Are gut bacteria to blame for anxiety, depression in obesity?

Obesity brought on by a high-fat diet might be accompanied by changes in gut bacteria that alter brain chemistry in such a way as to promote anxiety and depression.

This was the conclusion that researchers from the Joslin Diabetes Center of Harvard Medical School in Boston, MA, and colleagues came to after studying the link between gut microbes and brain function in mice with diet-induced obesity.

They report their findings in a paper that is now published in the journal Molecular Psychiatry.

In the paper, they note how giving the animals antibiotics — which changed the composition of their gut bacteria — reduced inflammation, improved "insulin signaling in the brain," and reduced "signs of anxiety and depression."

"What this study says," says senior study author C. Ronald Kahn, a professor of medicine at Harvard University and co-head of the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center, "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."

Obesity, diabetes, and gut microbes

Obesity and diabetes are serious public health problems across the globe. Since 1975, worldwide prevalence has almost tripled. Global figures for 2016 estimate that around 650 million people, or 13 percent of the world's population, are obese.

Much of this obesity epidemic is fuelled by diets that are high in fat and "energy-dense foods," along with reductions in physical activity.

Global rates of diabetes have also risen significantly in the past 30 years. In 1980–2014, they rose from 108 to 422 million.

The vast majority of cases are type 2 diabetes, which is driven largely by excess weight and lack of physical activity.

Our guts contain vast and complex populations of microbes that exert a significant influence on our health, especially through their effects on metabolism and immune function.

Diet is recognized as the main driver of gut microbe composition, as it is in both obesity and type 2 diabetes. This effect occurs throughout our lives, during which an average of 66 tons of food will pass through our guts.

Probing link to mood disorders

In their study paper, the researchers note that diabetes and obesity "are associated with increased rates of anxiety and depression."

In addition, symptoms of these mood disorders can be replicated in mice by feeding them on a diet that makes them obese.

The team considered whether the gut microbiome might be a factor in this relationship because other studies have revealed that changing the composition of gut bacteria in mice "can improve neurobehavior."

In previous work, they had found that changes in gut bacteria were partly responsible for mice fed on high-fat diets becoming obese and developing diabetes and "related metabolic diseases."

They also found that giving the animals antibiotics, which changed their gut bacteria, reversed these conditions.

In this new study, the researchers added a new feature to the previous set of experiments. After developing obesity and diabetes from being fed a high-fat diet, the mice underwent behavioral tests for anxiety and depression.

These tests were the same as those used in screening drugs for mood disorders.

Gut microbes and insulin resistance

The additional tests showed that mice fed on a high-fat diet had behaviors that were "reflective of increased anxiety and depression," compared with mice that were fed a normal diet.

But, when the mice were given antibiotics in their drinking water, the levels of raised anxiety and depression disappeared and the animals' behavior "returned to normal."

Can the changes to gut microbe composition wrought by the antibiotics be responsible for the reduction in anxiety and depression behaviors?

To test this idea, the scientists transferred fecal samples, which are laden with gut bacteria, from the diet-induced obese and diabetic mice into the guts of germ-free mice.

The previously germ-free mice began to show raised levels of anxiety and depression behavior. However, this was not the case when they received antibiotics in addition to the gut bacteria.

Finally, examination of brain tissue showed that the high-fat diet had induced insulin resistance in the brain. Insulin resistance is a condition in which cells lose their ability to use insulin to convert glucose into energy and is a hallmark of type 2 diabetes.

"We demonstrated," Prof. Kahn explains, "that just like other tissues of the body, these areas of the brain become insulin resistant in mice on high-fat diets."

Insulin resistance given to germ-free mice

He and his team also found that "this response to the high fat is partly, and in some cases almost completely, reversed by putting the animals by antibiotics."

In addition, the researchers found that the insulin resistance in the brain transferred to the germ-free mice when they introduced gut microbes from the high-fat diet mice.

This shows, Prof. Kahn says, that the "the insulin resistance in the brain is mediated at least in part" by influence from the gut microbes.

The scientists also managed to pinpoint some of the chemical messengers in the brain that were involved in the process.

They now want to identify which microbes are responsible for these changes and, in particular, which of the molecules that they produce exert the most influence.

The idea is that this could lead to supplements or medications that promote "metabolic profiles" that improve brain health.

"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."

Prof. C. Ronald Kahn