Gut Microbes May Contribute to Depression and Anxiety in Obesity

Summary: Researchers report a link between gut bacteria and psychological distress associated with obesity. Switching mice to high fat diets, researchers reported the animals experienced more depressive and anxiety symptoms. These were improved when antibiotics that alter the gut bacteria were administered.

Source: Joslin Diabetes Center.

Like everyone, people with type 2 diabetes and obesity suffer from depression and anxiety, but even more so. Researchers at Joslin Diabetes Center now have demonstrated a surprising potential contributor to these negative feelings – and that is the bacteria in the gut or gut microbiome, as it is known.

Studying mice that become obese when put on a high-fat diet, the Joslin scientists found that mice on a high-fat diet showed significantly more signs of anxiety, depression and obsessive behavior than animals on standard diets. “But all of these behaviors are reversed or improved when antibiotics that will change the gut microbiome were given with the high fat diet,” says C. Ronald Kahn, M.D., co-Head of the Section on Integrative Physiology and Metabolism at Joslin and the Mary K. Iacocca Professor of Medicine at Harvard Medical School .

“As endocrinologists, we often hear people say that they feel differently when they’ve eaten different foods,” notes Kahn, who is senior author on a paper in Molecular Psychiatry describing the research. “What this study says is that many things in your diet might affect the way your brain functions, but one of those things is the way diet changes the gut bacteria or microbes. Your diet isn’t always necessarily just making your blood sugar higher or lower; it’s also changing a lot of signals coming from gut microbes and these signals make it all the way to the brain.”

His lab has long studied mice that are prone to developing obesity, diabetes and related metabolic diseases when given high-fat diets. Earlier this year, the team showed that at least part of this development is driven by changing bacteria in the gut microbiome. The condition was reversed in mice who were given antibiotics in their drinking water, which altered the microbiome.

In the most recent study, the Joslin scientists followed up by giving mice on a high-fat diet four classic lab animal behavioral tests, which are often employed in screening drugs for anxiety and depression. In each case, mice on high-fat diet showed higher signs of anxiety and depression than mice on a regular diet. However, when the mice were given antibiotics with the high fat diet, their behaviors returned to normal.

One of the ways the researchers showed this was an effect of the microbiome was by transferring gut bacteria from these experimental mice toto germ-free mice, who did not have any bacteria of their own. The animals who received bacteria from mice on a high-fat diet showed began to show increased levels of activity associated with anxiety and obsessive behavior. However, those who received microbes from mice on a high-fat diet plus antibiotics did not, even though they did not receive the antibiotics themselves. “This proves that these behaviors are driven to some significant extent by the gut microbiome,” says Kahn.

But what exactly were the microbes doing? The Joslin looked for clues in two areas of the brain, the hypothalamus (which helps to control whole body metabolism) and the nucleus accumbens (which is important in mood and behavior).

“We demonstrated that, just like other tissues of the body, these areas of the brain become insulin resistant in mice on high-fat diets,” Kahn says. “And this response to the high fat is partly, and in some cases almost completely, reversed by putting the animals by antibiotics. Again, the response is transferrable when you transfer the gut microbiome from mice on a high-fat diet to germ-free mice. So, the insulin resistance in the brain is mediated at least in part by factors coming from the microbiome.”

The Joslin team went on to link the microbiome alterations to the production of certain neurotransmitters–the chemicals that transfer signals across the brain.

a stomach is shown
One of the ways the researchers showed this was an effect of the microbiome was by transferring gut bacteria from these experimental mice toto germ-free mice, who did not have any bacteria of their own. NeuroscienceNews.com image is in the public domain.

Kahn and his colleagues are now working to identify specific populations of bacteria involved in these processes, and the molecules that the bacteria produce. The eventual goal is to find drugs or supplements that can help to achieve healthier metabolic profiles in the brain.

“Antibiotics are blunt tools that change many bacteria in very dramatic ways,” Kahn says. “Going forward, we want to get a more sophisticated understanding about which bacteria contribute to insulin resistance in the brain and in other tissues. If we could modify those bacteria, either by putting in more beneficial bacteria or reducing the number of harmful bacteria, that might be a way to see improved behavior.”

Overall, this study highlights how basic research that draws on expertise from multiple fields can lead in unexpected directions, Kahn emphasizes. “Understanding one area of biology, like diabetes and metabolism, can often give new and different perspectives in another field, like psychiatric and behavioral disorders,” he says. “Even if that’s not what you start out to do!”

[divider]About this neuroscience research article[/divider]

Lead author on the paper was Marion Soto. Joslin’s Clémence Herzog also contributed to the work. Other coauthors included Julian Pacheco, Kevin Bullock and Clary Clish of the Broad Institute of MIT and Harvard, as well as Shiho Fujisaka of the University of Toyama.

Funding: The work was supported by the National Institutes of Health.

Source: Jeffrey Bright – Joslin Diabetes Center
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism” by Marion Soto, Clémence Herzog, Julian A. Pacheco, Shiho Fujisaka, Kevin Bullock, Clary B. Clish & C. Ronald Kahn in Molecular Psychiatry. Published June 18 2018
doi:10.1038/s41380-018-0086-5

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[cbtabs][cbtab title=”MLA”] Joslin Diabetes Center “Gut Microbes May Contribute to Depression and Anxiety in Obesity.” NeuroscienceNews. NeuroscienceNews, 18 June 2018.
<https://neurosciencenews.com/microbiome-obesity-depression-9364/>.[/cbtab][cbtab title=”APA”] Joslin Diabetes Center (2018, June 18). Gut Microbes May Contribute to Depression and Anxiety in Obesity. NeuroscienceNews. Retrieved June 18, 2018 from https://neurosciencenews.com/microbiome-obesity-depression-9364/[/cbtab][cbtab title=”Chicago”] Joslin Diabetes Center “Gut Microbes May Contribute to Depression and Anxiety in Obesity.” https://neurosciencenews.com/microbiome-obesity-depression-9364/ (accessed June 18, 2018).[/cbtab][/cbtabs]


Abstract

Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism

Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.

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