Research News

In a finding that could spur GLP‑1 probiotic therapies, Cleveland Clinic researchers have identified a new way the gut microbiome helps regulate hormones after meals. The new PNAS study from the laboratory of J. Mark Brown, PhD, showed gut bacteria naturally make lipids that regulate how our bodies produce and sense hormones like GLP‑1 and insulin after meals. 

The lipids, called N-acyl serinols, add a missing piece to our understanding of the heart-microbiome connection.  

The study was led by a “dream team” of three trainees who served as co-first authors for the paper: Sumita Dutta, PhD; William “BJ” Massey, PhD; and Kala Mahen, PhD. 

“We needed this group of different experts to make this discovery, because it spanned so many fields,” Dr. Brown explains. “I call this type of diet-microbe-host interaction metaorganismal endocrinology, meaning metabolites originating from gut bacteria can engage with hormone receptors to elicit a metabolic response.” 

How do mealtime hormones shape metabolism? 

Hormones play a key role in controlling our metabolism after we eat. Dysregulated hormonal control after mealtimes can lead to obesity, diabetes and cardiovascular disease. This control is a key part of why GLP-1 receptor agonists are so successful in cases where people couldn’t maintain a healthy weight through diet and exercise alone. They keep our hormone levels (in this case, insulin and GLP-1) steady so our bodies can process food properly. 

N-acyl serinol lipids appear to work similarly. Preclinical models treated with steady amounts of the metabolites had enhanced GLP-1 and insulin levels after mealtimes. This was associated with a striking reorganization of meal-related metabolism.  

Drs. Dutta, Massey and Mahen also showed that manipulating the gut microbiome could internally control the amount of N-acyl serinol lipids our bodies receive. These internal changes caused similar hormone stability after mealtimes. 

“Although more work needs to be done, our research does suggest that bacterial N-acyl amides could help our bodies to produce more sustained GLP-1 levels without the need for common GLP-1 receptor agonist drugs like semaglutide, tirzapatide, duraglutide or exenatide,” Dr. Brown explains. “Our work also suggests that manipulating gut microbial lipid metabolism may have very profound effects on GLP-1, insulin and other hormonal responses following a meal.”  

Many foods break down into the materials needed to produce N-acyl serinol lipids, so it's difficult to pinpoint one food to consume more of to enhance production, Dr. Brown says. The Brown Lab is now developing targeted probiotic and postbiotic therapies to regulate GLP-1 and insulin levels based on their findings.   

What is postbiotic therapy? 

Postbiotic therapy involves ingesting beneficial compounds that don’t naturally occur in the foods we eat but are instead produced by our gut bacteria. The study clearly showed that supplemental N-acyl serinol helps regulate hormone levels in healthy preclinical models, so, the Brown Lab is now investigating whether the supplement and its hormonal effects can help treat or prevent metabolic disease.  

What is probiotic therapy? 

Probiotic therapy involves ingesting bacteria that make beneficial molecules out of foods we eat but can’t digest, in the hopes that the bacteria will become a permanent part of our gut microbiomes and act as “living medicine.” A GLP-1 probiotic therapy would be a bacterium that can help regulate GLP-1 levels after a meal. 

The Brown Lab found several unique bacteria that produce high levels of N-acyl serinol and can safely live in human intestines without causing disease. They are now testing whether these bacteria can improve preclinical models of metabolic disease.  

“Although the field of metaorganismal endocrinology is still in its infancy, there is clearly untapped therapeutic potential in understanding diet-microbe-host endocrine pathways,” Dr. Brown says.