New research indicates that gut microbiota plays a role in the heightened social fear response associated with Social Anxiety Disorder (SAD), presenting a potential therapeutic target for addressing the growing issue of social fear-related behaviors.
Researchers from APC Microbiome Ireland and University College Cork (UCC) conducted a study using fecal microbiota transplants (FMT) to transfer microbiota from SAD or healthy control (HC) patients to mice. They then evaluated the mice through various behavioral tests and analyzed fecal samples, ileal tissue, and hormonal levels. The findings suggest that FMT from an SAD donor negatively affects gut bacterial colonization, leading to increased sensitivity to social fear stimuli.
“This is a crucial step in establishing a causal link between the gut microbiome and the regulation of brain circuits underlying social fear,” said Prof. John Cryan, Vice President for Research and Innovation at UCC and the lead author of the study. “Moving forward, the goal will be to target the microbiome with psychobiotic-based probiotics or prebiotics, or whole-diet approaches that can reverse some of the observed alterations.”
Researcher Dr. Nathaniel Ritz, involved in the study while at APC, emphasized the importance of finding effective treatments for this psychiatric disorder: “SAD has become a relevant issue, causing fear and anxiety in common social situations, significantly impacting quality of life. Our study indicates that the microbiota in SAD can drive symptoms characteristic of the disorder, offering exciting possibilities in developing therapeutics for SAD patients.”
Recently, gut microbiota has emerged as a key regulator of both brain and behavior, particularly those related to social function. The research team demonstrated that patients with SAD have a different microbiota composition than age-matched healthy controls (HC). Moreover, increasing data supports a role for immune function and oxytocin signaling in social responses.
In this recent study, after depleting the microbiota with antibiotics, 72 mice received specified donor FMT (SAD or HC microbiota) and were tested for social fear, sociability, social cognition, and stress-coping behaviors, as well as gastrointestinal transit and motility. The authors reported a significant alteration in murine recipient bacteriome beta diversity between SAD and HC groups measured at the end of the study. Three bacterial species—Bacteroides nordii, Bacteroides cellulosiyticus, and Phocaeicola massiliensi—were differentially abundant in the SAD and HC groups at the study’s end.
According to the authors, this alteration in bacteriome community composition confirms that FMT from SAD and HC donors led to differential recolonization and engrafting of microbiotas following antibiotic microbiota depletion.
Social fear, sociability, anxiety-like behaviors, and stress-coping behaviors were assessed using elevated plus maze, three-chamber test, carmine red gastrointestinal transit and motility test, social fear conditioning, and forced swim test. Results showed a significant reduction in social interaction over six social stimuli trials (W(1) = 3.239, P < 0.05) with no difference in non-social investigatory behavior.
The study stated that the observed reduction in social fear extinction rate provides evidence that the SAD microbiota is capable of increasing sensitivity to social fear stimuli.
The glucocorticoid stress hormone corticosterone was measured in mouse plasma before and after the forced swim test. After euthanasia, small intestinal ileal tissue was explanted and stimulated with lipopolysaccharide (LPS), concanavalin A (ConA), T cell receptor clusters of differentiation 3 and 28 (CD3/CD28), or vehicle (buffer) to assess gut immune function in response to paradigmatic antigens between groups. These data indicate that the SAD microbiota transfer reduced circulating stress hormone and peripheral immunity.
“Altogether, the findings from APC Microbiome Ireland and University College Cork (UCC) provide new evidence that the microbiota in individuals with SAD can trigger an increase in social fear associated with impaired peripheral immune activation and neuronal oxytocin within the BNST in mice,” concluded this study. “This indicates that the microbiota can play a causal role in heightened social fear responses in this disorder. Moving forward, the microbiota–gut–brain axis is an ideal target for identifying new therapies that can improve symptoms in SAD.”
Director of APC Prof. Paul Ross added, “At APC, we continue to discover how microorganisms in our gut can affect a wide variety of human illnesses and conditions, including those related to mental health and well-being. Social Anxiety Disorder can be a crippling condition, and this new discovery opens up new therapeutic avenues that take the microbiome into account, with the possibility to change its composition to improve health.”
