Microbiomes and mental health

MICROBIOMES AND MENTAL HEALTH

The microbiome at birth becomes a compelling new target for neuro-psychiatric disorders in exploratory new NIH-funded research

More and more, the microscopic inhabitants of our gut are being shown to play a prominent role in human health. They aid digestion, metabolism and immune-system responses. But their influence hardly ends there. Instead, it extends into the farther reaches of our being, shaping who we are, how we feel, and how we respond to and relate to others.

Beginning at birth, new research suggests, gut microorganisms exert an influence on the development of brains and behavior. The depletion or imbalance of these microorganisms in mothers and newborn offspring may contribute to a higher risk of developing depression, anxiety and stress-related disorders in the future, as well as disorders of social behavior, such as autism.

In light of such findings, a newly launched NIH-funded study led by PBS researcher Jeffrey Alberts seeks to explore the development of brain and behavior in tandem with the microbiome with the ultimate goal of preventing the disabling consequences of microbiome dysfunction, or dysbiosis, at birth.

As a researcher in the neonatal intensive care unit in the Cincinnati Children’s Hospital since 2012, Alberts has worked with mothers and many preterm infants. He has now assembled a highly collaborative team at IU to tackle a related interdisciplinary puzzle in a mouse model. Among the team members are Chris Harshaw, a faculty researcher in Alberts’ lab, PBS neuroscientist Cara Wellman and IU biologist Gregory Demas. Alberts’ Cincinnati colleague Ardythe Morrow, an epidemiologist and pediatrician, is also a collaborator, overseeing the genomic analysis of the mice microbiomes contained in their stool samples.

Together they will measure immune and neuro-endocrine responses, brain structures, as well as the behavior of mothers and infants, whose gut microbiota are altered by antibiotics or stress. The data they collect at different stages will ultimately enable them to form hypotheses about the causal pathways between these systems that might lead to problems with social behavior.

Who stands to benefit from this research?

To start, the 12 percent of all infants born prematurely in the U.S. each year. That percentage has remained unchanged for decades though the survival rate among them has risen. Among preterm mothers and infants, moreover, dysbiosis is extremely common, due to the frequent use of antibiotics and certain medical interventions at birth, particularly cesareans. This dysbiosis leads to a series of short-term negative consequences, such as difficulty digesting mother’s milk, a weak immune system, intestinal disorders, possibly even changes in sleep patterns. But the long-term effects have yet to be fully explored.

At a glance here are the angles from which they are currently exploring the problem.

As a biologist who studies the immune system, Demas explains how his own area of immune system development figures into the project. In both humans and rodents, he observes, “connections have been shown between the microbiome and the immune system, as well as between the immune system and behavior. Yet no one has put it all together, and not on a developmental trajectory.” To this end his lab will measure the levels of pro-inflammatory and anti-inflammatory molecules called cytokines at different stages of development and in both healthy and dysbiotic mothers and offspring.

“Sometimes,” as he has observed in his work, “the anomalies in the dysbiotic offspring’s behavior don’t manifest themselves until adulthood and affect the offspring in a sex-specific manner,” a factor they will look for in this study.

His hypothesis: “I predict the changes in the microbiome will definitely affect immune markers and we’ll see a clear connection between a rise in cytokines and differences in behavior.”

What I expect to find is that those changes in neurochemistry and brain structure are going to be correlated with differences in behavior as a result of antibiotic treatment.

Cara Wellman

While Demas looks at the immune system at different stages of early development, Wellman is looking at brain structure and chemistry at each stage. “I’m going to be looking at brain regions implicated in social and emotional behavior, amygdala and prefrontal cortex,” she explains, “to see if we find changes in neurochemistry, and possibly in dendritic and neuronal structure.

“What I expect to find,” she notes, “is that those changes in neurochemistry and brain structure are going to be correlated with differences in behavior as a result of antibiotic treatment.”

Finally, Alberts and Harshaw are measuring the social behavior of mothers and infants at varying stages of the infants’ development. What they are likely to see, says Alberts, is that mothers will respond differently to the dysbiotic infants, while infants might respond differently to dysbiotic mothers, creating a situation in each case in which the offsprings’ social behavior develops differently from those with a healthy microbiome.

“It wouldn’t be surprising to find that a dysbiotic infant behaves a little bit differently from an intact infant,” Alberts explains. “Other people’s work says that offspring of dysbiotic moms grow up to have altered social development, though the vast majority of other studies, unlike the current one, compare offspring raised in a completely germ-free environment with no microbiome, nor do they have a developmental component.”

The study, Harshaw says, lays the groundwork for a more ambitious, wide-ranging project. “Soon we’ll be writing a much larger grant, potentially with a larger consortium of researchers interested in microbiome-brain-behavior relationships,” he explains. “The idea is that this will generate a lot of interesting data. We’ll look to see if there are correlations between microbiome, behavior, immune mediators, brain mediators, and other measurements.”

What they find could ultimately revolutionize mother and infant care and dramatically improve the future lives and mental health of many newborn infants.