Adverse childhood trauma and reoccurrence of illness impact the gut microbiome, which affects suicidal behaviors and the phenome of major depression: towards enterotypic-phenotypes

Abstract

The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours and cognitive deficits; the effects of adverse childhood experiences (ACE) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc). We determined isometric log-ratio abundances or prevalences of gut microbiome phyla, genera, and species by analysing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing. Six microbiome taxa accounted for 36% of the variance in the depression phenome, namely Hungatella and Fusicatenibacter (positive associations) and Butyricicoccus, Clostridium, Parabacteroides merdae, and Desulfovibrio piger (inverse association). This profile (labeled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to suicidal behaviours. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, and Romboutsia were positively associated, while Proteobacteria and Clostridium sensu stricto were negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current suicidal behaviours. In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and suicidal behaviours, and possibly for the prevention of future episodes.

The effects of adverse childhood experiences on depression and suicidal behaviors are partially mediated by neuroticism, a forme fruste of major depression

“…Recent research indicates that ACEs may influence the microimmuneoxysome (changes in the microbiome and immune and oxidative pathways), resulting in increased neurotoxicity and, consequently, depressive symptoms (Maes et al, 2023). First, increased ACEs are associated with a particular compositional gut dysbiosis enterotype, which mediates the effects of ACEs on the severity of the depression phenotype (Maes et al, 2023). This is significant because depression is associated with an increase in bacterial translocation caused by a leaky gut (Maes et al, 2008).…”

“…These findings expand upon those of prior studies indicating that early-life trauma may contribute to neuroticism (Barlow et al, 2014, Lahey, 2009, Winokur et al, 1987). There is now overwhelming evidence that ACEs are predictors of major depression, depression severity, and suicidal behaviors (Maes et al, 2018, Maes et al, 2019, Maes et al, 2021, Maes et al, 2022b, Maes et al, 2023, Maes et al, 2021).…”

“…The latter is fueled by the depression-associated enterotype, which promotes abnormalities in epithelial cells, the gut barrier, leaky gut, and bacterial translocation, resulting in increased plasma LPS concentrations that stimulate the Toll-like receptor (TLR)4 complex and thus inflammatory and oxidative pathways (Lucas and Maes, 2013, Maes et al, 2023). Second, ACEs may lead to decreased antioxidant levels, such as paraoxonase 1 (PON 1) and high-density lipoprotein cholesterol, as well as activated nitro-oxidative stress pathways (Maes et al, 2019, Maes et al, 2022b), which, in combination with elevated plasma LPS, may result in a breakdown of the blood-brain barrier and increased neurotoxicity (Maes et al, 2023). Thirdly, ACEs induce immune sensitization with increased activation of the cytokine and growth factor networks following ex vivo administration of LPS and mitogens to whole blood (Maes et al, 2022b).…”

Towards a major methodological shift in depression research by assessing continuous scores of recurrence of illness, lifetime and current suicidal behaviors and phenome features: focus on atherogenicity and adverse childhood experiences

“…Using ACEs, ROI, depressive traits, lifetime and current SI and SA, and the acute phase phenome and phenomenome, we first tested various models and ultimately constructed a parsimonious final model after feature reduction. This new precision nomothetic model builds on earlier work [5,6,11,15,16,17] by integrating measures of atherogenicity and depressive traits, such as neuroticism, dysthymia, and anxiety disorders. We demonstrated how to calculate RADAR scores, which monitor the various aspects of the disorder, such as a) the severity of the acute phenome of depression, comprising symptom domains based on interviews (phenome) and self-rated domains, including HR-QoL (phenomenome), b) the lifetime phenome, comprising ROI (recurrence of episodes and SBs) and depression traits (neuroticism, dysthymia, and anxiety disorders); and c) atherogenicity.…”

“…A fourth model demonstrated that ROI and activation of the pro-inflammatory immune network could be combined with ROI, and that this new pathway-phenotype accurately predicted the current phenome of depression [6]. A fifth model incorporated gut enterotypes (a specific gut microbiota composition) in association with ROI and the phenome of depression [17].…”