Credit: Ajay Kumar Chaurasiya/CC BY-SA 4.0
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.
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 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, Ph.D. 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.
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.
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.
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 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, Ph.D. 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.
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:Achieving the rare feat of connecting a single bacterium (A. muciniphila), the molecule it makes, the pathway it operates through, and the biological outcome (protecting against inflammation and raising sensitivity to cancer immunotherapies).
Showing that the gut bacterium R. gnavus produces an immune-stimulating sugar-molecule chain that could explain its association with Crohn's disease and IBD.
Discovering that a seemingly innocuous fatty molecule on the surface of the "strep throat" bacterium S. pyogenes can actually activate the immune system to release inflammatory cytokines—explaining why the bacterium sometimes leads to serious immune complications, how it may contribute to autoimmune diseases like lupus, and how cancer immune therapies might be improved.
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.
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