The role of short chain fatty acids in alleviating anxiety by reducing gut corticotropin releasing factor receptor (CRFR) expression and systemic inflammation
Introduction. Generalized anxiety disorder (GAD) is one of the top causes of mental illness in the U.S., affecting around 3.1% of the population.1 Current pharmaceutical therapies are associated with unpleasant and potentially harmful side effects, and only around 45-55% of those affected achieve remission following treatment.1,2 Studies have shown that the prevalence of GAD is significantly higher in people with conditions associated with gut microbiota dysbiosis, including chronic stress and inflammatory bowel disease.3 Research is underway to elucidate the link between dysbiosis and GAD.3 This understanding may result in novel therapies. In particular, short chain fatty acid supplementation is being investigated for its potential anxiolytic effects in people with concurrent gut microbiota dysbiosis.3,4 Methods. C57BL/6J mice received oral supplementation with the short chain fatty acids acetate, propionate, and butyrate.4 Effects on intestinal permeability were measured through the FITC-dextran permeability assay, and a gene expression analysis was performed through real-time polymerase chain reaction to measure the changes in colonic receptors involved in stress signaling.4 Since inflammation may result from intestinal permeability changes, additional studies examined the effects of systemic inflammation on brain function by measuring the serum phenylalanine/tyrosine ratio as an index of tetrahydrobiopterin (BH4) activity in subjects with significant body-wide inflammation.5 Results. Supplementation with short chain fatty acids protected mice from increased intestinal permeability following exposure to psychosocial stress.4 Additionally, these mice had a significantly decreased expression of the gut corticotropin releasing factor receptors CRFR1 and CRFR2 (p < 0.05), which are involved in enhancing intestinal permeability.4 In the studies investigating effects of systemic inflammation, it was found that patients with higher disease activity (more inflammation) had a higher serum phenylalanine/tyrosine ratio, indicating decreased BH4 activity.5 These patients also showed higher rates of anxiety.5 Conclusions. These findings indicate that gut microbiota dysbiosis (which decreases levels of short chain fatty acids) may result in increased expression of corticotropin releasing factor receptor, which enhances intestinal permeability.4 This leads to systemic inflammation, as endotoxins can now translocate into the circulation and activate toll-like receptors.3 The findings suggest that this inflammation interferes with the activity of BH4, a cofactor involved in the synthesis of serotonin, dopamine, and norepinephrine.5 Therefore, this pathway may explain why conditions linked to gut dysbiosis are associated with increased susceptibility to GAD. Prebiotics, which increase levels of short chain fatty acids, may be beneficial as an anxiolytic therapy in people who have coexisting gut dysbiosis and GAD.6
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- Korte-Bouws GAH, Albers E, Voskamp M, et al. Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression. Pharmaceuticals (Basel). 2019;12(1):9.
- Burokas A, Arboleya S, Moloney RD, et al. Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. Biol Psychiatry. 2017;82(7):472-487.