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

{"title":"Carbon monoxide produced by HO-1 upregulation is the main factor behind the abnormal motility seen in experimental ulcerative colitis in mice.","authors":"Mengchao Zhao, Yaru Lei, Mengyuan Wang, Yixin Chen, Shaozhang Hou, Xinyuan Dai, Di Gao, Yudan Liu, Bruno Mazet, Lei Sha","doi":"10.1152/ajpgi.00179.2023","DOIUrl":"10.1152/ajpgi.00179.2023","url":null,"abstract":"<p><p>The colonic motility is altered in patients with ulcerative colitis (UC), but the mechanism is not clear. Carbon monoxide (CO) is the molecule regulating the resting membrane potential (RMP) gradient across colonic smooth muscle wall. Changes in RMP will affect the contractility of smooth muscle. In this study, we investigated the altered colonic motility in dextran sodium sulfate-induced UC mice and the role of CO. The results showed that in the UC group, the frequency of spontaneous colonic contractions was increased while the AUC was decreased compared with the control group. HO-1-, but not HO-2-, positive cells were increased in the colonic smooth muscle wall of the UC group. These HO-1-positive cells were mainly in the myenteric plexus and PGP9.5 positive, suggesting neuronal overproduction of CO. The RMP of circular smooth muscle cells (SMCs) in the colon of UC group was hyperpolarized compared with that of control group. In control group, application of CORM-3, a CO donor, altered colonic spontaneous contractions by increasing their frequency and decreasing amplitude. In the UC group, ZnPPIX, a HO-1 inhibitor, reduced the frequency and increased the amplitude. CORM-3 hyperpolarized the RMP of colonic SMCs and abolished its gradient in the control group, while ZnPPIX depolarized the RMP of colonic SMCs and restored its gradient in the UC group. CO produced by HO-1 upregulation is the main factor behind the altered colonic motility seen in UC mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer from abnormal colonic motility.<b>NEW & NOTEWORTHY</b> Carbon monoxide (CO) produced by HO-1 upregulation in myenteric plexus is the main factor that abolishes the RMP gradient across colonic muscle wall causing the altered colonic motility seen in experimental ulcerative colitis (UC) mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer from abnormal colonic motility.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G311-G322"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381562","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":"Dysregulated hepatic alcohol metabolism: a key factor involved in the pathogenesis of alcohol-associated liver disease.","authors":"Mukund Srinivasan, Sumedha Kota, Kamlesh Bhopale, Anna Caracheo, Lata Kaphalia, Jennifer Linares, Trevor Romsdahl, William Russell, Vsevolod Popov, Paul Boor, Bhupendra Kaphalia","doi":"10.1152/ajpgi.00394.2024","DOIUrl":"10.1152/ajpgi.00394.2024","url":null,"abstract":"<p><p>Alcohol use disorder is a major risk factor for alcohol-associated liver disease (ALD), characterized by reduced hepatic alcohol dehydrogenase (ADH) activity, increased body burden of alcohol, and its nonoxidative metabolism to fatty acid ethyl esters (FAEEs). However, the mechanism(s) underlying ALD remain unclear. This study investigated the metabolic basis and mechanism(s) of ALD in chronic ethanol (EtOH)-fed hepatic ADH1-deficient (ADH^-) deer mice administered with a single dose of binge EtOH with/without FAEEs. Hepatic ADH^- and ADH normal (ADH⁺) deer mice fed chronic EtOH daily for 3 mo, followed by a single dose of binge EtOH (3 g/kg·body wt) with/without FAEEs (100 mg/kg·body wt), 1 wk before euthanasia. Blood alcohol and acetaldehyde and liver injury markers in the plasma, hepatic FAEEs, lipids, and inflammatory markers were analyzed. Hepatic histology, ultrastructure, protein/mRNA expression of genes involved in alcohol metabolism and lipogenesis, cyclic adenosine monophosphate (cAMP), phosphodiesterase (PDE) activity, and AMP-activated protein kinase (AMPKα) signaling were assessed. Blood alcohol, hepatic lipids and FAEEs, inflammation, oxidative stress, and the expression of lipogenic proteins/genes were significantly increased in various chronic EtOH-fed groups of ADH^- versus ADH⁺ deer mice. In addition, hepatic cAMP levels were reduced, whereas PDE activity and plasma transaminases were elevated. Binge EtOH with/without FAEEs did not significantly exacerbate the liver injury in chronic EtOH-fed ADH^- as well as ADH⁺ deer mice. Overall, an increased body burden of EtOH and endogenously formed FAEEs due to hepatic ADH deficiency, along with dysregulated cAMP and AMPKα signaling, could be the determining factors for EtOH-induced liver injury leading to ALD.<b>NEW & NOTEWORTHY</b> Using hepatic alcohol dehydrogenase deficient (ADH^-) deer mouse, which mimics the metabolic conditions observed in chronic alcoholics, we found significant hepatic injury along with degenerative changes in endoplasmic reticulum and mitochondria. Our findings suggest that an increased nonoxidative alcohol metabolism under hepatic alcohol dehydrogenase deficiency and associated hepatic lipid dysregulation and injury appear to be the key factors involved in the pathogenesis of alcohol-associated liver disease.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G289-G308"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188204","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":"Modeling the kinetics of interorgan arginine metabolism during bacterial sepsis in swine.","authors":"Caitlin Vonderohe, Douglas Burrin","doi":"10.1152/ajpgi.00375.2024","DOIUrl":"10.1152/ajpgi.00375.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G309-G310"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063132","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":"Voltage-gated calcium channel α₂δ-1 subunit is involved in the regulation of glucose-stimulated GLP-1 secretion in mice.","authors":"Yuhan Yang, Shunsuke Yamane, Norio Harada, Eri Ikeguchi-Ogura, Kana Yamamoto, Naoki Wada, Muhammad Fauzi, Takaaki Murakami, Daisuke Yabe, Yoshitaka Hayashi, Nobuya Inagaki","doi":"10.1152/ajpgi.00279.2024","DOIUrl":"10.1152/ajpgi.00279.2024","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca²⁺ channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca²⁺ channel α₂δ-1 subunit (Ca_Vα₂δ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of Ca_Vα₂δ-1 by gabapentin (GBP), an inhibitory ligand of the α₂δ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific <i>Cacna2d1</i>, a gene encoding Ca_Vα₂δ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that Ca_Vα₂δ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in the treatment of diabetes and obesity.<b>NEW & NOTEWORTHY</b> In this study, we establish high expression of the voltage-gated Ca²⁺ channel α₂δ-1 subunit (Ca_Vα₂δ-1) subunit in enteroendocrine glucagon-like peptide-1 (GLP-1) producing cells and elucidate its role in GLP-1 secretion, providing a more detailed understanding of the mechanism of GLP-1 secretion.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G243-G251"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363192","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":"Regulation of pathologic fibroblast functions in digestive diseases: a role for hypoxia?","authors":"Cian M Ohlendieck, Carlos Matellan, Mario C Manresa","doi":"10.1152/ajpgi.00277.2024","DOIUrl":"10.1152/ajpgi.00277.2024","url":null,"abstract":"<p><p>The recent uncovering of fibroblast heterogeneity has given great insight into the versatility of the stroma. Among other cellular processes, fibroblasts are now thought to contribute to the coordination of immune responses in a range of chronic inflammatory diseases and cancer. Although the pathologic roles of myofibroblasts, inflammatory fibroblasts, and cancer-associated fibroblasts in disease are reasonably well understood, the mechanisms behind their activation remain to be uncovered. In the gastrointestinal (GI) tract, several interleukins and tumor necrosis factor superfamily members have been identified as possible mediators driving the acquisition of inflammatory and fibrotic properties in fibroblasts. In addition to cytokines, other microenvironmental factors such as nutrient and oxygen availability are likely contributors to this process. In this respect, the phenomenon of low cellular oxygen levels known as hypoxia is common in a plethora of GI diseases. Indeed, the cross talk between hypoxia and inflammation is well-documented, with an abundance of studies suggesting that oxygen-sensing enzymes may have regulatory effects on inflammatory signaling pathways such as NF-κB. However, the impact that this has in GI fibroblasts in the context of chronic diseases has not been fully uncovered. Here we discuss the role of fibroblasts in GI diseases, the mediators that have emerged as regulators of their functions and the potential impact of hypoxia in this process, highlighting areas that require further investigation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G229-G242"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051374","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":"The central neural control of the posterior belly of the digastric muscles during swallowing in rats.","authors":"Yuhei Tsutsui, Titi Chotirungsan, Charng-Rong Pan, Satomi Kawada, Jin Magara, Takanori Tsujimura, Keiichiro Okamoto, Makoto Inoue","doi":"10.1152/ajpgi.00374.2024","DOIUrl":"10.1152/ajpgi.00374.2024","url":null,"abstract":"<p><p>The aim of this study was to clarify whether the posterior belly of the digastric (post-Dig) muscle is activated during the swallowing reflex and whether the post-Dig muscle is directly controlled by the swallowing central pattern generator (CPG) in anesthetized rats, using physiological and immunohistochemical approaches. In physiological study, electromyograms (EMGs) of the post-Dig, sternohyoid and thyrohyoid muscles, and the diaphragm were recorded during respiration and swallowing with and without airway stenosis. In the immunohistochemical study, c-Fos immunoreactivity for expression of cells during swallowing was analyzed. Motoneurons were identified using immunohistochemistry with Fluoro-gold (FG). EMG bursts were observed in the hyoid muscles during the inspiratory phase and swallowing. With airway stenosis, the swallowing EMG activity was facilitated in terms of duration and area only in the post-Dig muscle. The coordination of these EMG activities during swallowing was maintained with airway stenosis. In contrast, the offset of the post-Dig EMG burst was delayed with airway stenosis. c-Fos-positive cells were observed in the accessory facial nucleus (Acs7), but only in the rostral portion. FG-labeled cells were observed in Acs7. Several c-Fos/FG double-labeled cells were observed only in the rostral Acs7. These results suggested that the post-Dig muscle is activated during swallowing, the activation of which is controlled by the swallowing CPG, and that the distribution of Acs7 neurons, which innervate the post-Dig muscle, was uneven in the nucleus. In addition, the modulation of post-Dig muscle activity during inspiration might be due to changes in peripheral conditions via respiratory CPG.<b>NEW & NOTEWORTHY</b> The posterior belly of the digastric muscle is activated during the inspiratory phase and swallowing. Increased airway resistance facilitates both inspiratory and swallowing activities of this muscle. Immunohistochemistry revealed that the motoneurons innervating the posterior belly of the digastric muscle were activated during swallowing only in the rostral portion of the accessory facial nucleus. These results suggested that the posterior belly of the digastric muscle is controlled by the respiratory and swallowing central pattern generators.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G277-G288"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188205","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":"Intestinal organoid coculture systems: current approaches, challenges, and future directions.","authors":"Ghanyah Al-Qadami, Anita Raposo, Chia-Chi Chien, Chenkai Ma, Ilka Priebe, Maryam Hor, Kim Fung","doi":"10.1152/ajpgi.00203.2024","DOIUrl":"10.1152/ajpgi.00203.2024","url":null,"abstract":"<p><p>The intestinal microenvironment represents a complex and dynamic ecosystem, comprising a diverse range of epithelial and nonepithelial cells, a protective mucus layer, and a diverse community of gut microbiota. Understanding the intricate interplay between these components is essential for uncovering the mechanisms underlying intestinal health and disease. The development of intestinal organoids, three-dimensional (3-D) mini-intestines that closely mimic the architecture, cellular diversity, and functionality of the intestine, offers a powerful platform for investigating different aspects of intestinal physiology and pathology. However, current intestinal organoid models, mainly adult stem cell-derived organoids, lack the nonepithelial and microbial components of the intestinal microenvironment. As such, several coculture systems have been developed to coculture intestinal organoids with other intestinal elements including microbes (bacteria and viruses) and immune, stromal, and neural cells. These coculture models allow researchers to recreate the complex intestinal environment and study the intricate cross talk between different components of the intestinal ecosystem under healthy and pathological conditions. Currently, there are several approaches and methodologies to establish intestinal organoid cocultures, and each approach has its own strengths and limitations. This review discusses the existing methods for coculturing intestinal organoids with different intestinal elements, focusing on the methodological approaches, strengths and limitations, and future directions.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G252-G276"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880792","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":"Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine.","authors":"Elizabeth C Rose, Jeremy M Simon, Ismael Gomez-Martinez, Scott T Magness, Jack Odle, Anthony T Blikslager, Amanda L Ziegler","doi":"10.1152/ajpgi.00194.2024","DOIUrl":"10.1152/ajpgi.00194.2024","url":null,"abstract":"<p><p>Intestinal ischemic injury damages the epithelial barrier and predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age dependency in intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier compared with older patients. We have developed a pig model that demonstrates age-dependent failure of intestinal barrier restitution in neonatal pigs, which can be rescued by the direct application of juvenile pig mucosal tissue, but the mechanisms of rescue remain undefined. We hypothesized that by identifying a subpopulation of restituting enterocytes by their expression of cell migration transcriptional pathways, we can then predict novel upstream regulators of age-dependent restitution response programs. Superficial mucosal epithelial cells from recovering ischemic jejunum of juvenile pigs underwent single-cell transcriptomics and the predicted upstream regulator, colony stimulating factor-1 (CSF-1), was interrogated in our model. A subcluster of absorptive enterocytes expressed several cell migration pathways key to restitution. Differentially expressed genes in this subcluster predicted their upstream regulation by colony stimulating factor-1 (CSF-1). We validated age-dependent induction of <i>CSF-1</i> by ischemia and documented that CSF-1 and colony-stimulating factor-1 receptor (CSF1R) co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued neonates. Furthermore, the CSF-1 blockade reduced restitution in vitro, and CSF-1 improved barrier function in injured neonatal pigs in preliminary ex vivo experiments. These studies validate an approach to inform potential novel therapeutic targets, such as CSF-1, to improve outcomes in neonates with intestinal injury in a unique pig model.<b>NEW & NOTEWORTHY</b> These studies validate an approach to identify and predict upstream regulation of restituting epithelium in a unique pig intestinal ischemic injury model. Identification of potential molecular mediators of restitution, such as CSF-1, will inform the development of targeted therapeutic interventions for the medical management of patients with ischemia-mediated intestinal injury.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G182-G196"},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031842","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":"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}