Scientists have increasingly recognized that the gut microbiome plays an important role in overall health, including the brain. However, researchers are still working to identify which specific bacteria are involved in disease and exactly how they influence the body.
One bacterium in particular, Morganella morganii, has been linked in several studies to major depressive disorder. Until recently, though, it was unclear whether this microbe contributes to depression, whether depression changes the microbiome, or whether another factor explains the connection.
Researchers at Harvard Medical School have now identified a biological mechanism that strengthens the case that M. morganii can affect brain health. Their findings offer a clearer explanation of how this bacterium may influence depression.
Published in the Journal of the American Chemical Society, the study points to an inflammation-triggering molecule and suggests a possible new target for diagnosing or treating certain cases of depression. It also provides a framework for studying how other gut microbes may shape human health and behavior.
“There is a story out there linking the gut microbiome with depression, and this study takes it one step further, toward a real understanding of the molecular mechanisms behind the link,” said senior author Jon Clardy, the Christopher T. Walsh, PhD Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at HMS.
How an Environmental Chemical Triggers Inflammation
The researchers discovered that an environmental contaminant called diethanolamine, or DEA, can sometimes replace a sugar alcohol in a molecule produced by M. morganii in the gut.
This altered molecule behaves very differently from the normal version. Instead of remaining harmless, it activates the immune system, prompting the release of inflammatory proteins known as cytokines, especially interleukin-6 (IL-6).
This chain of events provides a potential explanation that links M. morganii to depression. Chronic inflammation is known to play a role in many diseases and has also been associated with major depressive disorder.
Previous research supports this connection. Studies have linked IL-6 to depression and have also associated M. morganii with inflammatory conditions such as type 2 diabetes and inflammatory bowel disease (IBD).
More research will be needed to determine whether this altered molecule directly causes depression and to understand how many cases might be influenced by this process.
New Possibilities for Diagnosis and Treatment
DEA is commonly found in industrial, agricultural, and consumer products.
“We knew that micropollutants can be incorporated into fatty molecules in the body, but we didn’t know how this occurs or what happens next,” Clardy said. “DEA’s metabolism into an immune signal was completely unexpected.”
The researchers suggest that DEA could potentially be used as a biomarker to help identify certain cases of major depressive disorder.
Their findings also add weight to the idea that depression, or at least some forms of it, may involve the immune system. This raises the possibility that treatments targeting immune responses, such as immune-modulating drugs, could be effective for some patients.
More broadly, the study shows how a bacterial molecule can change human immune function by incorporating a contaminant. This insight may help scientists investigate how other gut bacteria influence immunity and different biological systems.
“Now that we know what we’re looking for, I think we can start surveying other bacteria to see whether they do similar chemistry and begin to find other examples of how metabolites can affect us,” said Clardy.
Collaborative Research Advances Microbiome Science
This breakthrough was made possible by combining expertise from two research groups. The Clardy Lab focuses on the chemistry of small molecules produced by bacteria, while the lab of Ramnik Xavier, the HMS Kurt J. Isselbacher Professor of Medicine at Massachusetts General Hospital, specializes in understanding how the microbiome affects health at a molecular level.
Together, these collaborations have advanced the understanding of how gut bacteria interact with the immune system and influence disease. Their recent work includes:
- Demonstrating how a single bacterium (A. muciniphila), the molecule it produces, the biological pathway it uses, and its effects on the body are connected (protecting against inflammation and increasing sensitivity to cancer immunotherapies).
- Showing that the gut bacterium R. gnavus produces an immune-activating sugar-molecule chain that may explain its link to Crohn’s disease and IBD.
- Discovering that a fatty molecule on the surface of the “strep throat” bacterium S. pyogenes can trigger the immune system to release inflammatory cytokines — helping explain severe immune complications, possible links to autoimmune diseases like lupus, and ways to improve cancer immunotherapies.
That fatty molecule belongs to a group called cardiolipins, which are known to stimulate cytokine release. In the new study, researchers found that when DEA is incorporated into the molecule produced by M. morganii, it begins to behave like a cardiolipin, triggering inflammation.
Authorship, Funding, Disclosures
Sunghee Bang and Yern-Hyerk Shin are co-first authors. Additional authors are Sung-Moo Park, Lei Deng, R. Thomas Williamson, and Daniel B. Graham.
Co-author Xavier is a core institute member of the Broad Institute of MIT and Harvard, where he also directs the Klarman Cell Observatory and the Immunology Program and co-directs the Infectious Disease and Microbiome Program.
This work was funded by the National Institutes of Health (grant R01AI172147) and The Leona M. and Harry B. Helmsley Charitable Trust (2023A004123). The authors also acknowledge the HMS Analytical Chemistry Core, HMS Bio-molecular NMR Facility (formerly East Quad NMR facility; NIH OD028526), and Institute of Chemistry and Cell Biology (ICCB)-Longwood Screening Facility.