The Microbiota-Inflammasome Hypothesis of Major Depression

Abstract

We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long-lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress-induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive-like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co-morbid conditions. A number of testable predictions surface from this microbiota-gut-inflammasome-brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change.

Keywords: NLRP3; depression; dysbiosis; gut microbiota; inflammasome; probiotics.

Figure 1.

The microbiome-inflammasome hypothesis of major depression and co-morbid systemic illnesses. Psychological stress exposure increases NLRP3 signaling, that increases anxiety- and depressive-like behaviors. Stress-associated gut microbiome changes mediated by the NLRP3 inflammasome and IL1B pathways affect anxiety- and depression-like behaviors and increase the likelihood of developing co-morbid systemic conditions. This is mediated by: 1) increased representation of pro-inflammatory bacterial clades; 2) decreased representation of anti-inflammatory and immunoregulatory bacterial clades; 3) altered bioavailability of monoamine precursors and neuroactive compounds produced by the gut microbiome; and 4) alterations in intestinal structural integrity (e.g., leaky gut), which result in the translocation of bacteria and by-products in physiologically sterile bodily compartments, fuelling pro-inflammatory signaling.

Figure 2.

Molecular links connecting the microbiome-inflammasome hypothesis of major depression and co-morbid systemic illnesses. Psychological stress exposure increases pro-inflammatory signaling (e.g., NLRP3, IL1B, IL18, IL6, TNF). This heightened inflammatory state decreases the availability of neurotransmitters (e.g., serotonin) and their precursors (i.e., tryptophan) and increases the turnover of neuro-transmitters (e.g., increased kynurenine), leading to anxiety- and depressive-like behaviors. Such heightened inflammatory status increases the likelihood of co-morbid conditions. At the same time, increased pro-inflammatory signaling modulates gut microbiota composition, increasing the representation of bacterial clades conducive to pro-inflammatory signaling (e.g., Proteobacteria, Allistipes, Prevotella, Oscillibacter, Actinobacteria) and decreasing the representation of bacterial clades conducive to anti-inflammatory signaling (e.g., Firmicutes, Faecalibacterium, Lachnospiraceae, Bacteroidetes). At the same time, gut dysbiosis caused by intestinal and co-morbid conditions increases pro-inflammatory signaling via increasing the representation of pro-inflammatory bacterial clades, which increases the production of LPS and other bacterial toxins and decreases the production of microbiota-produced anti-inflammatory compounds (e.g., SCFA). Such shifts in gut microbiota composition increase the likelihood of developing MDD and other mental illnesses.