Drawing a line between the gut microbiome and inflammation and depression

It is becoming increasingly clear that the gut microbiome can affect human health, including mental health. However, we are only just beginning to understand which bacterial species influence disease development and how they do so.

For example, some studies have found clear links between a species of gut bacteria, Morganella morganii, and major depressive disorder. But until now, no one could say whether this bacteria somehow helped cause the disorder, whether the disorder altered the microbiome, or whether something else was at play.

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

The results, published in the Journal of the American Chemical Societyinvolve a molecule stimulating inflammation and offer a new target that could be useful for diagnosing or treating certain cases of the disease. They also provide a roadmap for determining how other members of the gut microbiome influence human health and behavior.

“There is a history linking the gut microbiome to depression, and this study takes it one step further, toward a true understanding of the molecular mechanisms behind this link,” said lead author Jon Clardy, Christopher T. Walsh, Ph.D. . Professor of Biological Chemistry and Molecular Pharmacology at the Blavatnik Institute of HMS.

An inflammatory discovery

The study reveals that an environmental contaminant known as diethanolamine, or DEA, sometimes replaces a sugar alcohol in a molecule produced by M. morganii in the gut.

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

This tells a consistent 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 associated with depression.

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

Future research will be needed to confirm this defective product of M. morganii as the definitive cause of major depressive disorder and to assess the percentage of cases for which it may be responsible.

A new approach to fighting depression

DEA is used in industrial, agricultural and consumer products.

“We knew that micropollutants could be incorporated into fat molecules in the body, but we didn’t know how this happened or what would happen next,” Clardy said. “The metabolism of DEA into an immune signal was completely unexpected.”

The team proposes that DEA could be added to the growing list of biomarkers used to detect certain 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 treated successfully with immunomodulatory medications, Clardy said.

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

“Now that we know what we’re looking for, I think we can start looking at other bacteria to see if they have similar chemistry and start finding other examples of how metabolites can affect us,” he said. Clardy said.

Connecting Labs to Connect the Dots

This advance was made possible by combining the Clardy lab’s focus on the chemistry of medically relevant bacterial small molecules with the lab of Ramnik Xavier, HMS Kurt J. Isselbacher Professor of Medicine at Massachusetts General Hospital, who has expertise in discovery of how the microbiome affects health and disease at the molecular level.

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

This fatty molecule belongs to a family known as cardiolipins, and the team went on to show that other cardiolipins can trigger the release of cytokines. In the new study, the researchers were surprised to discover that when DEA is replaced in the molecule produced by M. morganii, the molecule begins to act like a cardiolipin.

This story is courtesy of the Harvard Gazette, the official newspaper of Harvard University. For more information about the university, visit Harvard.edu.