Myosin 5b (MYO5B) is a motor protein that plays an essential role in trafficking proteins to the apical membrane. Recent studies have demonstrated that MYO5B traffics ion transporters, like NHE3, DRA, and SGLT1, water ch...Myosin 5b (MYO5B) is a motor protein that plays an essential role in trafficking proteins to the apical membrane. Recent studies have demonstrated that MYO5B traffics ion transporters, like NHE3, DRA, and SGLT1, water channels, like AQP7, and efflux transporters, like P-glycoprotein. However, the role of MYO5B in trafficking glycoproteins involved in mucosal defense remains unclear. Here, we investigate whether MYO5B is required for the apical localization of MUC13 and DMBT1; two glycoproteins critical for epithelial protection and wound healing. To address the requirement of MYO5B in glycoprotein trafficking, we immunostained the small intestine and colon of neonatal germline and adult inducible intestine-specific MYO5B-knockout (KO) mice and examined MUC13 and DMBT1 localization. Organoids derived from germline and inducible KO mice were analyzed to confirm findings in an epithelial-only system. Additionally, staining was performed on human organoids expressing MYO5B-Tail GFP. MYO5B loss resulted in the intracellular accumulation of MUC13 and DMBT1, reducing their colocalization with the apical marker γ-actin in both models. MUC13 colocalized with the lysosomal marker LAMP1 in adult mice after MYO5B loss, indicating that a portion of cytoplasmic MUC13 undergoes lysosomal degradation. Mislocalization of MUC13 was observed in intestinal MYO5B-deficient organoids. MYO5B-Tail GFP was associated with MUC13 in human intestinal organoids. MYO5B is required for the apical delivery of MUC13 and DMBT1 in the intestinal epithelium. Disrupting this pathway may contribute to mucosal dysfunction in MYO5B-related diseases, highlighting potential therapeutic targets for restoring epithelial barrier integrity.
Lin LY, Lin YH, Tu CH
… +5 more, Wu MS, Kuo WT, Sun CH, Hsin LW, Yu LC
Am J Physiol Gastrointest Liver Physiol
· 2026 Jun · PMID 42370976
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Post-infectious irritable bowel syndrome (PI-IBS) is defined by persistent gastrointestinal symptoms that follow recovery from an episode of infectious enteritis, which worsen after experiencing psychological stress. Muc...Post-infectious irritable bowel syndrome (PI-IBS) is defined by persistent gastrointestinal symptoms that follow recovery from an episode of infectious enteritis, which worsen after experiencing psychological stress. Mucosal neurite outgrowth stimulated by neurotrophins and serotonin/5-hydroxytryptamine receptor subtype 7 (5-HT) activation is linked to visceral hypersensitivity. Rifaximin (RFX) is a poorly absorbed antibiotic that improves IBS symptoms; however, the exact mechanisms remain unclear. The aims are to evaluate changes in microbiota and neuroplasticity in PI-IBS mice after RFX treatment, and the analgesic effects of combined treatment with a novel 5-HT antagonist CYY1005 (CYY). A mouse model with dual triggers of postinfection and water avoidance stress exhibited intestinal hyperalgesia, as measured by visceromotor responses (VMRs). Higher Shannon diversity and increased relative abundances of , , and were observed in the microbiota of PI-IBS mice, which were restored to baseline after RFX treatment. Reduced VMRs were associated with attenuated mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression after RFX treatment. BDNF/TrkB activation induced mTOR-dependent nerve fiber elongation and upregulated tryptophan hydroxylase 2 and 5-HT expression via Rac1/ROCK pathway in SH-SY5Y neuron cultures. Combined treatment with RFX and CYY reduced VMRs to levels comparable to those of the control groups. Lastly, bacteria-free colonic mouse supernatants induced neurite elongation in SH-SY5Y cells, which was inhibited by neutralizing anti-BDNF antibodies. In conclusion, microbiota restoration by RFX treatment attenuated BDNF-induced neurite outgrowth and alleviated visceral hypersensitivity in mice. Analgesic combinations of RFX and a 5-HT receptor antagonist reduced intestinal nociception to baseline levels.
Moutsoglou D, Jarrah M, Jaques J
… +4 more, Aguilar L, Shahi SK, Mangalam AK, Mokadem M
Am J Physiol Gastrointest Liver Physiol
· 2026 Jun · PMID 42339741
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The circadian clock and gut microbiome are integral regulators of metabolic homeostasis, with disruptions in either system contributing to obesity pathogenesis. Roux-en-Y gastric bypass (RYGB) effectively treats severe o...The circadian clock and gut microbiome are integral regulators of metabolic homeostasis, with disruptions in either system contributing to obesity pathogenesis. Roux-en-Y gastric bypass (RYGB) effectively treats severe obesity, yet the mechanisms underlying its benefits remain incompletely characterized. We investigated the impact of RYGB on cecal gut microbial composition and function using 16S rRNA sequencing in relation to host circadian gene expression and metabolic parameters in diet-induced obese mice. Diet-induced obese mice underwent RYGB or sham surgery and were compared with lean controls across multiple circadian Zeitgeber time (ZT) points (ZT3, ZT9, ZT15, ZT21). Principal component analysis at the ASV level revealed significant differences in all ZT points (ZT3, ZT9, ZT15, and ZT21) in the lean and sham-operated mice; however, only a significant difference between ZT9 and ZT21 was observed in RYGB mice. Microbial gene counts and microbial pathways were also different between RYGB and sham-operated mice, with several correlating with hepatic and gene expression. Notably, specific taxa showed differential associations with glucose homeostasis, independent of surgical intervention. These findings demonstrate that RYGB alters the gut microbiome and host circadian rhythms, suggesting an association between microbial remodeling, circadian gene expression, and metabolic improvement following bariatric surgery.
Bose A, Bopanna Y, Shetty P
… +9 more, Sharma K, Mathew JKK, Mishra V, Bannerjee S, Ramani H, Pulimood AB, Bhat R, Shenoy AR, Visweswariah SS
Am J Physiol Gastrointest Liver Physiol
· 2026 Jun · PMID 42339686
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Hyperactivating mutations in guanylyl cyclase C (GC-C) are monogenic causes of early-onset inflammatory bowel disease, familial diarrheal syndrome and congenital secretory diarrhea. The mechanisms linking elevated cGMP l...Hyperactivating mutations in guanylyl cyclase C (GC-C) are monogenic causes of early-onset inflammatory bowel disease, familial diarrheal syndrome and congenital secretory diarrhea. The mechanisms linking elevated cGMP levels to immune imbalance remain poorly defined. Here, using a preclinical model of a disease-associated GC-C mutation, we observe pleiotropic alterations in the small intestinal epithelium. Transcriptomic and functional analyses revealed impaired Paneth and goblet cell differentiation, compromised barrier integrity, heightened epithelial permeability, and increased proinflammatory cytokine levels. Intestinal organoids from mutant mice exhibited amplified cGMP responses to GC-C ligands and defects in secretory lineage specification, confirming cell-autonomous mechanisms. Strikingly, oral zinc administration suppressed aberrant GC-C activity, normalized cGMP levels and restored barrier function. These findings highlight the central role of epithelial cGMP signaling in coordinating barrier integrity and immune-epithelial interactions, and identify zinc as a tractable therapeutic strategy for GC-C-mediated intestinal disorders.
Wu H, Mu C, Li X
… +4 more, Shen L, Liu Z, Yu K, Zhu W
Am J Physiol Gastrointest Liver Physiol
· 2026 Jun · PMID 42315096
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The potential role of human milk oligosaccharides (HMO) in regulating intestinal epithelial cell proliferation and differentiation in mammals has attracted considerable attention. Fucosylated HMO can provide fucosylated...The potential role of human milk oligosaccharides (HMO) in regulating intestinal epithelial cell proliferation and differentiation in mammals has attracted considerable attention. Fucosylated HMO can provide fucosylated glycans to the intestine of newborns, an outcome similar to genetic overexpression of fucosyltransferase. However, how HMO, such as 2'-fucosyllactose (2'-FL), may impact small intestinal fucosylation to regulate intestinal stem cell (ISC)-mediated intestinal epithelial development remains unknown. In the present study, we employed a model of small intestinal fucosylation inhibition in rats by orally administering a fucosylation inhibitor, 2F-peracetyl-fucose (2F-Fuc) from postnatal day 4 (PN4) to postnatal day 21 (PN21). Inhibition of jejunal fucosylation of rats during the breastfeeding stage significantly promoted ISC differentiation toward the secretory lineage through inhibiting Notch signaling pathways. Further, fucosylation inhibition caused ISC differentiation deregulation in the jejunum that persisted until PN day 42, even though 2F-Fuc was no longer administered after weaning at PN21. 1,2-fucosylated oligosaccharide supplementation by 2'-FL after weaning ameliorated the long-term effects of fucosylation inhibition in rats on ISC differentiation, changes in mucus-degrading microbiota. These results demonstrate that intestinal fucosylation in rats paly an important role in maintaining the balance between ISC proliferation and differentiation. Our study offers new insights into the interactions between intestinal fucosylation and ISC function. It also establishes a research foundation for using 2'-FL as a donor for α1,2-fucosylated glycans, enabling targeted modifications in intestinal fucosylation to enhance gut health, particularly small intestine health.
The potential role of pancreatic fat on human β-cell dysfunction and its association with fibrosis are controversial. From the PANC-DB database, we estimated β-cell function with glucose-stimulated insulin secretion (GSI...The potential role of pancreatic fat on human β-cell dysfunction and its association with fibrosis are controversial. From the PANC-DB database, we estimated β-cell function with glucose-stimulated insulin secretion (GSIS) and quantified fat infiltration and fibrosis using pancreatic histology sections from 45 organs from cadaveric organ donors. In the donors without diabetes, high fat infiltration and adipocyte size in the pancreatic septum were associated with lower GSIS. Low GSIS in fatty pancreas was confirmed in living pancreatic tissue slices. This association is dependent on age and global adiposity and independent of fibrosis. These results suggest that the localization and phenotype of fat infiltration in the pancreas are important factors to determine the role of adipose tissue on pancreatic endocrine function. Adipose tissue infiltration in the pancreas and its potential implication in the development or maintenance of diabetes has been and is still intensively investigated. In this short communication, we showed negative association between pancreatic fat infiltration and glucose-stimulated insulin secretion (GSIS), specifically in T2D. In addition, interlobular adipocyte size correlated positively with body mass index, age, and HbA1c, and negatively with GSIS. This suggests that adipocyte phenotype, rather than fat quantity alone, may influence β-cell function.
Although recognized as a key regulator of gastrointestinal tissues, Wnt signaling pathway function in the stomach is poorly understood. This study aimed to define Wnt functions and identify Wnt-regulated genes in the sto...Although recognized as a key regulator of gastrointestinal tissues, Wnt signaling pathway function in the stomach is poorly understood. This study aimed to define Wnt functions and identify Wnt-regulated genes in the stomach. Reporter mouse analysis localized Wnt signaling to the base and proliferative region in both the corpus and the antrum. Canonical Wnt inhibition in vivo using ; mice reduced epithelial cell proliferation with loss of gastric stem cells. Wnt-regulated genes and potential effector pathways were studied by bulk RNA sequencing (RNA-Seq) analysis of corpus and antral organoids 24 h after Wnt inhibition in vitro. Cell signature analysis revealed that gastric organoids adopt a surface cell transcriptional profile following Wnt inhibition instead of a basal cell profile. Furthermore, retinoid metabolism terms were differentially expressed after Wnt inhibition, with decreased expression of retinoic acid target genes. Inhibition of retinoic acid signaling in corpus and antral organoids showed a marked increase in surface cell marker expression, consistent with the effects of Wnt inhibition. In the mouse, immunostaining showed differential localization of retinoid metabolic components in luminal pit cells (ALDH3A1) and basal chief/deep mucous cells (STRA6), with expression changes after β-catenin deletion in ; mice, consistent with the Wnt-regulated cell fate changes observed in organoids. Together, these studies showed that Wnt signaling is required for gastric stem cell survival and promotes differentiation of cell types at the gland base. We identified retinoid metabolism as a candidate Wnt-regulated pathway, with cell-specific expression of key components, and regulation of surface cell marker expression by retinoic acid signaling. Using mouse genetic and organoid models, we show that canonical Wnt signaling promotes gastric epithelial cell proliferation and regulates differentiation along the base-lumen gland axis in the stomach. Transcription profiling of Wnt-inhibited gastric organoids identified retinoic acid signaling as a potential Wnt-regulated effector pathway in the stomach. Accordingly, manipulation of retinoic acid signaling in organoids altered differentiated marker expression consistent with Wnt inhibition, supporting the presence of a Wnt-retinoic acid signaling axis in the stomach.
Hirschsprung disease (HSCR) is a life-threatening congenital disorder characterized by defective migration and proliferation of enteric neural crest cells (ENCCs), a process in which the receptor tyrosine kinase plays a...Hirschsprung disease (HSCR) is a life-threatening congenital disorder characterized by defective migration and proliferation of enteric neural crest cells (ENCCs), a process in which the receptor tyrosine kinase plays a central regulatory role. However, the regulatory mechanisms governing expression remain incompletely understood. In the present study, we identify the circular RNA circRET (hsa_circ_0093651) as a critical translational regulator of its parental gene and explore its role in HSCR pathogenesis. We demonstrate that circRET is significantly downregulated in the colonic tissues from patients with HSCR and directly binds mRNA, modulating RET protein synthesis at the translational level without altering mRNA abundance. Notably, circRET interacts with the coding region of mRNA, potentially facilitating its translation. circRET knockdown suppresses signaling and impairs ENCC migration, proliferation, and distal colon colonization. Our study uncovers a novel circRET-mediated regulatory mechanism of its parental gene , with potential implications for therapeutic targeting in HSCR. Hirschsprung disease (HSCR) results from impaired enteric neural crest cell development, in which plays a central role. Here, we identify circRET as a translational regulator of . circRET is downregulated in HSCR tissues and modulates RET protein by directly binding mRNA without affecting mRNA levels. Loss of circRET suppresses /AKT signaling and ENCC migration, highlighting a novel regulatory mechanism with therapeutic relevance.
Swift KA, Shumway AJ, Aloia M
… +12 more, Hedges M, Pung R, Liu M, Rodriguez Santiago C, Shanahan MT, Drake A, Hakar MH, Selesner L, Kuhn M, Yung C, Sethupathy P, Andres SF
Am J Physiol Gastrointest Liver Physiol
· 2026 Jun · PMID 42242905
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Necrotizing enterocolitis (NEC) is the most deadly gastrointestinal disease in preterm neonates, with up to 50% mortality. There is no cure for NEC. Enhancing our understanding of intestinal epithelial cell (IEC) respons...Necrotizing enterocolitis (NEC) is the most deadly gastrointestinal disease in preterm neonates, with up to 50% mortality. There is no cure for NEC. Enhancing our understanding of intestinal epithelial cell (IEC) responses to NEC will provide novel therapeutic targets. The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) plays roles in intestinal development and repair. Notably, roles for IMP1 in NEC are unknown. Intestinal goblet cells produce protective mucus, and their function depends on the transcription factor Spdef. Evidence suggests that goblet cell mucus glycosylation affects barrier function and inflammation. We aimed to define the role of IMP1 in NEC damage response using neonatal human enteroids and a NEC-like intestinal injury model. At post-natal day 3, wild-type mice or littermates with IEC-specific Imp1 overexpression () or loss () were assigned to control or NEC groups. NEC was induced with stress, formula feeding, bacterial exposure, and hypoxia. Imp1 effects on NEC response were assessed using RNA sequencing, western blotting, immunostaining, and a cytokine array. We found that pro-inflammatory bacteria induced expression in neonatal human enteroids. During NEC, mice exhibit more severe intestinal damage and priming for lytic cell death. Elevated Imp1 levels were linked to a Spdef transcriptional signature and in silico analysis predicted Imp1 binding to and mucus glycosylation mediator mRNAs. Functionally, Imp1 increased fucosylation in the intestinal epithelium. Collectively, results suggest that Imp1 primes the intestine for lytic death and promotes the production of fucosylated mucus, changes which could alter the damage response.
Yadav V, Sharma D, Yadav V
… +15 more, Kilambi R, Mohapatra N, Bhardwaj A, Patil NS, Sasturkar SV, Rastogi A, Bhatia G, Kumari A, Perumal N, Agrawal K, Maras JS, Trehanpati N, Pamecha V, Sarin SK, Ramakrishna G
Am J Physiol Gastrointest Liver Physiol
· 2026 Jun · PMID 42223192
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India accounts for 10% of the global gallstone disease (GSD) and gallbladder cancer (CaGB) burden. CaGB's poor prognosis necessitates early detection of biomarkers. We used targeted/untargeted plasma metabolomics in huma...India accounts for 10% of the global gallstone disease (GSD) and gallbladder cancer (CaGB) burden. CaGB's poor prognosis necessitates early detection of biomarkers. We used targeted/untargeted plasma metabolomics in human and mouse models to identify metabolite biomarkers for gallbladder disease. LC-MS-based metabolomics was performed on plasma samples in the discovery cohort (14 healthy controls, 30 GSD, and 56 CaGB). The identified metabolite signature was validated in 45 samples, and the candidate metabolite was further examined using targeted LC-MS in an independent cohort (N=30). Trimethylamine N-oxide (TMAO) emerged as a significant metabolite that was evaluated in female C57BL/6 mice fed a lithogenic diet. Untargeted metabolomics from the discovery cohort identified 172 significantly altered metabolites (p<0.05), with a 20-metabolite signature discriminating groups with high accuracy (AUC: GSD 0.98, CaGB 0.93; validation: GSD 0.87, CaGB 0.95). TMAO was significantly elevated in GSD and CaGB (p<0.001), with predictive values (AUC: GSD 0.96, CaGB 0.85). Targeted analysis confirmed two-fold higher plasma TMAO in patients (p<0.001). Female C57BL/6 mice fed on lithogenic diet (LD) with 0.3% TMAO (LD+TMAO) showed higher prevalence with early onset at 12 weeks. TMAO induced epithelial metaplasia, hyperplasia, and altered mRNA expression of bile acid regulators (ABCC3, FXR, TGR5), and IL-10. Immunohistochemistry in mouse gallbladder tissue showed increased FXR and reduced TGR5 expression, following TMAO treatment. TMAO is a key metabolite associated with GSD and CaGB. TMAO supplementation with lithogenic diet accelerated gallstone formation, accompanied by preneoplastic changes, and disrupted bile acid regulation.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder in which dysregulated inflammation plays a central role. We previously reported that macrophage-specific deletion of...Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder in which dysregulated inflammation plays a central role. We previously reported that macrophage-specific deletion of autotaxin (ATX) exacerbates inflammatory responses, including lipopolysaccharide -induced peritonitis and interleukin-10 deficiency-mediated colitis in mice. Moreover, circulating ATX levels are elevated in patients with MASLD. This study aimed to determine whether macrophage-specific ATX deficiency influences MASLD progression. To this end, MASLD was induced using amylin liver nonalcoholic steatohepatitis (AMLN) diet in macrophage-specific ATX knockout (Atx) and wild-type (Atx) mice. ATX deficiency in macrophages promoted lipid droplet deposition in hepatocytes and hepatic triglyceride accumulation, thereby aggravating liver steatosis. Serum alanine aminotransferase, aspartate transaminase, and total cholesterol levels were significantly higher in Atx AMLN mice compared with Atx AMLN mice. In addition, ATX deletion increased proinflammatory cytokine production in both Kupffer cells and hepatocytes. Notably, the expression of sterol regulatory element-binding transcription factor 1 and carbohydrate-responsive element-binding protein was elevated in Atx AMLN mice. Collectively, these findings demonstrate that macrophage-specific ATX deficiency accelerates MASLD progression by enhancing inflammation and upregulating lipogenic transcription factors, leading to increased hepatic lipid accumulation. This study reveals a protective role of macrophage-derived autotaxin (ATX) in liver homeostasis, demonstrating that its cell-specific deletion exacerbates hepatic steatosis, inflammation, and injury in a diet-induced metabolic dysfunction-associated steatotic liver disease model. Mechanistically, loss of ATX enhances proinflammatory cytokine production in Kupffer cells and hepatocytes, while upregulating lipogenic transcription factors, such as and . These findings highlight macrophage-derived ATX as a critical regulator of hepatic lipid metabolism by restraining inflammation-driven lipogenesis.
Ogasawara K, Uno K, Tamahara T
… +11 more, Asano N, Sudo K, Kusano K, Tanabe M, Kaise Y, Shindo T, Shimoyama Y, Kanno T, Koike T, Shimizu R, Masamune A
Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administrati...Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administration of a high-fat diet (HFD) and acid bile salts (ABS) to K19-Wnt1/C2mE mice might promote the metabolic-driven tumor growth at the squamocolumnar junction (SCJ) cooperatively with gut dysbiosis. To clarify whether ABx-induced dysbiosis promotes tumorigenesis, we evaluated the effects of HFD + ABS ± ABx treatment on tumor immune evasion in mice. In HFD + ABS + ABx-treated mice, SCJ tumor growth with increased tumor cell proliferation and infiltration of inflammatory cells positive for CD8, programmed cell death protein 1, and programmed cell death-ligand 1 (PD-L1) was observed, along with apoptosis suppression. Protein expressions of interferon-gamma (IFNγ) and phosphorylated signal transducer and activator of transcription (p-STAT) 3 were upregulated in the tumors of the HFD + ABS + ABx group, whose p-STAT1 expression was equivalent to that of the control group. The mice exhibited insulin resistance and metabolic endotoxemia, and metagenomic analysis of their ileal excrement revealed dysbiosis with a decrease in butyrate-producing bacteria and bacterial butanoate metabolism activity. Moreover, IFNγ stimulation of human-derived NUGC-4 cells increased the protein expression of PD-L1, p-STAT1, and p-STAT3, all of which decreased in response to STAT inhibitors. Transfection with small interfering RNA targeting or did not attenuate PD-L1 induction, which was inhibited by the combined knockdown. Therefore, oral HFD + ABS + ABx administration to K19-Wnt1/C2mE mice may promote SCJ tumors through tumor immune evasion via IFNγ-STAT1/STAT3-PD-L1 signaling, along with metabolic endotoxemia. Coadministration of antibiotics with a high-fat diet and acid bile salts exacerbated dysbiosis, insulin resistance, and systemic inflammation, thereby promoting tumor progression via tumor immune evasion at the squamocolumnar junction (SCJ) in K19-Wnt1/C2mE mice. In the tumor, interferon-gamma-induced programmed death-ligand 1 through the activation of signal transducer and activator of transcription 1 (STAT1) and STAT3. Understanding the link between dysbiosis and tumor immunity might aid in the development of new immunotherapies for SCJ tumors.
Severe acute pancreatitis (SAP) often leads to incomplete tissue repair and prolonged exocrine dysfunction. Acinar-to-ductal metaplasia (ADM) is a critical regenerative process postinjury, but persistent ADM impedes func...Severe acute pancreatitis (SAP) often leads to incomplete tissue repair and prolonged exocrine dysfunction. Acinar-to-ductal metaplasia (ADM) is a critical regenerative process postinjury, but persistent ADM impedes functional recovery. Axl and Mertk belong to the TAM family of receptor tyrosine kinases, which are expressed primarily in macrophages to mediate efferocytosis and promote pro-resolving macrophage polarization, and have been implicated in tissue repair. However, their roles in resolving ADM and restoring exocrine function remain unclear. We utilized cerulein-induced SAP models in mice with either global or cell-specific deletion of and . Pancreatic repair was assessed by histology, transcriptomics, and functional assays. Coculture of primary acinar cells with bone marrow-derived macrophages. The expression of AXL and MERTK in the pancreas was upregulated on during pancreatic repair after SAP. Global deletion of and similarly delayed tissue repair, resulting in persistent ADM, impaired acinar redifferentiation, and defective restoration of exocrine function. Transcriptomics revealed aberrant activation of developmental signaling pathways, including Hedgehog, Wnt, and Notch, and sustained suppression of acinar digestive enzyme genes. In vitro coculture experiments showed that M2 macrophages lacking and promoted persistent ADM, in contrast to M1 macrophages. AXL and MERTK in macrophages are crucial regulators of pancreatic regeneration after SAP, facilitating ADM resolution and exocrine recovery through interactions between acinar cells and M2 macrophages. These findings highlight that macrophage AXL and MERTK could act as a potential therapeutic target for enhancing long-term restoration of pancreatic function following SAP. Deleting Axl and Mertk in myeloid cells disrupts the healing process, resulting in persistent ductal structures and failure to recover exocrine function. This repair failure is linked to the abnormal persistence of developmental signaling pathways and is mediated by interactions between acinar cells and macrophages, emphasizing the importance of AXL and MERTK in macrophages in pancreatic functional recovery.
Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; howev...Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines, as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases, such as the inflammatory, proliferative, and remodeling phase, may result in severe complications, characterized by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer to understanding the underlying AL etiology. It is clear that ALs are multifactorial in nature and contribute to by patient-, technical-, and biological-related factors; however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation, and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors to failed anastomotic healing and AL etiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing, and describe the advancements made to improve AL rates by targeting the healing response.
Yeoh BS, Sah SK, Saha P
… +5 more, Joe B, Gewirtz AT, Sodeman T, Reddivari L, Vijay-Kumar M
Am J Physiol Gastrointest Liver Physiol
· 2026 May · PMID 42132441
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Cholemia, , elevated circulating bile acids (BA), is an early feature of hepatobiliary disorders. However, cholemia often goes undetected because BA are not measured in routine health screenings. We hypothesized that the...Cholemia, , elevated circulating bile acids (BA), is an early feature of hepatobiliary disorders. However, cholemia often goes undetected because BA are not measured in routine health screenings. We hypothesized that the membrane-disrupting properties of BA might impact red blood cell (RBC) osmotic resistance (OR), potentially providing a means to detect cholemia. To test this, RBC OR was examined in multiple mouse models of cholemia, germ-free animals, and patients with cholestatic liver disease. RBC from cholemic mice exhibited markedly elevated OR against hypotonic NaCl, KCl and NHCl solutions. Elevated OR was observed in an array of mouse models of cholemia, including mice with spontaneous portosystemic shunts, deficiencies in aryl hydrocarbon receptor, multidrug resistance protein 2 and farnesoid X receptor. The degree of OR correlated with serum BA levels. RBC OR increased upon treatment with cholemic plasma or unconjugated BA. Conversely, the absence of gut microbiota in germ-free animals was associated with reduced BA levels and decreased RBC OR. Colonizing gut microbiota into germ-free animals via co-housing increased their RBC OR. RBC from patients with cholestatic liver disease also displayed increased OR, indicating potential human relevance. The elevated cholesterol-to-phospholipid ratio in the membranes of RBC from both cholemic mice and humans suggests increased membrane rigidity. Consistent with this, treatment with dimethyl sulfoxide to enhance membrane permeability reduced RBC OR. Taken together, these findings provide that increased RBC OR is associated with cholemia and may serve as a basis for a whole-blood approach to its detection.
Gastrointestinal (GI) motility is coordinated by multiple neurotransmitter systems acting on distinct postjunctional cells within the smooth muscle-interstitial cell-platelet derived growth factor receptor alpha-positive...Gastrointestinal (GI) motility is coordinated by multiple neurotransmitter systems acting on distinct postjunctional cells within the smooth muscle-interstitial cell-platelet derived growth factor receptor alpha-positive (PDGFRα) (SIP) syncytium. This study integrates physiological, pharmacological, and single-cell transcriptomic data to define the cellular mechanisms underlying inhibitory and excitatory neuromuscular transmission in the human colon. Inhibitory signaling involves purinergic (P2Y) and adrenergic (αA) receptors, which activate small-conductance calcium-activated potassium channels in PDGFRα cells, whereas nitrergic [nitric oxide (NO)-soluble guanylate cyclase-cGMP] pathways are primarily mediated by interstitial cells of Cajal (ICCs) and smooth muscle cells (SMCs). VIPergic signaling also contributes to relaxation through cAMP-dependent mechanisms possibly located in PDGFRα cells. Excitatory transmission is mainly driven by muscarinic M3 and M2 receptors expressed in ICCs and SMCs, leading to calcium-dependent contractions. Pharmacologically, hyoscine butylbromide reduces acetylcholine-induced contractions by blocking M2/M3 receptors, whereas neostigmine enhances cholinergic transmission to restore motility. Blockade of voltage-gated calcium channels (Ca1.2, CACNA1C) by agents such as otilonium bromide further contributes to spasmolytic effects. These findings provide an integrated framework linking receptor expression, cellular mechanisms, and drug actions that modulate GI motility. In this manuscript, we correlate data from single-cell RNA analysis with previously published physiological findings. Based on this correlation, we discuss the mechanisms of action of clinically relevant drugs and reevaluate their effects within the context of the smooth muscle, interstitial cells, and PDGFRα cell (SIP) syncytium. This work also has translational relevance, providing clinicians with a more comprehensive understanding of drug mechanisms of action.