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

Transplanting gut bacteria alters depression-related behavior, brain inflammation in animals

Knowledge of stress biology may eventually yield bacterial treatments for psychiatric disorders

May 6, 2019

Science Daily/Children's Hospital of Philadelphia

Scientists have shown that transplanting gut bacteria, from an animal that is vulnerable to social stress to a non-stressed animal, can cause vulnerable behavior in the recipient. The research reveals details of biological interactions between the brain and gut that may someday lead to probiotic treatments for human psychiatric disorders such as depression.

"In rats that show depressive-type behavior in a laboratory test, we found that stress changes their gut microbiome -- the population of bacteria in the gut," said study leader Seema Bhatnagar, PhD, a neuroscientist in Department of Anesthesiology and Critical Care at Children's Hospital of Philadelphia (CHOP). "Moreover, when we transplanted bacteria from those stress-vulnerable rats into rats that had not been stressed, the recipient animals showed similar behavior."

Bhatnagar added that stress also increased inflammation in the brains of vulnerable rats, and that this inflammation appeared in unstressed rats after they received transplants from vulnerable animals.

The study team published its findings online March 4, 2019 in Molecular Psychiatry.

Bhatnagar leads the Stress Neurobiology Program at CHOP, and many of her co-authors are members of the PennCHOP Microbiome Program, a collaboration between researchers at CHOP and the Perelman School of Medicine at the University of Pennsylvania. The program aims to better understand the communities of microbes inside our bodies and alter their properties to improve human health. Chunyu Zhao, PhD, of that program, performed microbiome data analysis and is a co-author of the paper.

Scientists already know that brain and gut influence each other. In humans, patients with psychiatric disorders have different populations of gut microbes compared to microbes in healthy individuals, with parallel findings also seen in animal models of psychiatric disease. This study investigated mechanisms related to brain inflammation, microbiomes and stress.

"Humans do not all react identically to the same stresses -- some are more vulnerable than others to developing psychiatric disorders, others are more resilient," said Bhatnagar. "Something similar happens in laboratory animals as well."

In rodents, social hierarchies and territoriality are major sources of stress. In the laboratory, researchers model stressors with validated behavioral tools such as a forced swim test or a social defeat test to examine how animals use coping strategies to deal with stress. Rats that cope more passively are more vulnerable to the effects of stress because they also exhibit more anxiety- and depressive-type behaviors, while rats that cope more actively are resilient to the effects of social stress. Based on these assessments, the researchers classified the animals as either vulnerable or resilient.

The study team then analyzed the fecal microbiomes of vulnerable rats, resilient rats, a non-stressed control group, and a placebo group. They found that vulnerable rats had higher proportions of certain bacteria, such as Clostridia, than the other groups.

They then performed fecal transplants from three donor groups -- vulnerable rats, resilient rats or control non-stressed rats -- into naïve rats, animals that had not been stressed. They found that different microbiomes changed depressive-like behavior. Rats receiving transplants from vulnerable rats were more likely to adopt depressive-like behaviors, whereas rats receiving transplants from resilient animals or non-stressed animals did not exhibit any changes in behavior or in neural measures. Patterns of brain inflammatory processes in recipients also resembled those seen in the brains of vulnerable animals, suggesting that immune-modulating effects of gut bacteria such as Clostridia may have promoted that inflammation. However, transplants did not significantly change anxiety-like behavior.

The finding that gut transplants from vulnerable rats increased depressive-type behavior but not anxiety-type behavior in non-stressed recipients may point to different mechanisms. The authors said this difference suggests that depressive-type behaviors are more regulated by the gut microbiome, whereas anxiety-type behaviors are primarily influenced by neural activity changes produced by stress experience.

"Although much more research remains to be done, we can envision future applications in which we could leverage knowledge of microbiome-brain interactions to treat human psychiatric disorders," said Bhatnagar. "People already are taking over-the-counter probiotics as supplements. If we can eventually validate beneficial behavioral effects from specific bacteria, we could set the stage for new psychiatric treatments."

https://www.sciencedaily.com/releases/2019/05/190506163642.htm

A gut feeling for mental health

February 4, 2019

Science Daily/VIB (the Flanders Institute for Biotechnology)

The first population-level study on the link between gut bacteria and mental health identifies specific gut bacteria linked to depression and provides evidence that a wide range of gut bacteria can produce neuroactive compounds.

In their manuscript entitled 'The neuroactive potential of the human gut microbiota in quality of life and depression' Jeroen Raes and his team studied the relation between gut bacteria and quality of life and depression. The authors combined faecal microbiome data with general practitioner diagnoses of depression from 1,054 individuals enrolled in the Flemish Gut Flora Project. They identified specific groups of microorganisms that positively or negatively correlated with mental health. The authors found that two bacterial genera, Coprococcus and Dialister, were consistently depleted in individuals with depression, regardless of antidepressant treatment. The results were validated in an independent cohort of 1,063 individuals from the Dutch LifeLinesDEEP cohort and in a cohort of clinically depressed patients at the University Hospitals Leuven, Belgium.

Prof Jeroen Raes (VIB-KU Leuven): 'The relationship between gut microbial metabolism and mental health is a controversial topic in microbiome research. The notion that microbial metabolites can interact with our brain -- and thus behaviour and feelings -- is intriguing, but gut microbiome-brain communication has mostly been explored in animal models, with human research lagging behind. In our population-level study we identified several groups of bacteria that co-varied with human depression and quality of life across populations.'

Previously, Prof Raes and his team identified a microbial community constellation or enterotype characterized by low microbial count and biodiversity that was observed to be more prevalent among Crohn's disease patients. In their current study, they surprisingly found a similar community type to be linked to depression and reduced quality of life.

Prof Jeroen Raes (VIB-KU Leuven): 'This finding adds more evidence pointing to the potentially dysbiotic nature of the Bacteroides2 enterotype we identified earlier. Apparently, microbial communities that can be linked to intestinal inflammation and reduced wellbeing share a set of common features.'

The authors also created a computational technique allowing the identification of gut bacteria that could potentially interact with the human nervous system. They studied genomes of more than 500 bacteria isolated from the human gastrointestinal tract in their ability to produce a set of neuroactive compounds, assembling the first catalogue of neuroactivity of gut species. Some bacteria were found to carry a broad range of these functions.

Mireia Valles-Colomer (VIB-KU Leuven): 'Many neuroactive compounds are produced in the human gut. We wanted to see which gut microbes could participate in producing, degrading, or modifying these molecules. Our toolbox not only allows to identify the different bacteria that could play a role in mental health conditions, but also the mechanisms potentially involved in this interaction with the host. For example, we found that the ability of microorganisms to produce DOPAC, a metabolite of the human neurotransmitter dopamine, was associated with better mental quality of life.'

These findings resulted from bioinformatics analyses and will need to be confirmed experimentally, however, they will help direct and accelerate future human microbiome-brain research.

Jeroen Raes and his team are now preparing another sampling round of the Flemish Gut Flora Project that is going to start next spring, five years after the first sampling effort.

https://www.sciencedaily.com/releases/2019/02/190204114617.htm