Gastroenterologists are no strangers to the link between the brain and the gut. Patients are more likely to experience disease flares, increased inflammation and poor health-related quality of life during periods of stress. While the bacteria present in the gut have long been studied for their importance in inflammatory processes and disease activity, their nuanced roles during times of stress have only recently been examined.
Physician-researchers at Nationwide Children’s Hospital have published research in PLoS One and the Journal of Pediatric Gastroenterology and Nutrition confirming a connection between exposure to stress, colonic inflammation, the levels and variety of gut bacteria and the levels of certain bacterial metabolites (short chain fatty acids) in mice.
“We are studying the effect stress exposure has on intestinal inflammation and the mechanism of how it is worsened,” says Ross Maltz, MD, a clinician-scientist and attending gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition at Nationwide Children’s. “Part of the microbiome is bacteria lining the GI tract. The bacteria break down food and produce many metabolites, which have the ability to communicate with the intestines and immune system, and we believe disruption of this mechanism is contributing to the inflammation seen in inflammatory bowel disease.”
To test the theory for their JPGN study, Dr. Maltz and his colleague, Michael Bailey, PhD, a principal investigator in the Center for Microbial Pathogenesis at The Research Institute at Nationwide Children’s, and their research team used mice who were either exposed to stress or left undisturbed, then infected with Citrobacter rodentium, a bacterial strain similar to E. coli in humans. The researchers studied the effect stress had on the microbiome, the levels of short chain fatty acids produced in the GI tract and the degree of inflammation. They examined colonic inflammation and attempted to identify correlations between inflammation, stress exposure and the levels of a range of bacteria and metabolites.
“When we exposed the mice to stress and infection at the same time, it significantly worsened the amount of inflammation seen in the colon,” says Dr. Maltz, who is also an assistant professor of Clinical Pediatrics at The Ohio State University and a principal investigator in the Center for Microbial Pathogenesis at The Research Institute at Nationwide Children’s. “At the same time, mice exposed to stress had very different microbiomes than those that weren’t exposed to stress.”
Some types of bacteria increased in the presence of both stress and infection while others — such as Parabacteroides, which are known to be low in patients with active IBD and potentially serve a protective role against inflammation — decreased. Furthermore, levels of short chain fatty acids decreased when exposed to only stress and the expression of their receptors changed in the presence of both stress and infection. The PLoS One study found very similar results using a different stress model.
In short, stress altered the microbiome, which in turn increased the level of colonic inflammation.
“This data supports our hypothesis that changes in the microbiome are connected to poor GI health during stress,” says Dr. Maltz. His team has additional studies in progress examining the changes in other metabolites in the microbiome in response to stress and infection, some of which are in mouse models that approximate IBD in humans.
To better understand the potential mechanism in humans, Dr. Maltz is also conducting clinical research to measure stress, cortisol levels, changes in the microbiome, and metabolites among patients with IBD in the first year after diagnosis. He hopes that better understanding the interaction between stress, the microbiome and disease activity in both mice and patients with IBD will also offer valuable information for patients.
“The end goals of our research are to understand how stress exposure makes the disease worse and how we can decrease the effect of stress in patients,” says Dr. Maltz. “Then we can try a range of therapeutics — such as pre- or probiotics, behavioral stress management techniques, dietary changes or medications — to lessen the effect of stress on the microbiome, and its subsequent impact on inflammation in the intestine.”
Maltz RM, Keirsey J, Kim SC, Mackos AR, Gharaibeh RZ, Moore CC, Xu J, Somogyi A, Bailey MT. Social stress affects colonic inflammation, the gut microbiome, and short chain fatty acid levels and receptors. Journal of Pediatric Gastroenterology and Nutrition. 2018 Dec 11. [Epub ahead of print]Maltz RM, Keirsey J, Kim SC, Mackos AR, Gharaibeh RZ, Moore CC, Xu J, Bakthavatchalu V, Somogyi A, Bailey MT. Prolonged restraint stressor exposure in outbred CD-1 mice impacts microbiota, colonic inflammation, and short chain fatty acids. PLoS One. 2018 May 9; 13(5): e0196961.