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.

Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort

“…The observed association between reduced alpha diversity and more severe anhedonia/amotivation is line with the view of high diversity as an hallmark of a healthy gut microbiome [36]. However, evidence on the association between reduced gut microbiota diversity and clinical conditions manifesting with anhedonia/amotivation (e.g., depression, schizophrenia) is mixed [10]. One hypothesis is that these mixed results might stem from the high heterogeneity of the clinical conditions examined.…”

“…Among the biological correlates of anhedonia and amotivation, the gut-microbiome has been receiving mounting attention given its modifiable nature and the potential implications for therapeutics [8,9]. Reduced gut-microbial diversity has been consistently associated with a range of conditions manifesting with anhedonia and amotivation [10], such as depression [11], schizophrenia [12] and chronic fatigue [13]. Recent evidence suggests a causal link between reduced gut-microbial diversity and features of mental disorders [14], including anhedonic/amotivational behaviours [10,15].…”

“…Reduced gut-microbial diversity has been consistently associated with a range of conditions manifesting with anhedonia and amotivation [10], such as depression [11], schizophrenia [12] and chronic fatigue [13]. Recent evidence suggests a causal link between reduced gut-microbial diversity and features of mental disorders [14], including anhedonic/amotivational behaviours [10,15]. However, while a multitude of gut-tobrain paths have been explored, there is no clear evidence to date explaining how perturbations of the gut-microbiome can manifest with mental health phenotypes [16,17].…”

Vortioxetine Add-On to Methylphenidate for the Treatment of Symptoms of Sickness Behavior in Attention-Deficit Hyperactivity Disorder: Report of Two Cases

“…Symptoms including, but not limited to, malaise, fatigue, depressed mood, impaired concentration, and reduced social drive and emotional range, have been gathered under the term symptoms of sickness behavior [8]. A very recent review of the evidence suggests that key sickness behavior symptoms represent a transdiagnostic feature, being reported across different diagnostic categories, and possibly share neurobiological underpinnings.…”

Hemorrhagic Transformation in Patients With Large-artery Atherosclerotic Stroke Is Associated With Gut Microbiota and LPS-TLR4 Signaling Pathway

“…Bacterial load in blood and lungs challenged by Escherichia coli in CD14-de cient mice was reduced (12,13). Recently, LBP and sCD14 have been suggested as clinical markers of endotoxemia that better re ect plasma exposure to LPS in stroke (14), its comorbidities (15,16) , and other neurological diseases (17). However, the association between the proxy biomarkers of gut dysbiosis and systemic low-grade in ammation (LPS, LPB, and sCD14) and HT pathophysiology remains unclear.…”