Researchers have increasingly acknowledged that the gut microbiome plays a vital role in general health, encompassing the brain. Yet, experts are still striving to pinpoint which specific bacteria drive disease and precisely how they impact the body.
One specific bacterium, Morganella morganii, has been associated in multiple studies with major depressive disorder. Until recently, however, it remained uncertain whether this microbe causes depression, if depression alters the microbiome, or if a third factor drives the link.
Scientists at Harvard Medical School have now uncovered a biological mechanism that bolsters the argument that M. morganii can impact brain health. Their results provide a sharper explanation of how this bacterium might influence depression. Published in the Journal of the American Chemical Society, the research highlights an inflammation-inducing molecule and proposes a potential new target for diagnosing or treating specific cases of depression. It also establishes a framework for investigating how other gut microbes might shape human health and behavior.
"There is a narrative connecting the gut microbiome with depression, and this study advances it further, toward a genuine understanding of the molecular mechanisms behind the connection," said senior author Jon Clardy, the Christopher T. Walsh, PhD Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at HMS. The team discovered that an environmental contaminant known as diethanolamine, or DEA, can occasionally substitute a sugar alcohol in a molecule generated by M. morganii in the gut.
This modified molecule acts very differently from the standard version. Rather than staying harmless, it activates the immune system, triggering the release of inflammatory proteins called cytokines, particularly interleukin-6 (IL-6). This sequence of events offers a potential explanation linking M. morganii to depression. Chronic inflammation is known to contribute to many diseases and has also been tied to major depressive disorder.
Earlier research supports this link. Studies have connected IL-6 to depression and have also associated M. morganii with inflammatory conditions like type 2 diabetes and inflammatory bowel disease (IBD).
Further research will be required to determine if this altered molecule directly causes depression and to grasp how many cases might be influenced by this process. DEA is frequently found in industrial, agricultural, and consumer goods. "We knew that micropollutants could be integrated into fatty molecules in the body, but we didn't know how this happens or what follows," Clardy said. "DEA's metabolism into an immune signal was entirely unforeseen."
The researchers propose that DEA could potentially serve as a biomarker to help identify certain cases of major depressive disorder. Their findings also reinforce the concept that depression, or at least some forms of it, may involve the immune system. This opens the possibility that treatments targeting immune responses, such as immune-modulating drugs, could work for some patients. More broadly, the study demonstrates how a bacterial molecule can alter human immune function by incorporating a contaminant. This insight may aid scientists in exploring how other gut bacteria affect immunity and various biological systems. "Now that we know what we're looking for, I think we can start surveying other bacteria to see whether they perform similar chemistry and begin to find other examples of how metabolites can affect us," said Clardy.
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."