Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review

Abstract

Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus-pituitary-adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut-brain axis (GBA) for the effective management of depressive behavior and anxiety.

Keywords: depression; gut dysbiosis; gut microbiota; gut–brain axis; hypothalamus–pituitary–adrenal axis; major depressive disorder; serotonin; short-chain fatty acids.

Figure 1

The gut–brain axis and depressive disorder. Gut dysbiosis increases intestinal barrier permeability, causing leaky gut with decreased levels of tight and adherent junction proteins, loss of goblet cells, increased lipopolysaccharide (LPS, an endotoxin derived from the Gram-negative bacterial cell wall), and increased blood–brain barrier permeability. These changes trigger the production of pro-inflammatory cytokines via HPA disruption and increased cortisol levels, which in turn leads to decreased levels of 5-HT and dopamine, BDNF, and IDO, TDO, kynurenine, resulting in depression.

Figure 2

Oxidative and nitrosative stress in depression. Pathobionts in GD elevate gut leakiness and circulating LPS levels, which trigger DAMP, TLR2/4 receptor, and inflammatory pathways. These lead to increased levels of reactive oxygen/nitrogen species (ROS/RNS), cyclooxygenase-2 (COX-2), NO, malondialdehyde, 4-hydroxynonenal, tryptophan catabolism, kynurenine, and decreased amounts of antioxidants (e.g., glutathione, melatonin, and serotonin). All these changes negatively affect neurotransmission and cause depression.

Figure 3

Taxonomic changes in fecal microbiota and relative abundance between healthy control (HC) and MDD groups at the levels of bacterial phylum (a), family (b), and genus (c). Enterobacteriaceae, Fusobacteriaceae, and Rikenellaceae were considerably higher, but Prevotellaceae, Bacteroidaceae, and Ruminococcaceae were significantly lower in MDD when compared to HC. Alistipes, Blautia, Lachnospiracea, Parabacteroides, Clostridium XIX, and Oscillibacter are more prevalent in MDD than in HC. Prevotella, Bacteroides, Faecalibacterium, and Ruminococcus are less abundant in MDD than in HC. The figure is reused as per journal copyright permission [10].