Novel Colonic Agonist Formulation Promising for Obesity

By Marilynn Larkin

July 05, 2021

NEW YORK (Reuters Health) - A colonic release formulation of medium-chain fatty acids (MFCA) curbed appetite and boosted levels of the anorexigenic hormone PYY in a small placebo-controlled crossover trial involving obese adults.

"We have shown that two nutrient-sensing receptors, GPR84 and FFAR4, are expressed on human L-cells;" Dr. Madusha Peiris of Queen Mary University of London, UK told Reuters Health by email. "L-cells are found in high levels in the colon and they store and release the potent appetite-reducing hormones, PYY and GLP-1."

"We also have shown that stimulating GPR84 and FFAR4 causes a synergistic release of PYY and GLP-1 from human colonic biopsies," she said. "This was a surprising result."

The clinical trial, reported in Gut, demonstrated that treating obese volunteers with a combination of nutrients that stimulated GPR84 and FFAR4 reduced calorific intake by increasing the levels of PYY in the blood, she explained. "This hormone travels from the gut to the brain to activate food control centers that tell us we are feeling 'full.'"

In essence, she said, "We are mimicking gastric bypass surgery but without the risk of surgery."

In a randomized crossover fashion, Dr. Peiris and colleagues had 20 volunteers come to the clinic on two separate days, separated by at least four weeks, to take combined GPR84 and FFAR4 agonists in colonic-release capsules or placebo before breakfast and lunch. Participants were not diabetic, had a mean age of 49, a mean BMI of 34.2, and had never undergone major gut surgery.

Active capsules contained 500 mg 3′3 diindolyl-methane (250 mg, Olympian Labs); 2100 mg alpha lino-lenic acid contained within perilla oil (500 mg, 90 LiCaps, Fairvital); and 2400 mg lauric acid (Sigma Aldrich).

Those who received the active treatment had reduced overall calorific intake and increased postprandial levels of PYY versus placebo. Specifically, the authors note, "there was no effect of MCFA capsules on subjective hunger ratings but modest yet significant effects on energy intake. This reduction in calorific intake of approximately 12% could result in weight loss of 12 kg over 24 weeks."

Tissue analyses showed that GPR84 and FFAR4 receptors, among others, were coexpressed on human colonic enteroendocrine cells. Activation of GPR84 alone induced intracellular pERK, whereas FFAR4 selectively activated pCaMKII.

Further, coactivation of GPR84 and FFAR4 induced both phosphoproteins, and a superadditive release of GLP-1 and PYY.

Using a special preparation in a mouse model, the team found that nutrients and hormones convergently activated colonic afferent nerves via GLP-1, Y2 and 5-HT3 receptors.

Dr. Peiris said, "We will begin a 24-week trial in obese volunteers next year, where capsules will be given twice a day. This will allow us to assess weight loss as well as changes to those all-important appetite-reducing hormones, PYY and GLP-1. Upon successful completion of this study, we aim to have a product for clinical use by 2025."

Dr. Kuldeep Singh, Director of the Maryland Bariatric Center at Mercy, commented in an email to Reuters Health, "This is an excellent study that shows it is possible to simultaneously and in an additive fashion increase the in vivo after-meal production of satiety hormones PYY and GLP-1. It is very promising as just recently GLP-1 agonists (liraglutide and simaglutide) have been approved by FDA (for diabetes) and have shown substantial weight loss, even in patients with no diabetes."

"The risk profile will dictate the long-term use of these approaches; however, I believe this is very promising and exciting," he said. "Only serious patients opt for surgery. Once a non-surgical method is introduced, I believe everybody will line up for that."

SOURCE: Gut, online June 3, 2021.