Gut instincts: Researchers discover first clues on how gut health influences brain health

October 23, 2019

Science Daily/Weill Cornell Medicine

New cellular and molecular processes underlying communication between gut microbes and brain cells have been described for the first time by scientists at Weill Cornell Medicine and Cornell's Ithaca campus.

Over the last two decades, scientists have observed a clear link between autoimmune disorders and a variety of psychiatric conditions. For example, people with autoimmune disorders such as inflammatory bowel disease (IBD), psoriasis and multiple sclerosis may also have depleted gut microbiota and experience anxiety, depression and mood disorders. Genetic risks for autoimmune disorders and psychiatric disorders also appear to be closely related. But precisely how gut health affects brain health has been unknown.

"Our study provides new insight into the mechanisms of how the gut and brain communicate at the molecular level," said co-senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine. "No one yet has understood how IBD and other chronic gastrointestinal conditions influence behavior and mental health. Our study is the beginning of a new way to understand the whole picture."

For the study, published Oct. 23 in Nature, the researchers used mouse models to learn about the changes that occur in brain cells when gut microbiota are depleted. First author Dr. Coco Chu, a postdoctoral associate in the Jill Roberts Institute for Research in Inflammatory Bowel Disease, led a multidisciplinary team of investigators from several departments across Weill Cornell Medicine, Cornell's Ithaca campus, Boyce Thompson Institute, Broad Institute at MIT and Harvard, and Northwell Health with specialized expertise in behavior, advanced gene sequencing techniques and the analysis of small molecules within cells.

Mice treated with antibiotics to reduce their microbial populations, or that were bred to be germ-free, showed a significantly reduced ability to learn that a threatening danger was no longer present. To understand the molecular basis of this result, the scientists sequenced RNA in immune cells called microglia that reside in the brain and discovered that altered gene expression in these cells plays a role in remodeling how brain cells connect during learning processes. These changes were not found in microglia of healthy mice.

"Changes in gene expression in microglia could disrupt the pruning of synapses, the connections between brain cells, interfering with the normal formation of new connections that should occur through learning," said co-principal investigator Dr. Conor Liston, an associate professor of neuroscience in the Feil Family Brain & Mind Research Institute and an associate professor of psychiatry at Weill Cornell Medicine.

The team also looked into chemical changes in the brain of germ-free mice and found that concentrations of several metabolites associated with human neuropsychiatric disorders such as schizophrenia and autism were changed. "Brain chemistry essentially determines how we feel and respond to our environment, and evidence is building that chemicals derived from gut microbes play a major role," said Dr. Frank Schroeder, a professor at the Boyce Thompson Institute and in the Chemistry and Chemical Biology Department at Cornell Ithaca.

Next, the researchers tried to reverse the learning problems in the mice by restoring their gut microbiota at various ages from birth. "We were surprised that we could rescue learning deficits in germ-free mice, but only if we intervened right after birth, suggesting that gut microbiota signals are required very early in life," said Dr. Liston. "This was an interesting finding, given that many psychiatric conditions that are associated with autoimmune disease are associated with problems during early brain development."

"The gut-brain axis impacts every single human being, every day of their lives," said Dr. Artis. "We are beginning to understand more about how the gut influences diseases as diverse as autism, Parkinson's disease, post-traumatic stress disorder and depression. Our study provides a new piece of understanding of how the mechanisms operate."

"We don't know yet, but down the road, there is a potential for identifying promising targets that might be used as treatments for humans in the future," Dr. Liston said. "That's something we will need to test going forward."

https://www.sciencedaily.com/releases/2019/10/191023172106.htm

Anxiety might be alleviated by regulating gut bacteria

Review of studies suggests a potentially useful link between gut bacteria and mental disorders

May 20, 2019

Science Daily/BMJ

People who experience anxiety symptoms might be helped by taking steps to regulate the microorganisms in their gut using probiotic and non-probiotic food and supplements, suggests a review of studies

Anxiety symptoms are common in people with mental diseases and a variety of physical disorders, especially in disorders that are related to stress.

Previous studies have shown that as many as a third of people will be affected by anxiety symptoms during their lifetime.

Increasingly, research has indicated that gut microbiota -- the trillions of microorganisms in the gut which perform important functions in the immune system and metabolism by providing essential inflammatory mediators, nutrients and vitamins -- can help regulate brain function through something called the "gut-brain axis."

Recent research also suggests that mental disorders could be treated by regulating the intestinal microbiota, but there is no specific evidence to support this.

Therefore a team of researchers from the Shanghai Mental Health Center at Shanghai Jiao Tong University School of Medicine, set out to investigate if there was evidence to support improvement of anxiety symptoms by regulating intestinal microbiota.

They reviewed 21 studies that had looked at 1,503 people collectively.

Of the 21 studies, 14 had chosen probiotics as interventions to regulate intestinal microbiota (IRIFs), and seven chose non-probiotic ways, such as adjusting daily diets.

Probiotics are living organisms found naturally in some foods that are also known as "good" or "friendly" bacteria because they fight against harmful bacteria and prevent them from settling in the gut.

The researchers found that probiotic supplements in seven studies within their analysis contained only one kind of probiotic, two studies used a product that contained two kinds of probiotics, and the supplements used in the other five studies included at least three kinds.

Overall, 11 of the 21 studies showed a positive effect on anxiety symptoms by regulating intestinal microbiota, meaning that more than half (52%) of the studies showed this approach to be effective, although some studies that had used this approach did not find it worked.

Of the 14 studies that had used probiotics as the intervention, more than a third (36%) found them to be effective in reducing anxiety symptoms, while six of the remaining seven studies that had used non-probiotics as interventions found those to be effective -- a 86% rate of effectiveness.

Some studies had used both the IRIF (interventions to regulate intestinal microbiota) approach and treatment as usual.

In the five studies that used treatment as usual and IRIF as interventions, only studies that had conducted non-probiotic ways got positive results, that showed a reduction in anxiety symptoms.

Non-probiotic interventions were also more effective in the studies that used IRIF alone. In those studies only using IRIF, 80% were effective when using non-probiotic interventions, while only 45% were found to be effective when using probiotic ways.

The authors say one reason that non-probiotic interventions were significantly more effective than probiotic interventions was possible due to the fact that changing diet (a diverse energy source) could have more of an impact on gut bacteria growth than introducing specific types of bacteria in a probiotic supplement.

Also, because some studies had involved introducing different types of probiotics, these could have fought against each other to work effectively, and many of the intervention times used might have been too short to significantly increase the abundance of the imported bacteria.

Most of the studies did not report serious adverse events, and only four studies reported mild adverse effects such as dry mouth and diarrhoea.

This is an observational study, and as such, cannot establish cause. Indeed, the authors acknowledge some limitations, such as differences in study design, subjects, interventions and measurements, making the data unsuitable for further analysis.

Nevertheless, they say the overall quality of the 21 studies included was high.

The researchers conclude: "We find that more than half of the studies included showed it was positive to treat anxiety symptoms by regulation of intestinal microbiota.

"There are two kinds of interventions (probiotic and non-probiotic interventions) to regulate intestinal microbiota, and it should be highlighted that the non-probiotic interventions were more effective than the probiotic interventions. More studies are needed to clarify this conclusion since we still cannot run meta-analysis so far."

They also suggest that, in addition to the use of psychiatric drugs for treatment, "we can also consider regulating intestinal flora to alleviate anxiety symptoms."

https://www.sciencedaily.com/releases/2019/05/190520190110.htm

Switching to hunter-gatherer lifestyle may increase diversity in children's gut microbes

August 29, 2018

Science Daily/American Society for Microbiology

Immersing city dwellers in the traditional lifestyle and diet of a rainforest village for two weeks increases the diversity of the visiting children's -- but not the adults' -- gut microbiota. In a small pilot study, researchers show that the immersion visit did little to shift the adults' skin, oral, nasal and fecal microbiota.

An international team of researchers has shown that immersing city dwellers in the traditional lifestyle and diet of a rainforest village for two weeks increases the diversity of the visiting children's -- but not the adults' -- gut microbiota. In a small pilot study published this week in mSphere®, an open-access journal of the American Society for Microbiology, the team shows that the immersion visit did little to shift the adults' skin, oral, nasal and fecal microbiota.

"We wanted to look at the question of whether microbiota change during a drastic, radical change of diet and lifestyle," says Maria Gloria Dominguez-Bello, a microbial ecologist at Rutgers University in New Brunswick, New Jersey who led the study with microbiologist Monica Contreras from the Venezuelan Institute of Scientific Research. "In this village, there was no market economy, no bodega, no Coca-Cola -- so this represented a radical shift in diet from a high percentage of processed foods in urban places to zero processed foods and an all-natural diet."

Dominguez-Bello, along with researchers from New York University and two Venezuelan institutes, took advantage of a visit planned by five, city-dwelling adult visitors -- and two of their children -- to live among an indigenous Yekwana village in the Bolivar State of Venezuela for 16 days. The village has a hunter-gatherer-gardener lifestyle and diet.

Typical fare includes cassava (a starchy, high-fiber tuber), corn, various wild fruits, including plantains, pineapples, and berries, fish, and small amounts of game meat and eggs gathered from wild birds. Visitors had two meals a day that consisted of soup with a bit of fish or meat. The rest of their diet consisted of "all-day snacking on cassava with fruit" says Dominguez-Bello. The visitors also bathed in the river without soap and followed the natural circadian rhythms of their hosts.

"The diet contains very little animal protein and it's very, very high in fiber and very low in fat," compared to Western diets, says Dominguez-Bello.

While it is known that people with traditional diets have higher gut microbiota diversity compared to those with urban diets, it was unknown if urban dwellers could shift the diversity of their microbiota higher simply by following a traditional lifestyle and diet. In the gut, a high diversity of microbes is considered a sign of good health.

Traditional people eat diets rich in unprocessed plant material, which are much more chemically complex compared to processed foods. The smorgasbord of chemicals acts as fuel for a higher variety of microbes. Traditional people use less antimicrobial medicines and compounds in daily life, which might also contribute to their increased gut microbe diversity.

During the 16-day visit, the researchers collected samples from the visitors' skin, mouth, nose, and from a fecal swab. Age-matched samples were also collected from villagers. The samples were sequenced and compared.

Surprisingly, none of the adult visitors' microbiota shifted significantly during the visit, while the two children's gut microbiota trended toward a higher number of total microbial species present. Although these results were not statistically significant and in just two subjects, the researchers saw this as interesting nonetheless, given the children's ages of 4 and 7.

Up to now, it was thought that children's gut microbiota become stable and more 'adult-like' by the time they reach 3 years of age. "This indicates that the window for maturing your microbiome may not be 3 years of age, but longer," says Dominguez-Bello. Her team plans to do a larger study with 12 children participating in an "immersion summer camp" to a traditional village.

Because the children's gut microbiota exhibited more plasticity, these results raise an interesting possibility that urban children who eat a more traditional, high-fiber, low-fat and low-processed diet early in life might cultivate a more diverse set of gut microbes. Conversely, adults may have a limited response due to their low microbiome plasticity.

Dominguez-Bello was not terribly surprised that the adults' gut and other microbiota changed so little: "If you take traditional people and bring them to New York, give them antibiotics and McDonald's to eat everyday, it's not surprising that they lose diversity," she says. "But if, as an urban dweller, you've already lost that gut microbe diversity and you move to a high-diversity diet, maybe you cannot 'bloom' diversity because you simply don't have those microbes present anymore."

https://www.sciencedaily.com/releases/2018/08/180829133429.htm