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“…current pharmacological treatment options for SAD are limited and often ineffective.”

Social anxiety disorder (SAD) is a common psychiatric disorder characterized by intense fear or anxiety in of being judged, negatively evaluated, or rejected in a social or performance situation. The symptoms can be broadly categorized into emotional (subjective fear and anxiety), behavioral (avoidance behaviors), and physical symptoms (including cardiovascular arousal, gastrointestinal discomfort, muscle tension). The onset of SAD typically occurs early in life (childhood or adolescence), and it may have a lifelong impact being associated with considerable functional disability and reduced quality of life. Cognitive behavioral therapy is the most effective treatment modality, while current pharmacological treatment options for SAD are limited and often ineffective.

“ [Evidence for] …a causal or clinically meaningful role of gut microbes in human psychiatric disorders, and new microbe- targeted treatment strategies has not emerged.“

As in other psychiatric conditions, interest in novel therapeutic approaches has developed over the last 10 years based on studies in laboratory mice that have shown an important role of the gut microbiome in influencing emotion-like behaviors. While convincing evidence has been presented to support the concept of brain gut microbiome interactions in emotion-like rodent behaviors and brain functions, there are no translational studies demonstrating a causal or clinically meaningful role of gut microbes in human psychiatric disorders, and new microbe-targeted treatment strategies have not emerged.

“…patients with SAD have a different microbiota composition than age-matched healthy controls.”

A recent study by M. Butler and coworkers from the Department of Psychiatry & Neurobehavioral Science, University College Cork, Ireland has demonstrated that patients with SAD have a different microbiota composition than age-matched healthy controls (HC). It is worth noting that there are now many such correlational studies in psychiatric disorders which are interesting, but do not prove a causal relationship between the observed gut microbial changes and the SAD symptoms, as well as clinical diagnosis.

One experimental approach which aims to establish causality between gut microbial alterations and human psychiatric conditions has been fecal microbial transplantation (FMT) from well characterized human patients with a clinical diagnosis into mice without their own functioning microbiome (“gnotobiotic mice”). Previous research in major depression, anxiety comorbid with irritable bowel syndrome, and schizophrenia have shown that transfer of the microbiota via FMT is able to transfer selective psychological and physiological traits of these disorders, including depression-and anxiety-like behavior, to the recipient mouse.

In order to support their hypothesis that gut microbes play a causal role in promoting clinical symptoms in patients with SAD, Nathaniel Ritz, and the research group under the leadership of John Cryan from the Alimentary Pharmacobiotic Center at the University College Cork, transplanted fecal samples from patients into a specific strain of adult male mice whose own gut microbes had been greatly depleted by antibiotic treatment. The recipient mice underwent a detailed analysis of their gut microbes, immune function, and aspects of the oxytocin neuroendocrine system, an important modulator of social behavioral. They were subsequently tested for several aspects of social fear, sociability, social cognition, and stress-coping behaviors, as well as gastrointestinal transit and motility.

“…the mice that received the SAD microbiota had normal behaviors across a battery of tests designed to assess depression and general anxiety-like behaviors, but they had a specific heightened sensitivity to social fear, a model of SAD.”

Although the mice that received the SAD microbiota had normal behaviors across a battery of tests designed to assess depression and general anxiety-like behaviors, they had a specific heightened sensitivity to social fear, a model of SAD. Interestingly, general sociability, tests of stress-coping behaviors and gastrointestinal transit were not different between the two groups.

Microbiota composition alterations previously observed in human patients with SAD were similar to the diversity differences found between mice that had received fecal microbiota from human donors that were healthy or had a diagnosis of SAD. The mice that received transplants from these two human groups were also found to differ in several bacterial but not viral species. In addition to these differences in gut microbial composition, mouse recipients of SAD fecal transplantation showed neuroinflammatory changes and changes in the brain’s oxytocin system.

“..before jumping to premature conclusions about …novel SAD therapies targeting the gut microbiota (so called “psychobiotics”), many caveats need to be considered.”

Together with the group’s earlier study showing a correlation of several of the same gut microbial changes with a diagnosis of SAD, this new study published in a prestigious research journal provides strong evidence for a relationship between the gut microbiome and a common, disabling psychiatric disorder. However, before jumping to premature conclusions about a causal role of the gut microbiome in human SAD, and of novel SAD therapies targeting the gut microbiota (so called “psychobiotics”), many caveats need to be considered.

“Many of such questions need to be answered, in addition to a need for results from randomized controlled interventions targeted at the gut microbiome, before revolutionary new treatment approaches for SAD become a reality.”

1) Are the microbial changes that affect emotional behaviors in mice sufficient to alter the much more complicated brain circuits underlying human SAD? In other words, what if these microbial changes are responsible for 5% of human SAD symptoms, while other factors, like genetics and early life adversity are responsible for 95%? In such a case, a therapy targeted at the 5% microbially mediated pathophysiology would probably not result in a meaningful clinical benefit.

2) What role do the elevated stress mediators in SAD patients play in causing some of the gut microbial changes? Brain gut microbiome interactions are always part of an integrated system with bidirectional communication between the brain and the gut microbiome, and the microbiome of SAD patients is almost certainly exposed to increased modulation by the autonomic nervous system. Thus the gut microbiome differences between SAD patients and healthy control subjects may be the result of chronic autonomic dysregulation of the gut and its microbes.

3) And how translatable are the behavioral and biological changes observed in artificial mouse models to complex human behaviors, brain and immune function?

Many of such questions need to be answered, in addition to randomized controlled interventions targeted at the gut microbiome, before truly effective new treatment approaches for SAD become a reality.