The recent study by Venkataraman et al. (Science, 2025) elucidates a novel peripheral mechanism that contributes to the higher prevalence of visceral pain disorders, such as irritable bowel syndrome (IBS) in females 1. Through the identification of an estrogen-mediated paracrine signaling pathway involving L cells, enterochromaffin (EC) cells, and mucosal sensory nerves, the researchers offer a cellular and molecular framework for understanding sex-specific gut sensitivity, addressing a longstanding puzzle in the fields of gastroenterology and pain research. This commentary underscores the transformative potential of these findings for advancing digestive neurobiology and informing clinical practice. The study elucidates that estrogen receptor alpha (ERα) in colonic L cells, rather than in EC cells, plays a pivotal role in modulating visceral hypersensitivity. Estrogen signaling leads to the upregulation of the short-chain fatty acid (SCFA) receptor Olfr78 on L cells, thereby increasing their responsiveness to bacterial metabolites such as acetate. This process induces the release of peptide YY1-36 (PYY1-36), which subsequently activates neuropeptide Y receptor 1 (NPY1R) on adjacent EC cells, resulting in the secretion of serotonin (5-HT). The activation of 5-HT3 receptors (5-HT3R) on spinal afferents further amplifies nociceptive signaling. This “L cell → EC cell → sensory nerve” pathway provides a comprehensive understanding of how hormonal fluctuations, dietary components (via SCFAs), and neural mechanisms interact to enhance pain sensitivity in females. Traditionally regarded as a satiety hormone, PYY1-36 is reconceptualized in this study as a pivotal nociceptive transmitter within the colon. This reorientation shifts the emphasis from its systemic metabolic functions to its role in local paracrine signaling involved in gut-brain communication. The study's key insight lies not only in assigning a new function to peptide YY (PYY), but in distinguishing between its molecular forms: whereas circulating PYY3-36 is known for its endocrine role in appetite control, the colonic mucosa utilizes paracrine signaling of PYY1-36 to mediate nociception. This molecular and spatial distinction underscores the potential for targeting local PYY1-36 signaling as a more precise therapeutic strategy, circumventing the systemic effects associated with global PYY modulation. Furthermore, EC cells are identified as coincidence detectors that integrate hormonal (estrogen), microbial (SCFAs), and neural signals, thereby establishing them as critical nodes in the modulation of sex-specific visceral pain. These findings also offer a potential mechanistic perspective on the efficacy of low-FODMAP diets in managing IBS 2. By restricting fermentable carbohydrate intake, such diets may alter the substrate availability for colonic microbiota, thereby indirectly modulating SCFA production and subsequent Olfr78 receptor activation. This insight opens new avenues for integrating dietary interventions with hormonal status in personalized treatment approaches. The study identifies two actionable targets: NPY1R antagonists (e.g., BIBO3304) and 5-HT3R antagonists (e.g., alosetron), both shown to reduce estrogen-induced hypersensitivity in preclinical models. These findings advocate for the development of sex-specific therapeutic approaches for IBS 2, 3, with a particular focus on premenopausal women. Furthermore, the study suggests that monitoring hormonal status, including factors such as the menstrual cycle and pregnancy, could enhance the precision of dietary interventions, as estrogen sensitizes L cells to fermentable carbohydrates. Venkataraman et al. elucidate the peripheral mechanisms underlying female visceral hypersensitivity; however, pain perception fundamentally involves integration within the central nervous system. Estrogen modulates pain transmission and affective processing both locally in the colon and at central sites, including the spinal cord, brainstem, and limbic system 4. Future research should clarify how these central pathways interact with the peripheral L cell-EC cell-sensory nerve axis to form a comprehensive gut-brain network. Psychosocial factors warrant significant consideration in the context of gut function. Stress impacts gut physiology through the hypothalamic-pituitary-adrenal (HPA) axis and engages in bidirectional interactions with estrogen signaling. Chronic stress can modify estrogen receptor expression, whereas estrogen, in turn, influences the reactivity of the stress axis 4, 5. This complex interaction suggests that the peripheral PYY-5-HT pathway may be subject to dual regulation by hormonal and stress-related inputs. From a translational perspective, it is imperative for human studies to validate the dynamics of PYY1-36 in the colonic mucosa and to evaluate the safety and efficacy of NPY1R antagonists in clinical trials, particularly among women with varying hormonal statuses, such as those associated with the menstrual cycle or pregnancy 3. Additionally, the influence of other sex hormones, such as progesterone, on EC cell function and pain pathways requires further exploration 3. The integration of peripheral biomarkers, neuroimaging, and psychosocial variables holds the potential to facilitate the development of personalized pain prediction models and advance precision medicine approaches for functional gastrointestinal disorders 3-5. Venkataraman et al. provide an insightful elucidation of a peripheral mechanism underlying female visceral hypersensitivity. By redefining PYY as a pain transmitter and EC cells as signal integrators, their study significantly reshapes the field of neurogastroenterology. The potential therapeutic benefits of NPY1R antagonism and hormonally-guided dietary interventions are evident; however, successful clinical translation necessitates rigorous validation across varied hormonal environments. Importantly, this research prompts further exploration beyond peripheral mechanisms: how do central neural pathways, stress, and other sex hormones interact within this circuit? Ultimately, this study not only addresses a longstanding question but also pioneers a new area of inquiry, emphasizing that sex is not merely a variable but a fundamental biological factor in the advancement of precision medicine. Yu Wang: conceptualization, methodology, writing – original draft, writing – review and editing. Jin Song: writing – review and editing, conceptualization. Yu Wang is a member of the Editorial Board of Gut Medicine and a co-author of this article. He was excluded from all editorial decisions regarding the acceptance of this article for publication. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
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