Friday, 31 August 2018 09:37

Does the Microbiome Program Mental Health in Infancy?

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Published in Microbial Sciences

From immune system development to healthy digestion, the microbiome plays a crucial role in human physiology. The microbiome encompasses the skin, mucous membranes, digestive tracts and even human breast milk. Microbes interact with virtually all biological levels of organization, including directly between cells, at the organ-level, and in systemic signalling. We are still learning the myriad ways that the microbiome impacts human health—but what about systems without a well-described microbiome, like the central nervous system?

Researchers are learning that the microbiome may impact our psychiatric well-being. A recent review explores how the vaginal and gut maternal microbiome may influence an infant’s susceptibility to psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorders in the future.

Vertical Transmission

The microbiome begins to take shape in early life. Specific strains such as Bifidobacterium bifidum, Coprococcus comes and Ruminococcus bromii undergo fetal-maternal transmission, and transmitted strains of Bacteroides and Bifidobacterium are found in the guts of both adults and infants. Early interaction with commensal microbes is essential for healthy immune system development in the infant, and decreases his or her lifetime risk for obesity, asthma and allergies. Exogenous factors such as diet, drugs and stress may cause dynamic changes in the maternal microbiome during pregnancy and affect chromatin plasticity within the host’s brain that can alter human behavior.

The study of the human microbiota during pregnancy is complicated by gestational age, and studies of maternal fecal microbiota have demonstrated differences between first, second and third trimesters. Alterations in microbiome diversity can be correlated with fetal changes such as cell formation, migration, programmed apoptosis, and the formation of synapses between neurons.

In general, Proteobacteria and Actinobacteria increase throughout gestation, and Lactobacillus decreases during pregnancy. These changes are important because they may impact human metabolism and immunity. Perhaps counterintuitively, the maternal diet has a minimal or absent role in the resulting microbiome composition of her child. Additional studies of microbiome variation in pregnant patients are needed in order to better characterize these effects.

Gut-Brain Axis and Mental Health

How can microbes affect mental health? One model for describing the connection between our bugs and our brain is the hypothalamic-pituitary-adrenal (HPA) axis. As a communication network for the body, the HPA axis integrates signaling from several organs at once. The HPA axis impacts growth, milk production and water balance, and directly affects the functions of the thyroid gland, adrenal gland and sex organs. Microbes can affect the HPA axis by secreting neurotransmitters (such as acetylcholine and serotonin), affecting gene expression of anxiety behavior-related receptors and amplifying the human stress response.

When we experience stress, our body secretes inflammatory cytokines. While inflammation is a key element of normal immune function, it can also lead to adverse outcomes for mother and child, such as preterm birth. Inflammation also increases risk for gestational diabetes, gestational hypertension, major depressive disorder and the development of obesity later in life. The gut microbiota may increase weight gain by modifying mechanisms of energy harvesting, short-chain fatty acid signaling, satiety control and inflammatory response systems.

By influencing signaling within the HPA axis, the gut microbiome may be a driver in individual variation in cognitive abilities and behavior. Additionally, modifications to the microbiome can alter and shape our mood and cognition, and scientists are now studying interventions that target the microbiome in order to treat common mental health disorders. The connection between our microbiome and our mood may help explain some of the common comorbidities of depression, such as inflammatory bowel syndrome (IBS); about 60% of anxiety and depression patients are described to have intestinal function disturbances. These studies show important new directions with potential for future therapeutic approaches.

Cesarean Section versus Vaginal Delivery

Cesarean section is a common mode of delivery in the United States (accounting for 31.9% of births) that has important implications for neonatal health. Specifically, different studies have shown cesarean section decreases important physiological stress on the infant, modifies epigenetic programming, and alters the composition of the infant microbiome, even later in life. These findings could have important ramifications for immune and metabolic health and well-being of the growing child.

Scientists have begun comparing the intestinal microbiome of babies exposed to cesarean section or vaginal delivery, and have found measurable changes (for example, babies delivered by cesarean section have lower proportions of Bacteroides, Parabacteroides and Clostridium). Additionally, microbes present within meconium (the in-utero intestinal content of the fetus before delivery) are significantly different from intestinal contents after delivery. Infants delivered by cesarean section may be partially influenced by vaginal microbe transfer.

Cognition, Stress and Learning

Variations in microbiome composition have been correlated with changes in cognition, learning and memory in experiments where diet, stress, infection and exercise are controlled. Studies on mood disturbances and mania have proposed several mechanisms to explain these effects: a potent infection may activate the immune system and subsequently induce mania, and antibiotic usage could change the microbiota. Although the mechanism is still unclear, we do know that the gut-brain axis helps us respond to stress and immunological insults from the environment, and that microbes may affect the gut-brain axis.

Animal models have tied maternal factors to psychiatric diseases such as anxiety, depression and autism spectrum disorders. A pregnant woman’s environment, such as her level of stress, may affect the neonate’s epigenetic disposition. Specifically, the metabolites of our microbiome can be epigenetic activators of gene expression, and impact proteins related to the sympathetic nervous system and immune system. By altering the baby’s stress response, maternal stress may affect the baby’s neurodevelopment and HPA axis.

The “microbiota-inflammasome” hypothesis is one possibility to explain how microbes could increase depression symptoms. Inflammation is thought to be closely linked with depression due to the upregulation of depression-related cytokines. The microbiota-inflammasome hypothesis states that gut microbiome dysbiosis caused by stress and gut conditions can result in the upregulation of pro-inflammatory pathways. These changes can upregulate “Nod-like receptors,” a class of receptors that responds to cellular damage and stress. Poor diet, stress or other inflammatory insults may lead to depression and cause changes in the gut microbiome, leading to dysbiosis. Determining a role for the microbiota-inflammasome may inform medical approaches to psychiatric care (including fecal microbiota transplantation or dietary change).

Genetics, Mental Health and the Microbiome

What role does the microbiome play in establishing a genetic basis for mental health? Microbes could induce epigenetic changes in the infant that may predispose the individual to psychological disease. Other human diseases have epigenetic pathophysiology; for example, scientists have measured epigenome-wide patterns of methylation linked to suicide attempt with schizophrenia. Of course, our understanding of how maternal microbes, genetics and mental health act in concert is still evolving, and all of these results will be built upon with future studies pertaining to developmental neurobiology and the role of the maternal microbiome.  

Further Reading

Development of the placental microbiome

Early life exposure to antibiotics

Last modified on Friday, 31 August 2018 11:35
Jennifer Brubaker

Jennifer Brubaker is a medical student at Ohio University Heritage College of Osteopathic Medicine. She received her graduate degree from Johns Hopkins University in Biotechnology, where she studied Human Molecular Genetics and Emerging Infectious Diseases. She graduated from Boston College with a degree in Biology in 2012.

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