Mood Disorders and the Disrupted Gut Microbial Milieu

Despite intense research efforts and recent advances in understanding major depressive disorder (MDD), the exact etiology of this condition remains largely undefined. Therapeutic agents are only modestly beneficial, while clinical need is significant.

It’s becoming evident that nearly 100 trillion bacteria and more than 3 million microbial genes in the human gut are important in healthy brain function. The abundance and diversity of intestinal microbial populations also plays a significant role in human disease, including neuropsychiatric disorders. Altered gut microbiota diversity and richness, for example, may influence the pathophysiology of various mood disorders such as depression and anxiety.

Recent findings published in the Journal of Psychiatric Research provide further insight into how the microbiome influences central nervous system function and behavior, as it relates to depression and anxiety. In line with previously reported data, investigators affiliated with the Cork University Hospital show that depression is associated with a disrupted gut microbial milieu. Additionally, fecal microbiota transplantation from individuals diagnosed with depressive disorder to microbiota-depleted adult rats triggers depressive- and anxiety-like behaviors, as well as neurobiological features typically observed in depression, in the recipient rats.

Investigators extracted DNA from stool samples of 34 patients (13 female) diagnosed with depression [Beck Depression mean=32.4 (SD=9.92)] and 33 typical, healthy control participants (14 female) matched for gender, age, and ethnicity. Approximately 12% of individuals in the experimental group presented with a co-morbid anxiety disorder [Beck anxiety median=25.5 (range=45)], while 24% and 9% had a history of alcohol or substance abuse, respectively.

Researchers analyzed the collected samples to distinguish between bacterial subtypes. The samples from individuals diagnosed with depression showed a lower total of bacterial species and lower diversity of microbial populations, compared with those found in the samples collected from controls.

Following the fecal microbiota transplantation from individuals with depression, microbiota-depleted rats exhibited a depressive-like phenotype in various standardized behavioral tasks designed to examine affective behavior in rodents.

Investigators used an elevated plus maze (2 closed and 2 open elevated runways) to assess anxiety-like behavior in rats. This is a conflict test, as rats have a natural tendency to actively explore a new environment, yet they show aversion toward an elevated open runway. Rats receiving fecal microbiota transplantation from persons with depression visited the elevated open arms significantly fewer times, compared with that of rats receiving the fecal microbiota transplantation from control participants.

Additionally, they assessed anhedonia (ie, lack of interest in rewarding stimuli) by using the sucrose preference test. Rats typically show a bias toward the sweetened drink, and failure to do so when presented with plain drinking water and 2% sucrose solution is indicative of anhedonia- or depressive-like behavior. Rats receiving fecal microbiota transplantation from persons with depression showed a reduced intake of sucrose solution but equal intake of total fluid intake (water + sucrose), compared with that of rats receiving the fecal microbiota transplantation from control participants.

With regard to the neurobiological measures, rats receiving fecal microbiota transplantation from persons with depression had significantly elevated levels of plasma kynurenine, as well as elevated kynurenine/tryptophan ratio, compared with those of rats receiving the fecal microbiota transplantation from control participants. There was a trend toward increase in plasma CRP (C-reactive protein), and no increase was found between the groups of rats in terms of pro-inflammatory cytokine expression including IL-6, TNF-α, or IL-1β. Also, no difference was reported with regard to plasma corticosterone levels, or in hippocampal BDNF expression.

Results of the study indicate that, “it is possible to reproduce aspects of depressed behavior and physiology via a gut microbiota transfer”… and therefore, “the gut microbiota could play a causal role in the complex mechanisms underlying the development of depression,” the authors concluded.

Reference

Kelly JR, Borre Y, O’Brien C, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioral changes in the rat. J Psychiatr Res. 2016;82:109-118.