Microbiome-Lax May Relieve Constipation

So great a need for constipation relief, so few constipation remedies. If only the estimated 4 million Americans who suffer from constipation had more options, particularly since dietary interventions so often fail. Additional options, new research suggests, may finally be on their way, in the form of genetically engineered probiotics.

According to researchers at the Mayo Clinic Center for Individualized Medicine, synthetic bacteria may spur the transit of food through the digestive system. The researchers add that synthetic bacteria may work better than generic probiotics, which don’t work for everyone because the gut microbiome – the community of bacteria found within the stomach and intestines – is unique to each person.

The synthetic bacteria produced by the Mayo scientists are genetically engineered to produce large amounts of the chemical tryptamine. These bacteria, the Mayo scientists report, “accelerated gastrointestinal transit” in a mouse model of constipation.

Details of the scientists’ work appeared in the journal Cell Host & Microbe, in an article entitled “Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion.” This article describes how the scientists genetically engineered Bacteroides thetaiotaomicron, introduced colonies of this bacterium to colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, and observed the physiologic effect of tryptamine in the gastrointestinal tract.

“…we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium,” wrote the article’s authors. “Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids.”

Tryptamine helps food pass through the intestines with potentially less risk of side effects than other constipation drugs. “Tryptamine is similar to the chemical serotonin, which is produced in our gut,” said the article’s lead author Purna C. Kashyap, M.B.B.S., associate director of the Center for Individualized Medicine Microbiome Program.

The Mayo scientists determined that the tryptamine-induced effect is mediated by the 5-HT₄ receptor, a G-protein-coupled receptor uniquely expressed in the colonic epithelium. When the 5HT₄ receptor is activated by tryptamine, the cAMP level increases and fluid secretion is enhanced.

“In this study, we found tryptamine can activate a receptor in the mouse gut that normally responds to serotonin, causing increased secretion of fluid from the lining of the colon,” Dr. Kashyap explained. “Bacteria can direct the colon to secrete water via tryptamine acting on a host receptor in mice. This accelerates the movement of food through the digestive system.”

Bacterially produced tryptamine quickly degrades in the intestine and does not appear to increase in the bloodstream. That reduces the risk of side effects outside the gastrointestinal tract. Other drugs for constipation can affect different areas of the body, including the heart.

“Our goal with this research is to find treatments that act only in the GI tract without creating problems in other parts of the body,” Dr. Kashyap added.

The findings are also important to the study of gastrointestinal disorders such as irritable bowel syndrome.

Additional preclinical studies will be done to verify the findings. A clinical trial with humans is likely at least three years away, Dr. Kashyap indicated.