Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis

Abstract

Reduced gut-microbial diversity ("gut dysbiosis") has been associated with an anhedonic/amotivational syndrome ("sickness behavior") that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I² index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10-1.85; P = 0.03, I² = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42-1.12; P < 0.01; I² = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27-1.70; P < 0.01, I² = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16-0.81; P < 0.01, I² = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25-1.48; P < 0.01; I² = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57-1.88; P < 0.01, I²: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need.

Fig. 1. Proxy biomarkers of gut dysbiosis.

Gut dysbiosis (i.e., reduced gut-microbial diversity) has been shown to trigger: a a local inflammatory response (alpha-1-antitrypsin; I-FABP); b loosening of tight-junction proteins (zonulin); c translocation of bacterial endotoxin from the gut lumen to the bloodstream (LPS, ASCA, etc.); d activation of a systemic low-grade inflammation (LBP, sCD14, antibodies against bacterial endotoxin). Experimental models of gut dysbiosis showed a causative link with symptoms of sickness behavior (more details in main text).

Fig. 2. Forest plots of proxy biomarker of gut dysbiosis in severe mental illness and chronic fatigue.

a Levels of circulating zonulin in patients with CFS and MDD vs. controls; b levels of circulating LPS in patients with CFS and MDD vs. controls; c levels of circulating antibodies to endotoxins in patient with BPD, CFS, MDD; SCZ vs. controls; d levels of circulating sCD14 in patients with BPD, CFS, MDD, SCZ vs. controls; e Levels of circulating LBP in patients with CFS and MDD vs. controls; f levels of circulating A-1-AT in patients with BPD, MDD, SCZ vs. controls; g levels of circulating I-FABP in patients with CFS and MDD vs. controls. A-1-AT alpha-1-antitrypsin, BPD bipolar disorder, CFS chronic fatigue syndrome, I-FABP intestinal fatty-acid binding protein, LBP lipopolysaccharide binding protein, LPS lipopolysaccharide, MDD major depressive disorder, sCD14 soluble CD14, SCZ schizophrenia.