Multi-strain Probiotic Formulation Reverses Maternal Separation and Chronic Unpredictable Mild Stress-Generated Anxiety- and Depression-like Phenotypes by Modulating Gut Microbiome–Brain Activity in Rats

Abstract

Depression is a debilitating mental disorder that affects >322 million people worldwide. Despite the availability of several antidepressant agents, many patients remain treatment refractory. A growing literature study has indicated the role of gut microbiota in neuropsychiatric disorders. Herein, we examined the psychobiotic-like activity of multi-strain probiotic formulation in maternal separation (MS) and chronic unpredictable mild stress (CUMS) models of anxiety-and depression-like phenotypes in Sprague-Dawley rats. Early-and late-life stress was employed in both male and female rats by exposing them to MS and CUMS. The multi-strain probiotic formulation (Cognisol) containing Bacillus coagulans Unique IS-2, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Bifidobacterium lactis UBBLa-70, Bifidobacterium breve UBBr-01, and Bifidobacterium infantis UBBI-01 at a total strength of 10 billion cfu along with L-glutamine was administered for 6 weeks via drinking water. Neurobehavioral assessment was done using the forced swim test (FST), sucrose preference test (SPT), elevated plus maze (EPM), and open field test (OFT). Animals were sacrificed after behavioral assessment, and blood, brain, and intestine samples were collected to analyze the levels of cytokines, metabolites, and neurotransmitters and histology. Animals exposed to stress showed increased passivity, consumed less sucrose solution, and minimally explored the open arms in the FST, SPT, and EPM, respectively. Administration of multi-strain probiotics along with L-glutamine for 6 weeks ameliorated the behavioral abnormalities. The locomotor activity of animals in the OFT and their body weight remained unchanged across the groups. Cognisol treatment reversed the decreased BDNF and serotonin levels and increased CRP, TNF-α, and dopamine levels in the hippocampus and/or frontal cortex. Administration of Cognisol also restored the plasma levels of L-tryptophan, L-kynurenine, kynurenic-acid, and 3hydroxyanthranilic acid; the Firmicutes-to-Bacteroides ratio; the levels of acetate, propionate, and butyrate in fecal samples; the villi/ crypt ratio; and the goblet cell count, which manifested in the restoration of intestinal functions. We suggest that the multi-strain probiotic and glutamine formulation (Cognisol) ameliorated the MS + UCMS-generated anxiety-and depression-like phenotypes by reshaping the gut microbiome−brain activity in both sexes.

Metabolic effects of early life stress and pre‐pregnancy obesity are long lasting and sex specific in mice

“…The weaker correlation observed in males could render them more susceptible to maladaptive changes in their metabolome content and to metabolic consequences of early life stress. This notion is supported by previous studies, indicating a close relationship between adversity early in life, sex, and later outcomes on metabolism, physiology and behaviour (Dandekar et al, 2022; Golubeva et al, 2015; Park et al, 2017; Rincel et al, 2019). However, our experiments do not provide direct evidence whether alterations in gut microbiota and metabolome drive the metabolic effects of early life adversity, if they are a consequence of metabolic alterations or if they are a largely unrelated phenomenon and this warrants further investigations.…”

The heterogeneity of late-life depression and its pathobiology: a brain network dysfunction disorder

“…Recent studies detected a significant difference in the gut microbial composition between patients with LLD and healthy controls, suggesting an association between depressive symptoms, brain structures and gut microbiota (Tsai et al 2022 ). These data and studies in rats showing that multi-strain probiotics ameliorated depression-like phenotypes (Dandekar et al 2022 ), suggest that gut microbiotic changes may play a role in the communication between the gut and the brain, thus enlarging the pathogenic spectrum of LLD.…”

SCFAs Supplementation Rescues Anxiety- and Depression-like Phenotypes Generated by Fecal Engraftment of Treatment-Resistant Depression Rats

“…In fact, several gut microbiota-based interventions improved the negative effects of chronic stress in rodents. For instance, the administration of live bacterial strains (probiotics) − and host-indigestible dietary fibers (prebiotics) that can be fermented by gut microbiota ,, displayed beneficial effects. However, several studies have also reported no effect of these microbiome-based therapeutics on depressive-like behavior .…”