By Rachel Sarnoff, MD
What are Disorders of Gut-Brain Interaction (DGBI)?
Disorders of Gut-Brain Interaction (DGBI) are highly prevalent clinical syndromes, such as irritable bowel syndrome and functional dyspepsia, in which individuals experience chronic and bothersome gastrointestinal symptoms due to disturbances in the brain-gut-microbiome system. They are exceedingly common, with 40% prevalence in adults and children, and have a predilection for women (2:1 women to men). Despite their prevalence and effect on quality of life, the pathophysiological reason for the development of these syndromes remains poorly understood, though it is known that stressful life events can be triggers for symptoms in DGBI patients. A recent study, published in Cells entitled, “Estrogens Play a Critical Role in Stress-Related Gastrointestinal Dysfunction in a Spontaneous Model of Disorders of Gut-Brain Interaction,” evaluated the impact of an early-life stressor on gastrointestinal dysfunction for both sexes of a spontaneous DGBI rat model.
Why This Study Matters
It is not entirely clear why women are more likely to develop DGBI compared to men. Given that early life stressors can increase risk for DGBI, scientists have wondered whether there might be a sex-specific response to such stressors that renders women more prone to the development of DGBI. DGBI pathophysiology is thought in many cases to involve abnormal gut sensitivity and intestinal immune responses. Theories have circulated about sex hormones, such as estrogen, playing a role in this DGBI pathophysiology. This study aimed to investigate the impact of an early life stressor on gastrointestinal alterations in a DGBI rat model, and to evaluate the role of estrogen in these alterations.
What Did They Do?
Utilizing a DGBI rat model, researchers stressed the female and male rats with early separation from their mothers and compared the effects on the gastrointestinal tract immune cells (specifically, cells called eosinophils and mast cells) as well as the sensitivity of their guts. Then, to evaluate what happened when the estrogen source (ovaries) were taken out, they removed the ovaries from some of the female rats. Then, in a subgroup of these, they injected estradiol (a form of estrogen) after their ovaries had been removed in order to see the effect on gut alterations when the estrogen had been added back. In a subgroup of the stressed male rates, they injected estradiol in them as well to see the effect of estrogen on the gut alterations in males.
What Did They Find?
- For male rats, early life stress did not alter gut sensitivity or GI immune cell activity.
- Early life stress increased gut sensitivity and GI immune cell activity in females, and also in males injected with estrogen.
- Removing the ovaries in female rats decreased gut sensitivity but did not change the GI immune activity.
Conclusions
This study supports that in a DGBI rat model, early life stress leads to gut alterations that are typical in DGBI in females but not males, and that estrogen may play a critical role in these alterations. This supports that the presence of estrogen – whether naturally, as in females, or artificially, as in estrogen injections – may increase vulnerability to the development of DGBI if a “trigger” occurs, such as early maternal separation. The study had a number of limitations, including that there was no ‘double-control’ since they did not include rats that were not separated from their mothers for comparison, and it is not known whether the estrogen that they injected into the mice reached levels that were realistic for rats’ natural physiology. Further, rats have substantial differences compared to humans, and no rat DGBI model perfectly approximates the human DGBI experience. Still, this study serves as an important launchpad for further mechanistic studies investigating the interaction between stress and estrogen in DGBI.