Should we consider microbiota-based interventions as a novel therapeutic strategy for schizophrenia? A systematic review and meta-analysis

Abstract

Schizophrenia is a chronic psychiatric disorder characterized by a variety of symptoms broadly categorized into positive, negative, and cognitive domains. Its etiology is multifactorial, involving a complex interplay of genetic, neurobiological, and environmental factors, and its neurobiology is associated with abnormalities in different neurotransmitter systems. Due to this multifactorial etiology and neurobiology, leading to a wide heterogeneity of symptoms and clinical presentations, current antipsychotic treatments face challenges, underscoring the need for novel therapeutic approaches. Recent studies have revealed differences in the gut microbiome of individuals with schizophrenia compared to healthy controls, establishing an intricate link between this disorder and gastrointestinal health, and suggesting that microbiota-targeted interventions could help alleviate clinical symptoms. Therefore, this meta-analysis investigates whether gut microbiota manipulation can ameliorate psychotic outcomes in patients with schizophrenia receiving pharmacological treatment. Nine studies (n = 417 participants) were selected from 81 records, comprising seven randomized controlled trials and two open-label studies, all with a low risk of bias, included in this systematic review and meta-analysis. The overall combined effect size indicated significant symptom improvement following microbiota treatment (Hedges' g = 0.48, 95% CI = 0.09 to 0.88, p = 0.004, I² = 62.35%). However, according to Hedges' g criteria, the effect size was small (approaching moderate), and study heterogeneity was moderate based on I² criteria. This review also discusses clinical and preclinical studies to elucidate the neural, immune, and metabolic pathways by which microbiota manipulation, particularly with Lactobacillus and Bifidobacterium genera, may exert beneficial effects on schizophrenia symptoms via the gut-brain axis. Finally, we address the main confounding factors identified in our systematic review, highlight key limitations, and offer recommendations to guide future high-quality trials with larger participant cohorts to explore microbiome-based therapies as a primary or adjunctive treatment for schizophrenia.

Keywords: Gut-brain axis; Microbiota; Probiotic; Psychosis; Schizophrenia.

Fig. 1

PRISMA flow diagram of the study.

Fig. 2

Descriptive analysis of studies on Schizophrenia: (A) Severity Quantifying Instruments used (%); (B) Study design (%); (C) Microbiota manipulation methods employed (%); (D) Study group design (%). PANSS: Positive and Negative Syndrome Scale; BACS: Brief Assessment of Cognition in Schizophrenia; BPRS: Brief Psychiatric Rating Scale; RCT: Randomized Controlled Trial; OL: Open-Label; SS: Single Strain; NI: Not Informed.

Fig. 3

Forest plot graph of microbiota manipulation on symptoms of schizophrenia according to the severity quantifying instrument (follow-up scale). In blue: Randomized Controlled Trials; In red: Open Label Studies; In green: Overall Effects. SS: Single Strain; NI: Not Informed. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

The Gut-Brain Axis. A – Neural Pathway: bacterial components activate the vagus nerve altering activity in the nucleus tractus solitarius (NTS), ventral tegmental area (VTA) and hippocampus (Hip). Lactobacillus and Bifidobacterium promote neuronal activation and hippocampal neurogenesis, as well as long-term potentiation (LTP) and increased dopamine (DA) release in the VTA in a vagus-dependent manner, modulating social behavior in rodents. Vagal activation can also modulate the immune pathway (C) through the suppression of the inflammatory response via acetylcholine (ACh) release and activation of nicotinic receptors on macrophages and other immune cells (H). B – Metabolic Pathway: Gut microbiota (Lactobacillus, Bifidobacterium) produces bioactive compounds, including short-chain fatty acids (SCFA), which act on metabolic pathways via interactions with different receptors, such as GPR41 (FFAR3), GPR43 (FFAR2), GPR109a (HCAR2), OR51E2 (human), and OLFR78 (mouse), expressed on enteroendocrine and immune cells, regulating gut motility and epithelial integrity.(G), and modulating endocrine and immune responses, promoting the production of anti-inflammatory cytokines. Additionally, SCFAs can regulate vagal activity through G protein-coupled receptors (GPCRs) (I) such as GPR41 and GPR43. Transported into systemic circulation by monocarboxylate transporters (MCT1 and MCT4), SCFAs can reach various organs, including the brain, crossing the blood-brain barrier (BBB) via MCTs (MCT1 and MCT2) to exert central effects (D, E, F). SCFAs can also exert central effects regulating synaptogenesis and myelination (D), reducing microglial activation (F), and regulating gene expression due to their ability to inhibit histone deacetylases. (E). C – Immune Pathway: In Peyer's patches, antigens presentation to immune cells induces both mucosal immune responses, including the production of IgA by B lymphocytes, and the differentiation of naive T lymphocytes into anti-inflammatory cytokines-producing regulatory T lymphocytes, which exert protective effects in the central nervous system. In these structures, Lactobacillus, Bifidobacterium, Faecalibacterium, and Christensenellaceae can generate systemic anti-inflammatory responses after the presentation of their components to lymphocytes, exerting various regulatory effects in the central nervous system (D, F). Collectively, these distinct mechanisms demonstrate the capacity for in vivo modulation of social behavior in rodents (J).