In one aspect of her most recent National Institutes of Health (NIH)-funded research, the UC San Francisco School of Nursing’s Sandra Weiss, the Robert C. and Delphine Wentland Eschbach Chair in Mental Health, has sought to understand the effects of maternal depression and corticosteroids during pregnancy on how preterm infants manage stress early in life.
The work has led Weiss to begin an innovative study that explores whether the microbiome could be a mediating factor for those infant exposures. A preliminary analysis of data from 50 infants during their first two to three weeks of life has already yielded some intriguing results.
“The microbiome of babies whose mothers are depressed during pregnancy is depleted of many important bacteria that may have beneficial effects for the infant’s well-being,” says Weiss. “We found similar effects for infants whose mothers had received corticosteroids during pregnancy.”
Weiss and her team are beginning to map the differences and, she says, “This initial data confirms for me the importance of this research and our need to continue to study the microbiome as the child develops.” In addition, the work is spawning other studies from School faculty in the Weiss Stress and Depression Research Lab. All of the work is in collaboration with the School of Medicine’s Susan Lynch, a molecular microbiologist who runs one of the country’s leading labs for the study of human microbiomes and their environments. “Sue is a very gifted, insightful colleague. We are both interested in the effects of early exposure to stressors, so our research collaboration is ideal,” says Weiss.
The Microbiome and Infant Stress Response
Ultimately, Weiss and her team will collect data from approximately 150 infants during their first two to three weeks of life, as well as at six months and 12 months of age. The research team is trying to determine if maternal depression, stress and/or corticosteroid exposure during pregnancy are linked with the proliferation or depletion of specific microbiota and any imbalance in beneficial versus pathogenic bacteria. The researchers theorize that a less diverse or unbalanced microbiome can have lasting effects on a child’s ability to react appropriately to stress.
“We have already found that stress-related hormones a mother secretes in response to her own psychological distress, as well as prescribed antenatal corticosteroids, appear to suppress the infant’s stress response,” Weiss says.
Two of the key biomarkers that Weiss will try to link to changes in the microbiome are telomere length – telomeres are caps at the ends of each strand of DNA, which protect the chromosomes and affect the integrity of cells – and cortisol reactivity to stressors, a marker of how effectively the infant’s hypothalamic-pituitary-adrenal (HPA) axis is developing. The HPA axis is responsible for releasing the appropriate stress-related hormones in response to environmental stimuli. In preterm infants, the HPA axis is still developing, so problems in its function could have lifelong implications for how the child copes with stress.
Weiss says if her work and that of others can characterize the links among maternal depression, corticosteroids, the microbiome and infant stress, it could open doors to more effective ways to support and advise mothers to prevent any adverse impact on their children. The findings can also inform studies of probiotic therapies during pregnancy and the postpartum period.
Connecting the Microbiome to Teen Depression
Weiss’ work on the microbiome is also creating opportunities for others in the Weiss Lab, including School faculty member Cherry Leung. Encounters she had as a pediatric nurse practitioner at what is now UCSF Benioff Children’s Hospital Oakland inspired Leung to earn a PhD degree in epidemiology at the University of Hong Kong, where her dissertation was on modifiable risk factors for adolescent depression. When Leung joined the faculty in 2016, Weiss became a mentor.
Since that time, Leung has completed a postdoctoral fellowship with Weiss and is now a co-investigator on Weiss’ fetal microbiome study. Leung has also earned a three-year, mentored K01 award from the NIH to study links between teen depression and the microbiome.
“There are more than a few studies linking the composition of the gut microbiome with adult depression and other areas of mental health, but my focus is working with teens, and we know that teens aren’t little adults,” says Leung. “I want to know how the composition of their microbiome might be different and whether there is an association between changes in the teen microbiome and teen depression.”
Her study, which will enroll 90 teens, is currently in the recruitment phase. “We will compare the diversity of the microbiome in healthy adolescents to those with depressive symptoms, trying to correlate which bacteria are associated with more or fewer symptoms,” says Leung.
She will also be measuring potential mediating factors, such as inflammatory cytokines in the immune pathway. “There is a lot of research that associates inflammation with depression, but very little in the teen population,” says Leung.
The work, she says, is challenging because the relationship between the brain and gut involves three bidirectional pathways. In addition to the HPA and the immune pathway, there is also a neural-serotonin pathway, and all three pathways are acting simultaneously.
“My study is rather small right now, but we still hope to look at all three pathways together, using statistical models to look at several variables that might have an effect on depression,” says Leung. She hopes by the end of the year to begin analyzing her data.
Leung also hopes to test whether two types of probiotic bacteria – lactobacillus and bifidobacterium – could protect against depression. “The hypothesis is that they are associated with fewer depressive symptoms, and in our intervention arm of the study, we will be looking at supplementing teens with probiotics to see if this leads to fewer depressive symptoms.”
She adds, “I’ve really appreciated the opportunity to do a mentored study that can fill in some gaps in my own background,” noting that in addition to Weiss’ mentorship on depression, she has learned a lot from Susan Lynch on the basic science behind the gut microbiome and about adolescent psychology from Mark Rubinstein of the Adolescent and Young Adult Clinic at Mount Zion.
“We’ve come to realize there are many measures of stress biology and mediators that interact with one another,” says Weiss. “Understanding these interactions has the potential to open doors to new areas of prevention and treatment.”