Drawing a Line From the Gut Microbiome to Inflammation and Depression

Study provides explanation for one bacterium’s link to mental health

By STEPHANIE DUTCHEN Research

3 min read

A gloved hand holds a Petri dish with bacteria growing in it

Morganella morganii bacteria on a plate. Image: Ajay Kumar Chaurasiya/CC BY-SA 4.0

At a glance:

  • Biochemical analyses provide an answer to the question of how the gut bacterium Morganella morganii might contribute to some cases of major depressive disorder.

  • Incorporation of an environmental contaminant into a molecule the bacterium makes appears to activate inflammation, which is known to contribute to disease development.

  • Findings suggest the contaminant could serve as a biomarker and strengthen arguments that major depressive disorder has links to autoimmune disease.

It’s become increasingly clear that the gut microbiome can affect human health, including mental health. Which bacterial species influence the development of disease and how they do so, however, is only just starting to be unraveled.

For instance, some studies have found compelling links between one species of gut bacteria, Morganella morganii, and major depressive disorder. But until now no one could tell whether this bacterium somehow helps drive the disorder, the disorder alters the microbiome, or something else is at play.

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Harvard Medical School researchers have now pinpointed a biologic mechanism that strengthens the evidence that M. morganii influences brain health and provides a plausible explanation for how it does so.

The findings, published Jan. 16 in the Journal of the American Chemical Society, implicate an inflammation-stimulating molecule and offer a new target that could be useful for diagnosing or treating certain cases of the disorder. They also provide a roadmap for probing how other members of the gut microbiome influence 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.

An inflammatory discovery

The study reveals that an environmental contaminant known as diethanolamine, or DEA, sometimes takes the place of a sugar alcohol in a molecule that M. morganii makes in the gut.

This abnormal molecule then activates an immune response that the normal molecule does not, stimulating the release of inflammatory proteins called cytokines, particularly interleukin-6 (IL-6), the team found.

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This tells a coherent story from M. morganii at the beginning to depression at the end, the authors propose, since chronic inflammation contributes to the development of many diseases and has been linked with depression.

The connection is further strengthened by previous studies associating IL-6 with major depressive disorder and linking M. morganii with inflammatory conditions such as type 2 diabetes and inflammatory bowel disease (IBD).

Future research will be needed to confirm this faulty product of M. morganii as a definitive cause of major depressive disorder and to gauge what percentage of cases it may be responsible for.

A new handhold for tackling depression

DEA is used 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 team proposes that DEA could be added to the growing list of biomarkers used to detect some cases of major depressive disorder.

The study also strengthens arguments that major depressive disorder, or a subset of cases, could be considered an autoinflammatory or autoimmune disease and be successfully treated with immune modulator drugs, Clardy said.

More broadly, revealing how a bacterial product can alter human immune function by incorporating a contaminant opens the door to probing the effects of other gut bacteria in immunity and other human biological systems, the authors said.

“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.

Connecting labs to connect the dots

The advance was enabled by combining the Clardy Lab’s focus on the chemistry of small, medically relevant, bacteria-made molecules with the lab of Ramnik Xavier, the HMS Kurt J. Isselbacher Professor of Medicine at Massachusetts General Hospital, which has expertise in uncovering how the microbiome affects health and disease at the molecular level.

The team’s collaborations in recent years have pushed boundaries in deciphering the mechanisms that drive the interplay between gut bacteria, the immune system, and health outcomes. These include:

That fatty molecule belongs to a family known as cardiolipins, and the team has gone on to show that other cardiolipins can trigger cytokine release. In the new study, the researchers were surprised to discover that when DEA gets substituted into the molecule M. morganii makes, the molecule begins to act like a cardiolipin.

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.