This groundbreaking study highlights the central role of the gut in human emotional health and behavior. Gut serotonin, often overlooked in discussions of mental health, plays a critical role in alleviating anxiety and depression, while exposure to SSRIs during pregnancy may have long-term consequences for child development.
The gut plays a crucial role in the production of serotonin, a molecule that acts as both a neurotransmitter and a hormone. About 90% of the body’s serotonin is produced in the gastrointestinal tract, primarily by enterochromaffin cells in the intestinal lining.
This serotonin regulates important digestive functions such as intestinal motility, secretion, and visceral pain perception. In addition, gut serotonin influences the central nervous system indirectly, through communication with the vagus nerve and other pathways.
This connection between the gut and the brain, known as the gut-brain axis, highlights the role of the gut not only in digestion, but also in modulating mood and emotions.
Mood disorders and gastrointestinal disorders based on brain-gut interactions (GBI) are highly prevalent health problems and often coexist in patients. Despite this, there is still a significant gap in the development of fully effective therapies for both.
Currently, selective serotonin reuptake inhibitors (SSRIs) are considered the first-line pharmacological treatment for these disorders due to their ability to increase serotonin levels in the body.
However, SSRIs can cause a number of adverse effects, such as increased anxiety, anhedonia (loss of pleasure), changes in gastrointestinal motility, and other negative effects.
When administered during pregnancy, they have also been associated with an increased risk of cognitive problems, mood disorders, and gastrointestinal dysfunction in children exposed in utero.
SSRIs act throughout the body by blocking the serotonin transporter (SERT), promoting an increase in serotonergic signalling in the brain, intestinal epithelium and enteric neurons.
However, it is still unclear which of these body compartments are responsible for the therapeutic effects and which are related to side effects. In addition, there are questions about how gestational exposure to SSRIs can directly influence the development of DGBI in humans.
To better understand these issues, researchers at New York University conducted a series of studies using transgenic, surgical and pharmacological techniques.
The focus was to explore the effects of intestinal SERT and epithelial serotonin on mood regulation and gastrointestinal function. In addition, they investigated the communication pathways between the intestine and the brain to identify the mechanisms by which these interactions occur.
Much of the research on the mechanisms of the serotonin transporter (SERT) and the role of intestinal epithelial serotonin has been conducted in animal models.
The researchers used transgenic mice and other experimental approaches to manipulate SERT and intestinal serotonin production. These techniques allowed them to observe the effects of these factors on behavior (such as anxiety and depression) and gastrointestinal function.
The scientists also conducted a prospective cohort study in humans that evaluated the effects of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on the development of gastrointestinal disorders based on brain-gut interaction (GBI) in infants during the first year of life, isolating these effects from maternal depressive symptoms.
The experiments revealed that ablating SERT specifically in the intestinal epithelium resulted in positive effects on mood, reducing anxiety-like behaviors and symptoms of depression. These effects were achieved without causing damage to the gastrointestinal tract or brain function.
In contrast, inhibiting serotonin synthesis in the intestinal epithelium had the opposite effect, increasing anxiety levels and depression-related behaviors. This suggests that serotonin balance in the gut plays a crucial role in emotional regulation.
In addition, the researchers identified vagal afferent pathways as the main mechanism by which gut serotonin affects emotional behavior. These pathways connect the gut to the brain, allowing bidirectional communication between the two systems.
The cohort study also yielded important findings. In utero exposure to SSRIs was shown to be a specific risk factor for the development of functional gastrointestinal disorders in infants, particularly functional constipation, during the first year of life.
This effect occurred independently of maternal depressive symptoms, suggesting a direct link between SSRI exposure and gastrointestinal problems in children.
These findings provide new insights into how the gastrointestinal tract influences emotional behaviors, reinforcing the central role of the gut in mood regulation.
In addition, the results suggest an innovative therapeutic approach that targets the gut to treat mood disorders more effectively and with fewer adverse effects.
Finally, the study establishes an important link between intrauterine exposure to SSRIs and the development of DGBI in humans, highlighting the need to consider the potential impacts of this class of drugs during pregnancy. This finding has significant implications for the treatment of pregnant women and for the development of interventions that can mitigate risks to newborns.
READ MORE:
Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood
Lin Y. Hung, Nuno D. Alves, Andrew Del Colle, Ardesheer Talati, Sarah A. Najjar, Virginie Bouchard, Virginie Gillet, Yan Tong, Zixing Huang, Kirsteen N. Browning, Jialiang Hua, Ying Liu, James O. Woodruff, Daniel Juarez, Melissa Medina, Jonathan Posner, Raquel Tonello, Nazli Yalcinkaya, Narek Israelyan, Roey Ringel, Letao Yang, Kam W. Leong, Mu Yang, Ji Ying Sze, Tor Savidge, Jay Gingrich, Robert J. Shulman, Michael D. Gershon, Annie Ouellet, Larissa Takser, Mark S. Ansorge, Kara Gross Margolis
Gastroenterology. December 11, 2024
DOI: 10.1053/j.gastro.2024.11.012
Abstract:
Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although SSRIs are first line pharmacological treatments for these disorders, they may impart adverse effects including anxiety, anhedonia, dysmotility and, in children exposed in utero, an increased risk of cognitive, mood and gastrointestinal disorders. SSRIs act systemically to block SERT and enhance serotonergic signaling in the brain, intestinal epithelium and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development. We utilized transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial SERT or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development. SERT ablation targeted to the intestinal epithelium promoted anxiolytic and anti-depressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms. These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation and suggest a new link in humans between in utero SSRI exposure and DGBI development.
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