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.
Highlights
In the past two decades, the view of severe mental illnesses as brain-centered disorders has been successfully
It was possible to provide a quantitative synthesis for the following biomarkers: zonulin, LPS, LBP, sCD14, antibodies against bacterial endotoxins, A-1-AT, and intestinal fatty-acid binding protein (I-FABP) (Fig. 2)
The pooled estimate showed a significant increase in zonulin in patients vs. controls (SMD = 0.97; 95% Cl = 0.10–1.85; P = 0.03), with evidence of high heterogeneity (I2 = 86.61%) (Fig. 2a)
Summary
In the past two decades, the view of severe mental illnesses as brain-centered disorders has been successfully. The existence of a shared central and peripheral pathophysiology across major psychiatric illnesses is not surprising, considering the common genetic vulnerability [16] This common ground may translate in clinical features that manifest across diagnostic boundaries, as hypothesized by a number of clinical and scientific high-profile initiative, such as the Research Domain Criteria [17]. To provide ground for this hypothesis, we conducted a systematic review and meta-analysis aimed at: (i) summarizing the evidence on differences in proxy markers of gut dysbiosis (Fig. 1) in severe mental illnesses (schizophrenia, depression, and bipolar disorder) and chronic fatigue vs controls; and (ii) investigating the association between these peripheral biomarkers and the severity of sickness behavior symptoms across diagnostic boundaries
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