The discovery: Mice born without colonic enteroendocrine cells develop unique microbiota that spark increased food intake
Obesity research and treatments are expanding rapidly, but we still have much to learn about the many overlapping factors that regulate appetite and eating. A recent study in mice clarifies some of these factors by showing that gut microbiota can lead to changes in the large intestine that inspire the host to eat more food.
Researchers at Children’s Medical Center Dallas, part of Children’s Health℠, and UT Southwestern studied mice that were genetically altered to have no enteroendocrine cells (EECs) in the colon. The mice showed signs of obesity at nine weeks, prompting a series of experiments that revealed a complex chain reaction: The lack of colonic EECs affected which bacteria were present and also how they behaved, signaling the body to increase production of glutamate, which in turn increased appetite and food intake.
“Our findings lay the groundwork for new inquiries into how the gut-brain axis functions and new possibilities for helping severely under- and overweight patients regulate their weight and avoid harmful health complications,” says Luis Sifuentes, M.D., Pediatric Gastroenterologist at Children’s Health and Assistant Professor at UT Southwestern.
Background: The function of colonic EECs was previously unknown
In the small intestine, EECs sense nutrients and secrete hormones to support digestion and absorption. But few beneficial nutrients make it to the large intestine, so the role of EECs in the colon has long been a mystery.
To investigate, Dr. Sifuentes and the research team genetically engineered a group of mice to be born without colonic EECs – and compared them against a group of normal mice. “The obesity finding was a complete surprise, and it took us several experiments to find the cause,” Dr. Sifuentes says.
Why did non-EEC mice become obese?
Ruling out hormones
Hormones were a logical place to start, since they are actively involved in appetite and digestion and certain EECs are known to secrete them. However:
Previous studies had already demonstrated that mice don’t gain weight when they are missing the specific EECs that produce GLP-1 and GLP-2.
The UT Southwestern team proved the same is true for the other hormone produced in the colon, Peptide YY. They developed a group of mice that didn’t produce this hormone, and the mice had normal appetite and weight gain.
“To become obese, the mice had to lack all colonic EECs, not just those responsible for producing PYY or GLP-1,” Dr. Sifuentes explains.
Landing on microbiota
The breakthrough came when the team caged mutant and normal mice together. Mice eat each other’s stool, so mice that share a cage also share the same gut bacteria.
In the shared cages, no mice developed obesity. The genetically engineered mice ate their normal cagemates’ stool, acquired their gut bacteria, and maintained normal appetite and weight gain.
The only mice that developed obesity were mutant mice who were caged with each other.
“That suggested it was their unique bacterial pool that made the difference,” Dr. Sifuentes explains.
Isolating glutamate
The researchers studied stool samples from both normal and mutant mice and found that mice with no colonic EECs had higher levels of glutamate, an amino acid with multiple functions throughout the body. Glutamate is also present in many foods, and oral intake has been known to increase appetite.
This begged the question: Did the mice have more glutamate in their stool because they were ingesting more, or because they were producing more?
To answer it, the team gave glutamate-enriched enemas to a group of normal mice. “We didn’t alter their genes or feed them glutamate-rich food. We introduced glutamate directly to their colons — and they developed obesity just like the mutant mice,” says Dr. Sifuentes.
The EEC-bacteria-obesity connection sparks more studies and possible treatments
Going forward, the team plans to study questions such as:
- How do colonic EECs influence the makeup and behavior of gut microbiota?
- By what circuit does increased glutamate in the colon lead to increased appetite in the brain?
- How do we measure these phenomena in humans?
“Ultimately, we hope this research feeds into new treatments that help people manage weight disorders,” says Dr. Sifuentes. Possibilities include treatments that lower glutamate levels in people who are overweight, to suppress appetite, and raise them in people who are underweight, to have the opposite effect.
Why Children’s Health: GI expertise and game-changing research
Children's Health is a leader in pediatric gastroenterology care, with 19 disease-specific programs dedicated to treating a diverse population with a range of complex conditions, from biliary atresia and weight management to inflammatory bowel disease and eosinophilic esophagitis (EoE). Other research efforts include multiple studies exploring how gut microbiota affects the body’s immune response to cancer and cancer treatment.