Pub Date : 2025-02-18DOI: 10.1053/j.gastro.2025.01.246
Javier Aguilera-Lizarraga, Cintya Lopez-Lopez, Josue Jaramillo-Polanco, Morgane V. Florens, Yang Yu, Quentin K. Tsang, Ananya Chakraborty, Sofie De Gand, Fedrica Pia, Runze Quan, María Cuende-Estévez, Samuel Van Remoortel, Jessica Strid, Alan E. Lomax, M. Cecilia Berin, Andrew W. Craig, Eva Kaufmann, Mark L. Ormiston, Stephen J. Vanner, Hind Hussein, David E. Reed
BACKGROUND & AIMS
We recently showed that a bacterial infection can break oral tolerance to food and lead to IgE-dependent mast cell activation and food-induced abdominal pain, which could constitute an important pathogenic mechanism in post-infectious irritable bowel syndrome (IBS). Here, we investigated whether similar immune mechanisms in response to psychological stress lead to food-evoked pain signaling, and thus potentially explain the pathophysiology in a larger group of patients with IBS.
METHODS
Mice were exposed to ovalbumin (OVA) during water avoidance stress (WAS) and re-exposed to OVA five weeks later. Nociception was evaluated by visceromotor responses and afferent nerve recordings to intestinal distension, and patch-clamp recordings of sensory neurons incubated with intestinal supernatants. The role of IgE and type 2 immunity was evaluated using pharmacological and genetic approaches.
RESULTS
Re-exposure to OVA increased pain signaling in the colon and small intestine only in mice exposed to OVA during WAS, in the absence of systemic allergy. OVA-induced increases in pain responses depended on mast cells, IgE and STAT6 signaling. Notably, incubation of sensory neurons with ileum and colon supernatants from WAS/OVA+OVA mice lowered their threshold of excitability. Finally, treatment with histamine receptor H1 antagonist pyrilamine blocked the increased sensory neuron excitability, and reduced ileal afferent nerve firing to distension in WAS/OVA+OVA mice.
CONCLUSIONS
Psychological stress induces a type 2 immune response to food antigens, with IgE-mediated mast cell activation and increased pain signaling in the small intestine and colon in response to food. These findings may explain the potential role of psychological stress in food-induced symptoms in IBS.
{"title":"Psychological stress-induced local immune response to food antigens increases pain signaling across the gut in mice","authors":"Javier Aguilera-Lizarraga, Cintya Lopez-Lopez, Josue Jaramillo-Polanco, Morgane V. Florens, Yang Yu, Quentin K. Tsang, Ananya Chakraborty, Sofie De Gand, Fedrica Pia, Runze Quan, María Cuende-Estévez, Samuel Van Remoortel, Jessica Strid, Alan E. Lomax, M. Cecilia Berin, Andrew W. Craig, Eva Kaufmann, Mark L. Ormiston, Stephen J. Vanner, Hind Hussein, David E. Reed","doi":"10.1053/j.gastro.2025.01.246","DOIUrl":"https://doi.org/10.1053/j.gastro.2025.01.246","url":null,"abstract":"<h3>BACKGROUND & AIMS</h3>We recently showed that a bacterial infection can break oral tolerance to food and lead to IgE-dependent mast cell activation and food-induced abdominal pain, which could constitute an important pathogenic mechanism in post-infectious irritable bowel syndrome (IBS). Here, we investigated whether similar immune mechanisms in response to psychological stress lead to food-evoked pain signaling, and thus potentially explain the pathophysiology in a larger group of patients with IBS.<h3>METHODS</h3>Mice were exposed to ovalbumin (OVA) during water avoidance stress (WAS) and re-exposed to OVA five weeks later. Nociception was evaluated by visceromotor responses and afferent nerve recordings to intestinal distension, and patch-clamp recordings of sensory neurons incubated with intestinal supernatants. The role of IgE and type 2 immunity was evaluated using pharmacological and genetic approaches.<h3>RESULTS</h3>Re-exposure to OVA increased pain signaling in the colon and small intestine only in mice exposed to OVA during WAS, in the absence of systemic allergy. OVA-induced increases in pain responses depended on mast cells, IgE and STAT6 signaling. Notably, incubation of sensory neurons with ileum and colon supernatants from WAS/OVA+OVA mice lowered their threshold of excitability. Finally, treatment with histamine receptor H<sub>1</sub> antagonist pyrilamine blocked the increased sensory neuron excitability, and reduced ileal afferent nerve firing to distension in WAS/OVA+OVA mice.<h3>CONCLUSIONS</h3>Psychological stress induces a type 2 immune response to food antigens, with IgE-mediated mast cell activation and increased pain signaling in the small intestine and colon in response to food. These findings may explain the potential role of psychological stress in food-induced symptoms in IBS.","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"130 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1053/j.gastro.2025.02.006
Lixia Pei, Gang Wang, Sihao Yang, Shuxin Zhou, Tianshu Xu, Jia Zhou, Wei Zhang, Kaixin Lu, Linyan Hu, Yang Wang, Ke Wang, Dongfang You, Yaqian Wu, Li Li, Jing Guo, Jianhua Sun
BACKGROUND & AIMS
Electroacupuncture (EA) may reduce the duration of postoperative ileus (POI) after laparoscopic gastrectomy for gastric cancer, though evidence is limited. We investigated the efficacy of EA in reducing POI duration and enhancing gastrointestinal (GI) recovery in patients undergoing laparoscopic surgery for gastric cancer.
METHODS
This multicenter randomized trial was conducted at seven hospitals in China, enrolling 585 participants who underwent laparoscopic resection for gastric cancer from October 27, 2021, to December 21, 2023. Participants received perioperative standard care and were randomized to four sessions of EA, four sessions of sham EA (SA), or standard care only. The primary outcome was the time to first flatus. Secondary outcomes included time to first defecation, dietary recovery, quality of life, postoperative mobilization, and duration of hospital stay.
RESULTS
578 participants were in the full analysis set. EA exhibited a shorter time to first flatus compared with both SA and standard care, with differences of -12.96 hours (95% CI, -19.17 to -6.75; P <.001) and -24.46 hours (95% CI, -30.61 to -18.30; P < .001), respectively. Similarly, EA significantly reduced the time to first defecation: -15.41 hours (95% CI, -27.73 to -3.09; P = .007) versus SA; -24.66 hours (95% CI, -36.76 to -12.55; P < .001) versus standard care. Incidence of prolonged POI was significantly lower in the EA group than in the SA and standard care groups, with group differences of -0.41 (95% CI, -0.66 to -0.16; P < .001) and -0.56 (95% CI, -0.82 to -0.31; P < .001), respectively. No severe adverse events were reported.
CONCLUSIONS
EA was superior to SA and standard care only for reducing POI duration and the risk of prolonged POI in patients undergoing laparoscopic gastrectomy for gastric cancer (Trial number: ChiCTR2100050660).
{"title":"Electroacupuncture Reduces Duration of Postoperative Ileus After Laparoscopic Gastrectomy for Gastric Cancer: A Multicenter Randomized Trial","authors":"Lixia Pei, Gang Wang, Sihao Yang, Shuxin Zhou, Tianshu Xu, Jia Zhou, Wei Zhang, Kaixin Lu, Linyan Hu, Yang Wang, Ke Wang, Dongfang You, Yaqian Wu, Li Li, Jing Guo, Jianhua Sun","doi":"10.1053/j.gastro.2025.02.006","DOIUrl":"https://doi.org/10.1053/j.gastro.2025.02.006","url":null,"abstract":"<h3>BACKGROUND & AIMS</h3>Electroacupuncture (EA) may reduce the duration of postoperative ileus (POI) after laparoscopic gastrectomy for gastric cancer, though evidence is limited. We investigated the efficacy of EA in reducing POI duration and enhancing gastrointestinal (GI) recovery in patients undergoing laparoscopic surgery for gastric cancer.<h3>METHODS</h3>This multicenter randomized trial was conducted at seven hospitals in China, enrolling 585 participants who underwent laparoscopic resection for gastric cancer from October 27, 2021, to December 21, 2023. Participants received perioperative standard care and were randomized to four sessions of EA, four sessions of sham EA (SA), or standard care only. The primary outcome was the time to first flatus. Secondary outcomes included time to first defecation, dietary recovery, quality of life, postoperative mobilization, and duration of hospital stay.<h3>RESULTS</h3>578 participants were in the full analysis set. EA exhibited a shorter time to first flatus compared with both SA and standard care, with differences of -12.96 hours (95% CI, -19.17 to -6.75; <em>P</em> <.001) and -24.46 hours (95% CI, -30.61 to -18.30; <em>P</em> < .001), respectively. Similarly, EA significantly reduced the time to first defecation: -15.41 hours (95% CI, -27.73 to -3.09; <em>P</em> = .007) versus SA; -24.66 hours (95% CI, -36.76 to -12.55; <em>P</em> < .001) versus standard care. Incidence of prolonged POI was significantly lower in the EA group than in the SA and standard care groups, with group differences of -0.41 (95% CI, -0.66 to -0.16; <em>P</em> < .001) and -0.56 (95% CI, -0.82 to -0.31; <em>P</em> < .001), respectively. No severe adverse events were reported.<h3>CONCLUSIONS</h3>EA was superior to SA and standard care only for reducing POI duration and the risk of prolonged POI in patients undergoing laparoscopic gastrectomy for gastric cancer (<em>Trial number: ChiCTR2100050660</em>).","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"25 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-17DOI: 10.1053/j.gastro.2025.01.224
John A. Hawley, Samuel C. Forster, Edward M. Giles
The benefits of regular physical activity (PA) on disease prevention and treatment outcomes have been recognized for centuries. However, only recently has interorgan communication triggered by the release of “myokines” from contracting skeletal muscles emerged as a putative mechanism by which exercise confers protection against numerous disease states. Cross-talk between active skeletal muscles and the gut microbiota reveal how regular PA boosts host immunity, facilitates a more diverse gut microbiome and functional metabolome, and plays a positive role in energy homeostasis and metabolic regulation. In contrast, and despite the large interindividual variation in the human gut microbiome, reduced microbial diversity has been implicated in several diseases of the gastrointestinal (GI) tract, systemic immune diseases, and cancers. Although prolonged, intense, weight-bearing exercise conducted in extreme conditions can increase intestinal permeability, compromising gut-barrier function and resulting in both upper and lower GI symptoms, these are transient and benign. Accordingly, the gut microbiome has become an attractive target for modulating many of the positive effects of regular PA on GI health and disease, although the precise dose of exercise required to induce favourable changes in the microbiome and enhance host immunity is currently unknown. Future efforts should concentrate on gaining a deeper understanding of the factors involved in exercise-gut interactions through the generation of functional ‘omics readouts (ie, metatranscriptomics, metaproteomics, and metabolomics) that have the potential to identify functional traits of the microbiome that are linked to host health and disease states, and validating these interactions in experimental and preclinical systems. A greater understanding of how PA interacts with the GI tract and the microbiome may enable targeted therapeutic strategies to be developed for individuals and populations at risk for a variety of GI diseases.
{"title":"Exercise, Gut Microbiome, and Gastrointestinal Diseases: Therapeutic Impact and Molecular Mechanisms","authors":"John A. Hawley, Samuel C. Forster, Edward M. Giles","doi":"10.1053/j.gastro.2025.01.224","DOIUrl":"https://doi.org/10.1053/j.gastro.2025.01.224","url":null,"abstract":"The benefits of regular physical activity (PA) on disease prevention and treatment outcomes have been recognized for centuries. However, only recently has interorgan communication triggered by the release of “myokines” from contracting skeletal muscles emerged as a putative mechanism by which exercise confers protection against numerous disease states. Cross-talk between active skeletal muscles and the gut microbiota reveal how regular PA boosts host immunity, facilitates a more diverse gut microbiome and functional metabolome, and plays a positive role in energy homeostasis and metabolic regulation. In contrast, and despite the large interindividual variation in the human gut microbiome, reduced microbial diversity has been implicated in several diseases of the gastrointestinal (GI) tract, systemic immune diseases, and cancers. Although prolonged, intense, weight-bearing exercise conducted in extreme conditions can increase intestinal permeability, compromising gut-barrier function and resulting in both upper and lower GI symptoms, these are transient and benign. Accordingly, the gut microbiome has become an attractive target for modulating many of the positive effects of regular PA on GI health and disease, although the precise dose of exercise required to induce favourable changes in the microbiome and enhance host immunity is currently unknown. Future efforts should concentrate on gaining a deeper understanding of the factors involved in exercise-gut interactions through the generation of functional ‘omics readouts (ie, metatranscriptomics, metaproteomics, and metabolomics) that have the potential to identify functional traits of the microbiome that are linked to host health and disease states, and validating these interactions in experimental and preclinical systems. A greater understanding of how PA interacts with the GI tract and the microbiome may enable targeted therapeutic strategies to be developed for individuals and populations at risk for a variety of GI diseases.","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"21 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-14DOI: 10.1053/j.gastro.2025.01.245
Xuefan Zeng
No Abstract
{"title":"Further Considerations on Dual Targeting of Syndecan-1 and Glucose Transporter-1 in Pancreatic Ductal Adenocarcinoma","authors":"Xuefan Zeng","doi":"10.1053/j.gastro.2025.01.245","DOIUrl":"https://doi.org/10.1053/j.gastro.2025.01.245","url":null,"abstract":"No Abstract","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"62 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-14DOI: 10.1053/j.gastro.2025.01.243
Anny Gravdal, Steven J. Wilhelm, Mark E. Lowe, Anders Molven, Xunjun K. Xiao
No Abstract
{"title":"The MODY-causing mutation of the human carboxyl ester lipase gene (CEL) triggers chronic pancreatitis but not diabetes in mice","authors":"Anny Gravdal, Steven J. Wilhelm, Mark E. Lowe, Anders Molven, Xunjun K. Xiao","doi":"10.1053/j.gastro.2025.01.243","DOIUrl":"https://doi.org/10.1053/j.gastro.2025.01.243","url":null,"abstract":"No Abstract","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"14 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-14DOI: 10.1053/j.gastro.2025.01.244
Daowei Yang, Xinlei Sun, Hua Wang, Ignacio I. Wistuba, Huamin Wang, Anirban Maitra, Yang Chen
BACKGROUND & AIMS
Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive.
METHODS
We generated a novel transgenic mouse model (KPPC;Trem2-/-) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was utilized to identify changes in the tumor immune microenvironment upon TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions of TREM2 in macrophages and PDAC development.
RESULTS
Unexpectedly, genetic depletion of TREM2 significantly accelerated spontaneous PDAC progression and shortened the survival of KPPC;Trem2-/- mice. Single-cell analysis revealed that TREM2 depletion enhanced pro-inflammatory macrophages and exacerbated pathogenic inflammation in PDAC. Specifically, TREM2 functions as a key braking mechanism for the NLRP3/NF-κB/IL-1β inflammasome pathway, opposing to microbial lipopolysaccharide (LPS) as the key activator of this pathway. TREM2 deficiency orchestrated with microbial LPS to trigger IL-1β upregulation and pathogenic inflammation, thereby fueling PDAC development. Notably, IL-1β inhibition or microbiome ablation not only reversed the accelerated PDAC progression caused by TREM2 depletion, but also further inhibited PDAC progression in the TREM2-depleted context.
CONCLUSIONS
TREM2 depletion accelerates tumor progression by enhancing pro-inflammatory macrophages and IL-1β-mediated pathogenic inflammation in PDAC. The accelerated tumor progression by TREM2 depletion can be reversed by blocking IL-1β-associated pathogenic inflammation.
{"title":"TREM2 depletion in pancreatic cancer elicits pathogenic inflammation and accelerates tumor progression via enriching IL-1β+ macrophages","authors":"Daowei Yang, Xinlei Sun, Hua Wang, Ignacio I. Wistuba, Huamin Wang, Anirban Maitra, Yang Chen","doi":"10.1053/j.gastro.2025.01.244","DOIUrl":"https://doi.org/10.1053/j.gastro.2025.01.244","url":null,"abstract":"<h3>BACKGROUND & AIMS</h3>Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive.<h3>METHODS</h3>We generated a novel transgenic mouse model (KPPC;Trem2<sup>-/-</sup>) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was utilized to identify changes in the tumor immune microenvironment upon TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions of TREM2 in macrophages and PDAC development.<h3>RESULTS</h3>Unexpectedly, genetic depletion of TREM2 significantly accelerated spontaneous PDAC progression and shortened the survival of KPPC;Trem2<sup>-/-</sup> mice. Single-cell analysis revealed that TREM2 depletion enhanced pro-inflammatory macrophages and exacerbated pathogenic inflammation in PDAC. Specifically, TREM2 functions as a key braking mechanism for the NLRP3/NF-κB/IL-1β inflammasome pathway, opposing to microbial lipopolysaccharide (LPS) as the key activator of this pathway. TREM2 deficiency orchestrated with microbial LPS to trigger IL-1β upregulation and pathogenic inflammation, thereby fueling PDAC development. Notably, IL-1β inhibition or microbiome ablation not only reversed the accelerated PDAC progression caused by TREM2 depletion, but also further inhibited PDAC progression in the TREM2-depleted context.<h3>CONCLUSIONS</h3>TREM2 depletion accelerates tumor progression by enhancing pro-inflammatory macrophages and IL-1β-mediated pathogenic inflammation in PDAC. The accelerated tumor progression by TREM2 depletion can be reversed by blocking IL-1β-associated pathogenic inflammation.","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"79 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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