Gut Dysbiosis Markers in Severe Mental Illness

Introduction

Gut dysbiosis has been correlated with innumerable poor health outcomes including severe mental illnesses such as bipolar disorder, depression amongst others. It is believed to trigger a chronic low-grade pro-inflammatory status by increasing the gut-barrier permeability. Based on previous studies, elevated pro-inflammatory cytokine levels have been observed in patients suffering from schizophrenia, depression and bipolar disorder.

Objective

To sum up the evidence on differences in proxy markers of gut dysbiosis in severe mental illnesses and chronic fatigue versus controls.
To evaluate the association between peripheral biomarkers and severity of sickness behaviour.

Study Design

A systematic review and meta-analysis

Methods

Web of Science and PubMed databases were searched and thirty-three studies (involving 2758 patients and 1847 healthy controls) published until April 2020 were included.

Results

A quantitative synthesis was provided for biomarkers such as: zonulin, LPS, LBP, sCD14, antibodies against bacterial endotoxins, A-1-AT and I-FABP.
Amongst the four studies on the circulating levels of zonulin in the patients, three were conducted on depression patients while the other was conducted on bipolar disorder patients.
The pooled estimate across all the studies demonstrated a notable increase in zonulin in patients versus controls (SMD = 0.97; 95% Cl = 0.10–1.85; P = 0.03), with high heterogeneity (I² = 86.61%).
Amidst the two studies conducted on circulating levels of endotoxins in patients (LPS), one was conducted on depression patients and the other was conducted on patients with chronic fatigue.
The pooled estimate demonstrated raised levels of LPS in patients as compared to controls. (SMD = 0.77; 95% Cl = 0.42–1.12; P < 0.01; I² = 0%).
Seven studies were available for data on circulating levels of antibodies against bacterial endotoxins amongst which three studies were carried out on schizophrenic patients and one on patients with bipolar disorder, depression and chronic fatigue each.
Based on the pooled estimate, increased levels of antibodies against bacterial endotoxins was seen in patients when compared to the controls (SMD = 0.99; 95% CI = 0.27–1.70; P < 0.01), with high heterogeneity (I² = 97.14%)
Amongst the six studies on circulating levels of sCD14 in patients, two of the studies had patients with bipolar disorder and schizophrenia and there was one study each with patients having bipolar disorder, schizophrenia, chronic fatigue and depression.
The pooled estimate displayed an increase in levels of sCD14 in patients when compared to the controls (SMD = 0.54; 95% Cl 0.16–0.81; P < 0.01) with high heterogeneity (I² = 90.68%).
The pooled estimate based on the two studies on circulating levels of lipopolysaccharide binding protein (LBP) in patients demonstrated an increase in levels of LBP in patients as opposed to controls (SMD = 0.87; 95% Cl = 0.25–1.48; P < 0.01; I² = 56.80%).
The pooled estimate basis the six studies on circulating levels of alpha-1-antitrypsin (A-1-AT) showed an increase in levels of (A-1-AT) in patients when compared to controls (SMD = 1.23; 95% Cl = 0.57–1.88; P < 0.01, I²= 89.25%).
Basis the four studies on circulating levels of intestinal fatty-acid binding protein (I-FABP), the pooled estimate did not display any remarkable difference between I-FABP levels of patients versus controls (SMD = 0.27; 95% Cl −0.07–0.60; P = 0.12; I2 = 23.05%).
Thus, the pooled estimates demonstrated increased circulating levels of: tight-junction proteins (zonulin); bacterial endotoxins (LPS); intestinal inflammation markers (A-1-AT); gut-related systemic inflammation markers (LBP and sCD14) and antibodies against endotoxins in patients.
An assessment of fourteen studies was carried out (seven on schizophrenia, five on depression, four on bipolar disorder and two on chronic fatigue syndrome) to evaluate the association between circulating levels of proxy markers of gut dysbiosis and severity of sickness behaviour symptoms.
It was found that greater circulating levels of proxy markers of gut dysbiosis (tight-junction proteins, endotoxins, antibodies against endotoxins) were notably linked with more severe and persistent negative symptoms amongst patients with schizophrenia.
Increased circulating levels of proxy markers of gut dysbiosis (A1-AT, I-FABP, endotoxins, antibodies against endotoxins) were found to be associated with severe depressive symptoms in major depressive disorder and bipolar disorder.
An increase in circulating levels of proxy markers of gut dysbiosis (antibodies against endotoxins) were associated with severe symptoms of chronic fatigue syndrome.
Normalization of circulating levels of antibodies against endotoxin was observed after successful treatment in patients with chronic fatigue.

Conclusion

Gut dysbiosis markers demonstrated a positive correlation with severity of sickness behaviour in patients with severe mental illnesses.