Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia

Abstract

Early life adversity and prenatal stress are consistently associated with an increased risk for schizophrenia, although the exact pathogenic mechanisms linking the exposures with the disease remain elusive. Our previous view of the HPA stress axis as an elegant but simple negative feedback loop, orchestrating adaptation to stressors among the hypothalamus, pituitary, and adrenal glands, needs to be updated. Research in the last two decades shows that important bidirectional signaling between the HPA axis and intestinal mucosa modulates brain function and neurochemistry, including effects on glucocorticoid hormones and brain-derived neurotrophic factor (BDNF). The intestinal microbiome in earliest life, which is seeded by the vaginal microbiome during delivery, programs the development of the HPA axis in a critical developmental window, determining stress sensitivity and HPA function as well as immune system development. The crosstalk between the HPA and the Microbiome Gut Brain Axis (MGBA) is particularly high in the hippocampus, the most consistently disrupted neural region in persons with schizophrenia. Animal models suggest that the MGBA remains influential on behavior and physiology across developmental stages, including the perinatal window, early childhood, adolescence, and young adulthood. Understanding the role of the microbiome on critical risk related stressors may enhance or transform of understanding of the origins of schizophrenia and offer new approaches to increase resilience against stress effects for preventing and treating schizophrenia.

Gallic Acid Alleviates Gut Dysfunction and Boosts Immune and Antioxidant Activities in Puppies Under Environmental Stress Based on Microbiome–Metabolomics Analysis

“…It is increasingly recognized that the acute and chronic stressors that activate the HPA axis can modulate GM and may be one causal factor in gut dysbiosis (1). In support, recent evidence has begun to connect GM and its metabolites to gastrointestinal diseases, inflammation, and psychological metrics in humans suffering from multiple stressors (8,17,18). Collectively, these studies provide preliminary evidence that GM may respond to environmental stress.…”

“…A series of metabolic and immune-suppressive effects (5) are elicited by GC, acting through the glucocorticoid receptor. Specifically, the HPA axis is activated by the secretion of corticotropin-releasing hormone (CRH) from the hypothalamus, which induces the anterior pituitary gland to release adrenocorticotropic hormone (ACTH), and then ACTH stimulates the adrenal cortex to release the GC, mainly cortisol (COR), which negatively regulates CRH production to terminate the stress response cascade (6)(7)(8). Moreover, heat shock proteins (HSPs), a kind of stress-induced proteins ubiquitously found in germs and mammals (9)(10)(11), are heavily involved in dealing with environmental stress (12).…”

How do established developmental risk-factors for schizophrenia change the way the brain develops?

“…Maternal stress is also another well-validated RF for schizophrenia in offspring 14 . Adverse events during pregnancy such as depression, unwanted pregnancy, death of a partner, and exposure to war and disasters, are associated with an increased incidence of schizophrenia in offspring 15 . A persistent alteration in glucocorticoid production via the maternal hypothalamic pituitary axis is believed causal.…”

Stress and the Role of the Gut–Brain Axis in the Pathogenesis of Schizophrenia: A Literature Review

“…These interactions of microbial and neurological pathways can affect each other during the development. Early childhood trauma can affect the gut microbiome and this may influence the risk of schizophrenia [ 92 ]. There are studies which show the possible connection between stress, the gut, and schizophrenia.…”

“…The role of the microbiome, which is affected by the environmental factors, such as stress, can be a very interesting topic for researchers. The combination of the microbiome with life stressors is a new topic that can explain features of schizophrenia [ 92 ].…”