Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mechanisms. The gut microbiome can modulate brain function and behaviors through the microbiota-gut-brain axis. Here, we found that unmedicated and medicated patients with SCZ had a decreased microbiome α-diversity index and marked disturbances of gut microbial composition versus healthy controls (HCs). Several unique bacterial taxa (e.g., Veillonellaceae and Lachnospiraceae) were associated with SCZ severity. A specific microbial panel (Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae) enabled discriminating patients with SCZ from HCs with 0.769 area under the curve. Compared to HCs, germ-free mice receiving SCZ microbiome fecal transplants had lower glutamate and higher glutamine and GABA in the hippocampus and displayed SCZ-relevant behaviors similar to other mouse models of SCZ involving glutamatergic hypofunction. Together, our findings suggest that the SCZ microbiome itself can alter neurochemistry and neurologic function in ways that may be relevant to SCZ pathology.

https://advances.sciencemag.org/content/advances/archive/5/2/eaau8317/1.full.pdf

The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice

Short chain fatty acids (SCFAs) being produced during fermentation of non-digestible polysaccharides are regulatory compounds with the potential to influence inflammatory, as well as emotional state and cognition through the gut–brain axis. We analyzed the association between stool concentration of SCFAs (acetic acid (C 2:0), propionic acid (C 3:0), isobutyric acid (C 4:0 i), butyric acid (C 4:0 n), isovaleric acid (C 5:0 i) valeric acid (C 5:0 n), isocaproic acid (C 6:0 i), caproic acid, and (C 6:0 n) heptanoic acid (C 7:0)) and depressive symptoms among women and looked for the potential confounders of microbiota byproduct synthesis. We enrolled 116 women aged 52.0 ± 4.7 years and recognized depression in 47 (40.52%). To analyze the emotional state, Beck’s Depression Inventory (BDI) was used. We assessed SCFAs content by means of gas chromatography. Fiber intake was estimated using parts of food frequency questionnaire. The content of acetic acid was significantly lowered compared to non-depressed women (median {IQR}: 29.49 {20.81} vs. 34.99 {19.55}, p = 0.04). A tendency toward decreased level of propionic acid was noticed (median {IQR}: 16.88 {9.73} vs. 21.64 {12.17}, p = 0.07), while the concentration of isocaproic acid was significantly increased in (median {IQR}: 0.89 {1.15} vs. 0.56 {0.95}, p < 0.01) comparison to matched healthy subjects. We found negative correlations between acetate, propionate, and Beck’s score (r = −0.2, p = 0.03; r = −0.21, p = 0.02, respectively). Statistically significant correlations between acetate and propionate and BDI somatic score (r = −0.21, p = 0.01; r = −0.17, p = 0.03), as well as correlations regarding isocaproic and both cognitive/affective (r = 0.37, p = 0.0001) and somatic (r = 9.37, p < 0.001) scores were found. Women who declared current usage of lipid-lowering and thyroid drugs in the past, had higher content of C6:0-i (Users; median {IQR}: 1.91 {3.62} vs. non-users; 0.55 {0.67}; p = 0.0048).and lower of C2:0 (Users; median {IQR}: 23.07 {12.80} vs. non users 33.73 {21.44}; p = 0.041), respectively. No correlations regarding SCFAs concentration and fiber intake were found. We concluded that SCFAs may potentially contribute to depression phenotype, however, due to the small size of groups suffering from moderately heavy (n = 5) and severe (n = 7) depression, the conclusion should be treated with caution. Pharmacotherapy of hyperlipidemia and thyroid disease might affect SCFAs synthesis. Studies with more participants are required.

Faecal Short Chain Fatty Acids Profile is Changed in Polish Depressive Women

Probiotics are living bacteria, which when ingested in adequate amounts, confer health benefits. Gut microbes are suggested to play a role in many psychiatric disorders and could be a potential therapeutic target. Between the gut and the brain, there is a bi-directional communication pathway called the microbiota-gut-brain axis. The purpose of this review is to examine data from recent interventional studies focusing on probiotics and the gut-brain axis for the treatment of depression, anxiety and schizophrenia. Probiotics are likely to improve depression but not schizophrenia. Regarding anxiety, there is only one trial which showed an effect of a multispecies probiotic. However, determinants like the duration of treatment, dosage and interactions have not been thoroughly investigated and deserve more scientific attention. Microbiome-based therapies such as probiotics could be cautiously recommended for depression to enhance beneficial bacteria in the gut and to improve mood through the gut-brain axis.

/pdf/probiotics-and-the-microbiota-gut-brain-axis-focus-on-4g3lkjvxfw.pdf

Probiotics and the Microbiota-Gut-Brain Axis: Focus on Psychiatry.

Cognitive impairment is a core symptom domain of schizophrenia. The effect of antipsychotics, the cornerstone of treatment in schizophrenia, on this domain is not fully clear. There is some evidence suggesting that antipsychotics may partially improve cognitive function, and that this improvement may vary depending on the specific cognitive domain. However, this research is confounded by various factors, such as age, duration/stage of illness, medication adherence, and extrapyramidal side effects that complicate the relationship between antipsychotics and cognitive improvement. Furthermore, antipsychotics-particularly the second generation, or "atypical" antipsychotics-can induce serious metabolic side effects, such as obesity, dyslipidemia and type 2 diabetes, illnesses which themselves have been linked to impairments in cognition. Thus, the inter-relationships between cognition and metabolic side effects are complex, and this review aims to examine them in the context of schizophrenia and antipsychotic treatment. The review also speculates on potential mechanisms underlying cognitive functioning and metabolic risk in schizophrenia. We conclude that the available literature examining the inter-section of antipsychotics, cognition, and metabolic effects in schizophrenia is sparse, but suggests a relationship between metabolic comorbidity and worse cognitive function in patients with schizophrenia. Further research is required to determine if there is a causal connection between the well-recognized metabolic adverse effects of antipsychotics and cognitive deficits over the course of the illness of schizophrenia, as well as, to determine underlying mechanisms. In addition, findings from this review highlight the importance of monitoring metabolic disturbances in parallel with cognition, as well as, the importance of interventions to minimize metabolic abnormalities for both physical and cognitive health.

/pdf/antipsychotics-metabolic-adverse-effects-and-cognitive-muz3gdvi1q.pdf

Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia.

Objective Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania. Methods Patients hospitalized for mania (N = 66) were randomized after discharge to receive 24 weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens. Results During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z = 2.63, P = .009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10, .69; P = .007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8 days for placebo and probiotic treatment, respectively; χ2 = 5.17, P = .017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline. Conclusion Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania.

Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial

The importance of interactions between the brain and the gastrointestinal tract has been increasingly recognized in recent years. It has been proposed that dysregulation and abnormalities in the brain-gut axis contribute to the etiology of a variety of central nervous system disorders. Particularly, dysbiosis, or impaired microbiota, has been implicated in multiple neurological and psychological disorders. The present paper reviews current evidence and theories concerning the possible mechanisms by which microbiota dysfunction contributes to the pathogenesis of schizophrenia and major depressive disorder. Clinical trials that investigated the possibility of treating both illnesses by correcting and rebalancing microbiota with probiotics are also reviewed. Overall, despite the accumulated knowledge in this field, more studies are warranted and required to further our understanding of the brain-gut axis and the possibility of targeting microbiota as a treatment option for schizophrenia and major depressive disorder.

The role of microbiota in the pathogenesis of schizophrenia and major depressive disorder and the possibility of targeting microbiota as a treatment option.

Fengli Lv

Papers

The role of microbiota in the pathogenesis of schizophrenia and major depressive disorder and the possibility of targeting microbiota as a treatment option.