By Reshma Kolala, Medical & Molecular Microbiology ‘22

Author’s Note: A recent switch into the Microbiology major prompted me to explore recent developments in the field. I came across this study that examined the role of gut microbiota in brain function and mood regulation. With the globally rising prevalence of depression, this study provides some potential insight into the development of the disorder on a physiological level and provides a novel approach to anti-depression therapeutics. 

Afflicting nearly 350 million individuals annually, depression is a leading cause of disability worldwide. Despite the widespread effort to uncover the environmental and genetic basis of the disorder, the pathophysiology of depression remains elusive. This is attributed to the fact that, similar to other mental disorders, depression is the result of a complex interplay between several biological and societal factors [1]. Several studies have found that the pathology of depression is influenced by dysfunction in neuromodulatory systems, such as the endocannabinoid system (ECS). The ECS is composed of endocannabinoids (eCB), lipid-based neurotransmitters that regulate mood, emotions, and stress responses [2,3]. Another physiological factor that contributes to depression is the impairment of the hippocampal region of the brain, specifically hippocampal impaired neurogenesis, which contributes to depressive-like behaviors in rodents [4]. This is due to the fact that adult hippocampal neurogenesis has been shown to help mediate stress responses and depressive behavior. The dysfunction of these critical processes has recently been investigated in relation to symbiotic microbiota. 

It has been well established that the diversity of intestinal microbiota contributes to enhanced host function (particularly in immunity, metabolism, and the central nervous system) allowing an individual to better combat disease and regulate metabolic function [5,6,7]. Previous studies have demonstrated that dysbiosis, or altered intestinal microbial composition, has been found in depressed patients when compared to healthy controls [8].  It has also been observed that microbiota modulate anxiety symptoms in mice via the release of bacterial metabolites that may affect critical pathways in the brain [9]. Finally, colitis, a digestive disease characterized by inflammation in the colon, is influenced by gut microbiota and is commonly observed in depression patients [10]. Overall, these studies imply a potential association between intestinal microbial composition and depressive-like behaviors. The following study aims to examine the direct effect of gut microbiota on depressive behaviors in mice, allowing for a broader understanding of the physiological basis of depression and provide new avenues for therapeutics and potential treatment [11].

Researchers used unpredictable chronic mild stress (UCMS), a mouse model of stress-induced depression. To simulate stress, mice in the UCMS group were exposed to various stressors including cage tilting, altered cage bedding, foreign odor, and altered light/dark cycle. The mice in the UCMS group were exposed to two stressors a day for eight weeks. As expected, UCMS mice exhibited depressive-like behaviors such as decreased feeding and self-grooming behavior, consistent with apathetic behavior in those diagnosed with depression. UCMS mice also exhibited reduced hippocampal neurogenesis, confirming a previous study by Snyder et al. that noted this observation in rodents with depression [3].

Once depressive-like behaviors were established in UCMS mice, researchers conducted a fecal microbiota transplant (FMT) from mice exposed to stressors to mice that have not been exposed to any stressors. FMT’s are an innovative form of treatment in which a stool sample is collected from one individual and transplanted in the colon of another individual. This can be administered in various ways, such as a colonoscopy, oral capsules, or via a tube that stretches from the nose into the stomach or bowel [12]. In this study, mice received transplants via an oral gavage which involves the passage of a feeding needle down the esophagus. The purpose of an FMT is to populate the recipient intestine with diverse microorganisms that preferentially provide some benefit to the host. When the microbiota from the UCMS mice was transplanted into the healthy mice, the healthy mice exhibited decreased hippocampal neurogenesis and mimicked the depressive-like behaviors exhibited in the UCMS mice, although the healthy mice had not been exposed to any stressors. 

The effect of the FMT on recipient mice illustrated the influence of intestinal microbial composition on the host. Researchers in this study hypothesized that this was due to alterations in the host’s metabolism. To investigate this further, the concentration of multiple small molecule metabolites in bodily fluids was measured. This revealed a significant decrease in levels of several short-chain fatty acids which may have resulted from dysbiosis-induced changes. As fat is primarily broken down in the small intestine via chemical and mechanical processes, an altered microbial composition in the intestinal tract would unsurprisingly influence fat breakdown. More specifically, there was a decrease in the concentration of an eCB precursor, fatty acids containing arachidonic acid (AA), in recipient mice. As dysregulation of the ECS has been studied in association with depression, this finding in recipient mice aligns with the typical model of depression. To further understand the role of impaired eCB signaling in the recipient mice, researchers observed whether enhancing eCB signaling via dietary supplementation could alleviate the depressive-like behaviors observed in the recipient mice. It was found that recipient mice that were orally administered AA had reversed the depressive-like behaviors indeed by UCMS microbiota. Additionally, AA supplementation aided hippocampal neurogenesis.

To determine how UCMS microbiota affected the microbial composition of recipient mice, fecal microbiota from UCMS mice was sequenced using 16s rRNA. As 16s rRNA is present in all bacteria, the 16s rRNA gene is highly conserved and therefore, a useful tool to identify microbes within complex biological mixtures. The analysis revealed increased levels of Ruminoccacaae and Porphyromonodaceae and a decrease in Lactobacillacae. This finding supports previous studies that report an association between decreased Lactobacillacae and stress in mice. The differences in the microbial composition of recipient mice and donor UCMS mice were maintained eight weeks after transplantation. To test the influence of decreased Lactobacillacae in recipient mice, Lactobacillacae was orally administered similarly to AA supplantation. Dietary complementation of Lactobacillacae had a similar effect as AA supplantation, where depressive-like behaviors and impaired hippocampal neurogenesis were reversed.

Using mice, researchers discovered that the onset of depressive-like behaviors is triggered by a reduction in lipid metabolites. These lipid metabolites, more specifically endocannabinoids, bind to receptors in regions of the brain that control emotion and memory. Surprisingly, the concentrations of endocannabinoids are biochemically influenced by the gut microbiota. Although the mechanism by which this occurs has yet to be understood, these studies have elucidated the impact of gut microbiota beyond digestive function, revealing the extensive scope of microbial composition on healthy host function. This study specifically illustrates the importance of balanced gut microbiota for healthy neural and metabolic function and supports the potential use of dietary or probiotic supplementation as a treatment option for those diagnosed with depression. However, it is important to note that this area of research is relatively new and further studies are required to determine the translational capacity of studies related to the gut-brain axis from mice to humans. With consideration of the limitations of this study, this finding does still provide an intriguing avenue of treatment for mood disorders by introducing a novel physiological approach to mediate depressive-like symptoms. 

References

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