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

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Take home message

Clinical outcomes for clients with severe mental illness and chronic fatigue may improve by targeting gut dysbiosis.

Evidence category

A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)

Summary review

Introduction

Gut dysbiosis is linked to mental health conditions and chronic fatigue.
Endotoxemia resulting from increased gut permeability presents with ‘sickness behaviours’ and flu like symptoms.
This paper summarises differences in gut health proxy biomarkers across patients with severe mental health issues and chronic fatigue versus controls and how they are linked to symptom severity.

Methods

The studies included were case control studies (Jan 2000 to April 2020) investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs controls and studies investigating treatment response in association with these biomarkers.
Age, length of illness and medication were not controlled for.
Biomarkers included, tight-junction proteins (e.g. zonulin), endotoxins (lipopolysaccharide), antibodies against bacterial endotoxins, protein response to bacterial antigens (lipopolysaccharide binding protein), proteins related to inflammation of the gut (alpha-1-anititrypsin), and intestinal fatty acid binding protein.

Results

Of 33 studies meeting the criteria –19 provided the required data.
Compared to controls, higher levels of proxy markers for gut dysbiosis were found in cases of mental illness and chronic fatigue.
When results were pooled significant increases in zonulin (SMD=0.97; 95% CI=0.10-1.85; P=0.03), endotoxins (lipopolysaccharides- LPS) (SMD=0.77; 95% CI=0.42-1.12; P<0.01), antibodies against bacterial endotoxins (SMD=0.99; 95% CI=0.27-1.70; P<0.01) sCD14 (SMD=0.54; 95% CI 0.16-0.81; P<0.01),lipopolysaccharide binding protein (LBP) (SMD- 0.87; 95% CI=0.25-1.48; P<0.01), alpha-1-antitrypsin (A-1-AT) (SMD=1.23; 95% CI=0.57-1.88; P<0.01) and intestinal fatty acid binding protein (I-FABP) (SMD-0.27; 95% CI -0.07-0.60; P=0.12) were recorded.
An association was established between the level of proxy markers of gut dysbiosis and severity of sickness behaviour symptoms in schizophrenia, depression, bipolar disorder and chronic fatigue syndrome.

Conclusion

The use of proxy markers of gut dysbiosis like zonulin, LPS and LBP show potential for use as trans-diagnostic markers to support treatment options in those with sickness behaviour symptoms.

Clinical practice applications

Testing for proxy markers of gut dysbiosis is advisable for clients who show symptoms of sickness behaviour.
In cases of severe mental illness and chronic fatigue removing endotoxins and supporting gut health may support treatment outcomes.
Testing for proxy markers of gut dysbiosis is advisable for clients who show symptoms of sickness behaviour.
In cases of severe mental illness and chronic fatigue removing endotoxins and supporting gut health may support treatment outcomes.
Testing for proxy markers of gut dysbiosis is advisable for clients who show symptoms of sickness behaviour.
In cases of severe mental illness and chronic fatigue removing endotoxins and supporting gut health may support treatment outcomes.

Considerations for future research

It would be beneficial to conduct more studies investigating the treatment response in patients after endotoxins levels have been effectively reduced.

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 I 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, I = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42-1.12; P < 0.01; I = 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, I = 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, I = 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; I = 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, I: 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.