American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"Plasticity of enteric neurotransmission varies during day-night cycles and with feeding state.","authors":"Anita J L Leembruggen, Gunes S Yildiz, Justin P Hardee, Lincon A Stamp, Joel C Bornstein, Marlene M Hao","doi":"10.1152/ajpgi.00286.2024","DOIUrl":"10.1152/ajpgi.00286.2024","url":null,"abstract":"<p><p>The circadian cycle is a fundamental biological rhythm that governs many physiological functions across nearly all living organisms. In the gastrointestinal tract, activities such as gut motility, hormone synthesis, and communication between the gut, central nervous system, and microbiome all fluctuate in alignment with the circadian cycle. The enteric nervous system (ENS) is critical for coordinating many of these activities; however, how its activity is governed by the circadian cycle remains unknown. In this study, we used live calcium imaging to examine alterations in enteric neurotransmission during the 24-h day/night cycle in mice. In addition, given the role of food timing as a potent circadian entrainer, we also investigated the impact of an acute 13-h fast on ENS activity. Our findings reveal that enteric neuronal activity typically increases during the dark phase but shifts to the light phase following an acute fast. Importantly, these changes in neuronal activity were not accompanied by alterations in the gene expression of associated neurotransmitter receptors.<b>NEW & NOTEWORTHY</b> Neuronal activity in the enteric nervous system changes during the 24-h day/night cycle, with increased neuronal function detected at night when mice are feeding and active. However, following an acute fast, neuronal sensitivity becomes more pronounced during the day. These changes in neuronal function did not correlate with changes in neurotransmitter receptor gene expression levels.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 2","pages":"G145-G151"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local tissue response to a C-X-C motif chemokine ligand 12 therapy for fecal incontinence in a rabbit model.","authors":"Hannah M Ruetten, Shannon S Lankford, Abolfazl S Abdolmaleki, Nicholas Edenhoffer, Gopal Badlani, James K Williams","doi":"10.1152/ajpgi.00343.2024","DOIUrl":"10.1152/ajpgi.00343.2024","url":null,"abstract":"<p><p>This study aimed to determine if local injection of C-X-C motif chemokine ligand 12 (CXCL12) reduces sphincter fibrosis, restores sphincter muscle content, vascularization, and innervation, and recruits progenitor cells in a rabbit model of anal sphincter injury and incontinence. Adult female rabbits were assigned to three groups: uninjured/no treatment (control), injured/treated (treated), and injured/no treatment (untreated) (<i>n</i> = 4 each). Injured groups were anesthetized, and a section of external anal sphincter was removed at the 9 o'clock position. The treated sphincters were injected with 200 ng of human recombinant CXCL12 6 wk after injury, and necropsy was performed 6-wk post-treatment. The external anal sphincter was removed, fixed, embedded in paraffin, sectioned, and mounted to slides for histologic analysis of collagen and muscle content and fiber characteristics: innervation, vascularization, and progenitor cell content. Compared with controls, untreated had significantly decreased total skeletal muscle, indistinct muscle layers, and disorganized circumferential and inner longitudinal layers at the injury site. Untreated also had significantly increased collagen fiber density at the injury site compared with treated and controls. Cells staining positive for CD34 within the skeletal muscle layer were increased in treated and untreated compared with controls. Staining density for markers of nerves and vascular endothelium, cells staining positive for CD34 within the mucosa/submucosae, and cells staining positive for PAX7 were similar among all groups. Local injection of CXCL12 reduces postinjury fibrosis and results in statistically similar muscle content and organization between treated animals and controls. Further studies are needed for this promising new treatment for postparturient anal sphincter injury.<b>NEW & NOTEWORTHY</b> Local injection of CXCL12 cytokine reduces postinjury fibrosis in a rabbit model of anal sphincter injury and fecal incontinence. The larger size of the rabbits aided in targeted injury and treatment. Further studies are needed to explore noninvasive treatment options for postparturient anal sphincter injury.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G136-G144"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota of patients insusceptible to olanzapine-induced fatty liver disease relieves hepatic steatosis in rats.","authors":"Qian Wu, Jing Wang, Chuyue Tu, Peiru Chen, Yahui Deng, Lixiu Yu, Xiaojin Xu, Xiangming Fang, Weiyong Li","doi":"10.1152/ajpgi.00167.2024","DOIUrl":"10.1152/ajpgi.00167.2024","url":null,"abstract":"<p><p>Olanzapine-induced fatty liver disease continues to pose vital therapeutic challenges in the treatment of psychiatric disorders. In addition, we observed that some patients were less prone to hepatic steatosis induced by olanzapine. Therefore, we aimed to investigate the role and the underlying mechanism of the intestinal flora in olanzapine-mediated hepatic side effects and explore the possible countermeasures. Our results showed that patients with different susceptibilities to olanzapine-induced fatty liver disease had different gut microbial diversity and composition. Furthermore, we performed fecal microbiota treatment (FMT), and confirmed that the gut microbiome of patients less prone to the fatty liver caused by olanzapine exhibited an alleviation against fatty liver disease in rats. In terms of mechanism, we revealed that the cross talk of leptin with the gut-short-chain fatty acid (SCFA)-liver axis play a critical role in olanzapine-related fatty degeneration in liver. These findings propose a promising strategy for overcoming the issues associated with olanzapine application and will hopefully inspire future in-depth research of fecal microbiota-based therapy in olanzapine-induced fatty liver disease.<b>NEW & NOTEWORTHY</b> Patients who were less inclined to have olanzapine-induced fatty liver had different gut microbiota profiles than did those in the susceptible cohort. Lachnospiraceae, Ruminococcaceae, Oscillospiraceae, Butyricicoccaceae, and Christensenellaceae were enriched in patients who were less prone to fatty liver disease caused by olanzapine. Fecal microbiota treatment (FMT) with these fecal samples promoted short-chain fatty acid (SCFA) production, which attenuated the circulating leptin and inhibited FASN and ACC1, thereby suppressing lipid synthesis in the liver, ultimately leading to alleviation of hepatic steatosis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G110-G124"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile acid sequestrant inhibits gluconeogenesis via inducing hepatic cysteine dioxygenase type 1 to reduce cysteine availability.","authors":"David J Matye, Huaiwen Wang, Yifeng Wang, Lei Xiong, Tiangang Li","doi":"10.1152/ajpgi.00353.2024","DOIUrl":"10.1152/ajpgi.00353.2024","url":null,"abstract":"<p><p>Bile acid sequestrants such as cholestyramine (ChTM) are gut-restricted bile acid-binding resins that block intestine bile acid absorption and attenuate hepatic bile acid signaling. Bile acid sequestrants induce hepatic bile acid synthesis to promote cholesterol catabolism and are cholesterol-lowering drugs. Bile acid sequestrants also reduce blood glucose in clinical trials and are approved drugs for treating hyperglycemia in type-2 diabetes. However, the mechanisms mediating the glucose-lowering effect of bile acid sequestrants are still incompletely understood. Here we showed that ChTM treatment decreased hepatic glucose production in Western diet-fed mice with paradoxically induced hepatic gluconeogenic genes. Cysteine dioxygenase type 1 (CDO1) mediates cysteine conversion to taurine and its expression is repressed by bile acids. We show that ChTM induced hepatic CDO1 and selectively reduced hepatic cysteine availability. Knockdown of liver CDO1 increased liver cysteine and glucose production in mice, whereas hepatocytes cultured in cystine-deficient medium showed reduced glucose production. By using dietary protein-restricted and cystine-modified Western diets that selectively alter hepatic cysteine availability, we found that reduced hepatic cysteine availability strongly inhibited glucose production in mice. Interestingly, chronic dietary protein restriction also prevented Western diet-induced obesity, which was fully reversed by restoring dietary cystine intake alone. Consistently, reduced cysteine availability dose-dependently inhibited adipogenesis in vitro. In conclusion, we report that the glucose-lowering effect of bile acid sequestrants is mediated by a CDO1-induced hepatic cysteine restriction mimetic effect. Furthermore, the anti-obesity effect of dietary protein restriction is largely mediated by reduced dietary cysteine intake.<b>NEW & NOTEWORTHY</b> Hepatic cysteine availability is a key driver of hepatic gluconeogenesis. Bile acid sequestrant inhibits gluconeogenesis by inducing CDO1-mediated cysteine catabolism to reduce cysteine availability. Dietary protein restriction causes hepatic cysteine deficiency without overall amino acid deficiency. The glucose-lowering effect of dietary protein restriction is largely mediated by lower dietary cysteine intake. The anti-obesity effect of chronic dietary protein restriction is largely mediated by lower dietary cysteine intake.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G166-G178"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deleterious impacts of Western diet on jejunum function and health are reversible.","authors":"Sarah Carpinelli, John Ahlert, Maxwell Rubin, Alex Aratani, Emma Smith, Dana Floyd, Ross M Potter, Layla Al-Nakkash","doi":"10.1152/ajpgi.00160.2024","DOIUrl":"10.1152/ajpgi.00160.2024","url":null,"abstract":"<p><p>The goal of this study was to determine whether the influence of a high-fat high-sugar diet (Western diet) on intestinal function and health was reversible. We measured transepithelial short circuit current (<i>I</i>_sc), across freshly isolated segments of jejunum from male C57Bl/6J mice randomly assigned to one of the following groups for the study duration: high-fat high-sugar diet for 24 wk (HFHS), HFHS diet for 12 wk then switched to standard chow and water for a further 12 wk (Std), and lean controls (standard chow and water for 24 wk). At the completion of the study, segments of jejunum were frozen for Western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum and tissue assays were performed. Basal <i>I</i>_sc was significantly decreased (by 42%, <i>P</i> < 0.05) in HFHS versus leans. This decrease in <i>I</i>_sc was fully reversed by switching to Std diet. The HFHS-induced decrease in <i>I</i>_sc was attributed to a significant loss of calcium-activated chloride channel (ClC2) expression. Changes in inflammatory state (TNF-α) and intestinal health [myeloperoxidase (MPO) activity] were associated with body weight changes. Our data suggests that the reduced basal jejunal <i>I</i>_sc in HFHS mice is reversible. Better understanding of Western diet-mediated intestinal disturbances may permit for improved treatment options for gastrointestinal abnormalities in obese individuals.<b>NEW & NOTEWORTHY</b> Our data suggests that the reduced basal jejunal <i>I</i>_sc (decreased secretory function) in Western diet-fed mice is reversible. A better understanding of Western diet-mediated intestinal disturbances may permit improved treatment options for gastrointestinal abnormalities in obese individuals.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G83-G93"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico integrative scRNA analysis of human colonic epithelium indicates four tuft cell subtypes.","authors":"Aydin I Herik, Sarthak Sinha, Rohit Arora, Caleb Small, Antoine Dufour, Jeff Biernaskie, Eduardo R Cobo, Derek M McKay","doi":"10.1152/ajpgi.00182.2024","DOIUrl":"10.1152/ajpgi.00182.2024","url":null,"abstract":"<p><p>This study integrated and analyzed human single-cell RNA sequencing data from four publicly available datasets to enhance cellular resolution, unveiling a complex landscape of tuft cell heterogeneity within the human colon. Four tuft subtypes (TC1-TC4) emerged, as defined by unique gene expression profiles, indicating potentially novel biological functions. Tuft cell 1 (TC1) was characterized by an antimicrobial peptide signature; TC2 had an increased transcription machinery gene expression profile consistent with a progenitor-like cell; TC3 expressed genes related to ganglion (neuronal) development; and TC4 expressed genes related to tight junctions. Our analysis of subtype-specific gene expression and pathway enrichment showed variances in tuft cell subtypes between healthy individuals and those with inflammatory bowel disease (IBD). The frequency of TC1 and TC2 differed between healthy controls and IBD. Relative to healthy controls, TC1 and TC2 in IBD tissue showed an upregulation of gene expression, favoring increased metabolism and immune function. These findings provide foundational knowledge about the complexity of the human colon tuft cell population and hint at their potential contributions to gut health. They provide a basis for future studies to explore the specific roles these cells may play in gut function during homeostasis and disease. We demonstrate the value of in silico approaches for hypothesis generation in relation to the putative functions of low-frequency gut cells for subsequent physiological analyses.<b>NEW & NOTEWORTHY</b> This study reveals the nuanced and novel landscape of human colonic tuft cells through integrative scRNA-seq analysis. Four distinct tuft cell subtypes were identified, varying markedly between healthy and individuals with IBD. We uncovered human colonic tuft cell subtypes with unexpected antimicrobial and progenitor-like gene expression signatures. These insights into tuft cell diversity offer new avenues for understanding gut health and disease pathophysiology.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G96-G109"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhamnogalacturonan promotes intestinal mucosal repair through increased cell migration.","authors":"Cristiane H Baggio, Judie Shang, Larissa L Périco, Raquel C Dos Santos, Marilyn H Gordon, Bruna B Da Luz, Matthew Stephens, Adamara M Nascimento, Maria Fernanda P Werner, Pierre-Yves von der Weid, Thales R Cipriani, Wallace K MacNaughton","doi":"10.1152/ajpgi.00170.2024","DOIUrl":"10.1152/ajpgi.00170.2024","url":null,"abstract":"<p><p>Mucosal healing is the primary goal for inflammatory bowel disease (IBD) treatment. We previously showed the direct beneficial effects of rhamnogalacturonan (RGal) on intestinal epithelial barrier function. Here, we aimed to evaluate the effect of RGal in intestinal epithelial wound healing. Confluent cancer cell lines and colonoid monolayers were wounded, treated with RGal for 48 h, and assessed using a live cell imaging system. Proliferation and apoptosis of cells were evaluated using 5-ethynyl-2'-deoxyuridine (EdU) and TUNEL assays, respectively. Inhibitors were used to determine the receptor and signaling pathways involved. Female and male mice with DSS-induced colitis were treated orally with RGal for 7 days during the recovery phase. RGal enhanced wound healing in Caco-2, T84, and primary cells by increasing cell migration. Inhibition of pretranscriptional signaling pathways FAK, Src, PI3K, Rho family, and JNK reversed the RGal-induced wound healing. RNAseq data from Caco-2 and primary cells treated with RGal showed the upregulation of the NF-κB pathway at 12 h. Actinomycin D, Bay 11-7082 or JSH-23, and NS-398 treatment significantly reversed the effect of RGal on wound healing, confirming that the response was also transcriptionally dependent and involved NF-κB signaling and downstream COX-2 protein activity. RGal treatment of male mice enhanced recovery from DSS colitis. RGal promoted wound healing in cancer and primary cells by increasing cell migration and accelerated epithelial mucosal healing in male mice. Our findings show a novel mechanism of action of RGal in wound healing that could help in mucosal healing and the resolution of intestinal inflammation.<b>NEW & NOTEWORTHY</b> RGal increases wound healing in colon cancer cell lines and primary cells through increased cell migration and participation of important pretranscriptional signaling pathways and the transcription factor NF-κB. In addition, RGal also accelerates intestinal mucosal healing of male mice with DSS-induced colitis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G152-G165"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered parasympathetic outflow and central sensitization response to continuous pain in cyclic vomiting syndrome: a functional magnetic resonance imaging study.","authors":"Andrew Bolender, Rowan Staley, Ronald G Garcia, Riccardo Barbieri, Ovidiu Andronesi, Shahar Castel, Andrea Thurler, Vitaly Napadow, Braden Kuo, Roberta Sclocco","doi":"10.1152/ajpgi.00011.2024","DOIUrl":"10.1152/ajpgi.00011.2024","url":null,"abstract":"<p><p>Cyclic vomiting syndrome (CVS) is a disorder of brain-gut interaction characterized by recurrent episodes of nausea and vomiting interspersed with asymptomatic periods and associated with autonomic nervous system dysfunction. We examined the dysautonomic response to noxious stimuli for patients with CVS using our previously validated approach to integrate peripheral autonomic outflow metrics, temporal summation of pain, and brain functional MRI (fMRI). Blood oxygen level-dependent (BOLD) fMRI and ECG were acquired from patients with CVS and healthy adults during both a rest condition and a sustained cuff pressure-pain stimulus at the leg. After the latter scan, participants rated pain for the first, middle, and last 2 min to calculate temporal summation. During sustained pain, patients, relative to healthy controls, exhibited greater reduction in heart rate variability within the high-frequency range (HF-HRV) and reduced anticorrelation between HF-HRV and fMRI signal in the anterior insula, pregenual anterior cingulate cortex, and ventrolateral and dorsolateral prefrontal cortex. Compared with healthy adults, patients also exhibited increasing pain intensity over the course of sustained cuff pressure. For healthy adults, seed-based functional connectivity analysis revealed pain sensitization correlated with pain-induced increases in connectivity between primary somatosensory cortex and regions of interest in both left anterior insula/posterior orbitofrontal cortex and right presupplementary motor area. These correlations were not seen in CVS, thus supporting a conclusion of altered central coding of nociceptive stimuli and autonomic responsivity of patients with CVS in key brain regions implicated in autonomic control and interoception.<b>NEW & NOTEWORTHY</b> Patients with cyclic vomiting syndrome exhibit multiple alterations in central function in response to a sustained pressure-pain stimulus, including altered high-frequency heart rate variability and associated changes in BOLD fMRI signal in key areas of the central autonomic and interoceptive networks, as well as abnormal temporal summation of pain associated with altered connectivity patterns between the primary somatosensory cortex and key regions associated with interoception.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G125-G135"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmenting anti-inflammatory macrophage function in colitis: a neuroimmune mechanism to drive intestinal wound repair.","authors":"Natalie Bhesania, Michael A Schumacher","doi":"10.1152/ajpgi.00368.2024","DOIUrl":"10.1152/ajpgi.00368.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G94-G95"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.","authors":"Alice L Mitchell, Iain R Tough, Hei Man Fan, Anita Lovgren-Sandblom, Caroline Ovadia, Jenny Chambers, Patricia Fonseca Pedro, Anastasia Tsakmaki, Gavin A Bewick, Hanns-Ulrich Marschall, Helen M Cox, Catherine Williamson","doi":"10.1152/ajpgi.00211.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00211.2024","url":null,"abstract":"<p><p>Sulfated progesterone metabolites (PMxS) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by pruritus and elevated serum bile acids. PMxS interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxS were quantified in pre-/postprandial serum samples (n=21) and feces (n=18) by ultra-performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (ΔIsc) in wildtype, GPBAR1^-/-, and PYY^-/- mice by PMxS metabolites, PM3S and PM5S, and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition (n=6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and GPBAR1^-/- murine crypts and human colonoids was measured by ELISA (n=3). Serum PMxS increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxS are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -ΔIsc in wildtype (p<0.01) but not GPBAR1^-/- or PYY^-/- colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids (p<0.001). ASBT inhibition blunted -ΔIsc by 68% after apical PM3S and PM5S addition (p<0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}