In a recently published article in Frontiers in Psychiatry, international researchers and clinicians reviewed the literature on the relationship between gut microbiota and the risk for severe mental disorders (SMD). The authors, led by Italian researchers Gabriele Sani and Mirko Manchia, looked at the evidence from animal and human studies to highlight the field’s current understanding of how gut microbiota changes in individuals with serious mental disorders (SMDs) and offer some speculative models to explain their relationship.
“One biological component, partly inherited, that has been so far neglected in risk prediction of SMD, is the microbiota. The human microbiota consists of the ensemble of microbes, including viruses, bacteria, and eukaryotes, that inhabit several ecological niches of the organism,” the authors explain.
“Due to its demonstrated role in modulating illness and health, much interest has focused on the characterization of the microbiota inhabiting the gut. In fact, alterations of the gut microbiota have been linked, among the others, to obesity, maturation of the immune system, and response to drugs. Of particular interest is the modulating role that the microbiota acquires in human behavior.”
The authors define SMDs as chronic and recurrent psychiatric diagnoses such as ‘schizophrenia,’ ‘bipolar disorder,’ and ‘major depressive disorder’ that often are less responsive to treatment. Citing the major health disparities and inequities of people diagnosed with SMDs, they focused on preventative methods to improve outcomes for those at clinical high risk for SMD.
Recent findings have demonstrated links between diet and mental health, linking pro-inflammatory diets of high-fat and sugar to poor mental health outcomes. Research has also found improved quality of life and depressive symptom reduction for patients diagnosed with depression who adhered to the Mediterranean diet.
Emerging research has also demonstrated links between the gut microbiota and mental health, named by neuroscientists as the microbiota-gut-brain axis. For instance, significant differences were found in the microbial makeup of those with increased depressive symptoms and lower reported quality of life than healthy controls.
The authors identified several studies showing decreased biodiversity in the microbiome for those diagnosed with SMDs compared to healthy controls. For instance, bacteria labeled as facultative anaerobes were more likely to be found in the gut microbiota of medication-free patients diagnosed with schizophrenia, bipolar disorder, and major depressive disorder.
It has been posited that gut dysbiosis (persistent imbalance of the gut’s microbial community) and leaky gut (increased permeability of the gut lining that allows for ‘leaking’ into the bloodstream) could affect mental health through pathways such as immune regulation, oxidative/nitrosative stress, and neuroplasticity.
While looking at the differences between specific disorders and healthy controls, the authors acknowledge there is limited evidence on how microbiota might vary in individuals at risk for SMD and individuals at later stages of SMD. Noting that the microbiome is simultaneously shaped with the nervous system and has similar critical development windows, the authors point to growing evidence of the microbiota’s key role in neurodevelopment, especially as a moderating factor of the central nervous system’s (CNS) maturity in early developmental stages.
The authors discuss studies of the perinatal period and the maternal microbiome with its impact on offspring’s psychological development. For one, maternal exposure to stress can alter the offspring’s gut microbiome and affect behavior. Research has connected offspring’s decreased levels of probiotics in the gut with increased anxiety and impaired cognitive functions; increased levels of interleukin-1β, an inflammatory cytokine associated with immune response, and decreased brain-derived neurotropic factor (BDNF) in the amygdala, which is related to neural plasticity, learning, and memory.
The authors concede that much of this research comes from animal studies with mice. In mice fed a high-fat diet, their offspring demonstrated reduced social interactions, poor interest in social novelty, altered sociability.
In another study, offspring from mothers who were given antibiotics during or immediately before mice’s pregnancy had decreased locomotor and explorative activity, low prepulse inhibition, poor social interactions, and anxiety. Interestingly, these behaviors remitted after fostering these mice pups by control mothers.
Lastly, a study of germ-free (GF) mice (those not exposed to bacteria) showed a heightened response to stress from being restrained, reduced BDNF in the hippocampus and cortex, displayed more anxious behavior, and had increased levels of serotonin in the hippocampus. However, when given a strain of Bifidobacterium infantis in early development (pre-weaning), the GF mice’s stress response normalized.
“Cumulatively, these data point toward the existence of specific, and limited, critical periods for the gut microbiota to act on neuronal circuits function and plasticity,” the authors write. “The window of opportunity for the microbiota to impact brain circuits might be different for distinct emotional/social behaviors and, eventually, sensory modalities.”
The authors note that only one study in this review looked at how altered microbiomes affected the risk of developing mental disorders in humans. They found that those at risk for SMD had a clinically significant difference in their global microbiome composition, with those at ultra-high-risk showing greater levels of Clostridiales, Lactobacillales, Bacteroidales, Acetyl coenzyme A synthesis, and anterior cingulate choline levels. The higher choline is thought to result from altered membrane metabolism due to activation of microglia, resident immune cells of the CNS that contribute to neuroinflammation.
From this literature review, the authors propose some mechanisms for how changes in the gut microbiota and gene expressions might moderate the risk of developing a SMD. They cite evidence suggesting that gut microbiota’s effects on the CNS influence mammal behavior and inhibit certain gene expressions. The authors also suggest that certain microbiota may increase blood-brain barrier permeability, predisposing someone to develop a neurodegenerative disorder (e.g., Parkinson’s disease). They also suggest that changes in neurogenesis could lead to cognitive deficits in attention, memory, emotional learning, and executive functioning.
The authors conclude that more research on gut microbiota modifications during the developmental trajectories of SMDs should be done, though only longitudinal research can indicate the directionality of changes in the microbiota-gut-brain axis. They suggest:
“…the analysis of microbiota should be included in the comprehensive assessment generally performed in populations at high risk for SMD as it can inform predictive models and ultimately preventative strategies.”
Sani, G., Manchia, M., Simonetti, A., Janiri, D., Paribello, P., Pinna, F., & Carpiniello, B. (2021). The role of gut microbiota in the high-risk construct of severe mental disorders: A mini-review. Frontiers in Psychiatry, 11, 585769. https://doi.org/10.3389/fpsyt.2020.585769 (Link)