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, the gut microbiome. In this animal study, published in Molecular Psychiatry, mice that become obese when put on a high-fat diet showed significantly more signs of anxiety, depression and obsessive behavior than animals on standard diets.
In addition to metabolic abnormalities, both obesity and diabetes are associated with increased risk of neuropsychiatric and mood disorders, including poorer cognitive performance, and increased rates of depression, anxiety and dementia, they write.
C. Ronald Kahn, MD, Senior Investigator, Head of the Section on Integrative Physiology and Metabolism and Chief Academic Officer at Joslin Diabetes Center, and the Mary K. Iacocca Professor of Medicine at Harvard Medical School
One potential contributor to these neurobehavioral
abnormalities is the gut microbiome. Other studies
have shown that modifying the gut microbiota of conventional mice by the use of prebiotics and probiotics can improve neurobehavior and that in addition to the abnormalities in gut development and metabolism, which can be reversed by microbial re-colonization, GF-mice have decreased anxiety-like behavior that are also reversed by microbiome colonization, says C. Ronald Kahn, M.D.
“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.
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!
Researchers Conclusion / Taken together, our data indicate that modifications in gut microbiome of diet-induced obesity mice drive changes in both host metabolism and host behavior. Indeed, high fat diet (HFD) mice develop central insulin resistance and altered behaviors indicative of anxiety and depression. Antibiotic treatment of HFD-fed mice, which causes major remodeling of the gut microbiome, improves peripheral and central insulin sensitivity, and reverses these behavioral/mood abnormalities. These effects are reversible when antibiotics are stopped and transferable to germ-free mice by cecal bacterial transfer. These effects of gut microbiota on the brain and behavior are mediated by changes in brain insulin signaling and inflammation, and by the modulation of neurotransmitters, metabolites and other neuroactive molecules, such as brain-derived neurotrophic factor. Understanding these gut-brain interactions may open novel approaches to treatment of mood and behavioral disorders.
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