptions in the gut microbiome rhythms and the signaling pathways that help modulate gut clocks. In other words, the mice became fat and unhealthy.

“Interestingly, restricting food access with TRF works not only by restoring patterns compromised by the unhealthy state, but also by opening new avenues,” said first author Ana Carolina Dantas Machado, PhD, a postdoctoral scientist in Zarrinpar’s lab.

“These findings underscore the influence of diet and time-restricted dietary patterns in maintaining a healthy gut microbiome, which in turn modulates the circadian rhythms that determine metabolic health,” Zarrinpar said. “It’s a very complicated relationship between the microbiome and the host, with the former helping to determine the gastrointestinal function and health of the latter.”

Their work, the authors said, could inform future studies, particularly examining how the gut works or how drugs affect gut function, depending on the state of the microbiome at a particular time or time of day.

Co-authors include: Steven D. Brown, Amulya Lingaraju, Vignesh Sivaganesh, Cameron Martino, Peng Zhao, Antonio FM Pinto, Max W. Chang, R. Alexander Richter Alan R. Saltiel, Rob Knight and Satchidananda Panda, all at UC San Diego; Amandine Chaix, University of Utah; and Alan Saghatelian, Salk Institute for Biological Studies.

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