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

{"title":"Localized immunotherapy for colitis: breakthroughs with CXCL12-expressing <i>Limosilactobacillus reuteri</i>.","authors":"Abhinava K Mishra","doi":"10.1152/ajpgi.00206.2024","DOIUrl":"10.1152/ajpgi.00206.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G872-G873"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581809","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":"Parenteral nutrition results in peripheral ileal to hepatic circadian discordance in mice.","authors":"Colin T Shearn, Aimee L Anderson, Michael W Devereaux, Ronald J Sokol","doi":"10.1152/ajpgi.00042.2024","DOIUrl":"10.1152/ajpgi.00042.2024","url":null,"abstract":"<p><p>We have developed a mouse model of parenteral nutrition-associated liver disease (PNALD) in which parenteral nutrition (PN) infusion results in cholestatic liver injury. In the liver, the master circadian genes <i>Arntl</i>/Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, farnesoid X receptor (FXR) signaling, and bile acid synthesis in mice. Wild-type mice were exposed to ad libitum Chow or continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On <i>day 4</i>, separate groups of Chow and PN-fed mice were euthanized every 6 h (7 AM, 1 PM, 7 PM, and 1 AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. Administration of 4-day PN increased hepatic injury, inflammatory cytokine expression, and gut permeability. In the ileum, PN activated FXR and induced expression of <i>Fgf15</i> and <i>Nr0b2</i>. In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression, which was discordant between the two organs. Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacological targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation.<b>NEW & NOTEWORTHY</b> This study used a novel short-term model of parenteral nutrition (PN) that is translationally relevant. We find that short-term PN is sufficient to induce hepatic and ileal changes in circadian transcription factor expression and to prevent normal concordant coordination of circadian transcription factors between the ileum and liver. These data suggest that targeting circadian transcription may have some clinical benefit in patients receiving parenteral nutrition.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G754-G764"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formal degree programs in physiology promote careers of clinical scientists and benefit basic science departments.","authors":"Irving Joshua, Hiram C Polk, Anne Macleod, R Maurice Eichenberger, Sarah A Gardner, Dale Schuschke, Susan Galandiuk","doi":"10.1152/ajpgi.00196.2024","DOIUrl":"10.1152/ajpgi.00196.2024","url":null,"abstract":"<p><p>Physiologists may play critical roles in the development of clinician-scientists who aspire to an academic career. The complexity of contemporary biomedical science and economic matters regarding postgraduate education pose real conundrums. We report a more than 22-year follow-up of surgical trainees pursuing bench laboratory science experience through a collaboration between a physiology postgraduate program and a surgical researcher program within a single public medical school. The sources and resources include selection, funding, physiology classroom work, and laboratory studies with personal involvement by faculty that have seldom been recorded, especially with longer term career outcomes. These selected PhD candidates have subsequently pursued several lines of activity, many with distinguished careers and major influences upon future generations of academic surgeons.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G737-G740"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339459","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":"Large animal models enhance the study of crypt-mediated epithelial recovery from prolonged intestinal ischemia reperfusion injury.","authors":"Caroline A McKinney-Aguirre, Cecilia R Schaaf, Elizabeth Goya-Jorge, John M Freund, Liara M Gonzalez","doi":"10.1152/ajpgi.00236.2024","DOIUrl":"10.1152/ajpgi.00236.2024","url":null,"abstract":"<p><p>Intestinal ischemia and reperfusion injury (IRI) is a deadly and common condition. Death is associated with sepsis due to insufficient epithelial repair, requiring stem cell-driven regeneration, typically beginning 48 h after injury. Animal models are critical to advancing this field. To effectively study epithelial healing, models must survive clinically relevant intestinal ischemic injury extending to the crypt. Although mouse models are indispensable to intestinal research, their application for studying epithelial repair following severe IRI may be limited. Ischemic injury was induced in mouse and porcine jejunum for up to 3 h, with up to 72 h of reperfusion. Histologic damage was scored by Chiu-Park grade, and animal survival was assessed. Findings were compared between species. A mouse IRI literature review was performed to evaluate the purported degree of injury, duration of recovery, and reported survival rates. In mice and pigs, 3 h of ischemia induced severe, reliable injury extending into the crypt. However, at 48 h, mouse survival was only 23.5% compared with 100% survival in pigs. In literature, ischemia was induced for >1 h in only 4 of 102 mouse studies and none to 3 h. Recovery was attempted for 48 h in only six reports. Forty-seven studies reported intestinal crypt injury. Of those that featured histologic intestinal crypt damage, survival rates at 48 h ranged from 10 to 50% (median 30%). Mouse models are not ideal for studying intestinal stem cell-mediated recovery from severe IRI. Alternative large animal models, like pigs, are recommended.<b>NEW & NOTEWORTHY</b> Additional research is needed to improve recovery from severe intestinal ischemia. The selection of the ideal animal model is critical to facilitating this work. Based on our experimentation and literature review, porcine models, with increased translatability and an improved ability to survive both prolonged ischemia and the recovery period, appear to be the most appropriate choice for future studies.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G783-G788"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Fabry disease-associated lyso-Gb₃ on mouse colonic ion transport and motility.","authors":"Cecilia Delprete, Friederike Uhlig, Marco Caprini, Niall P Hyland","doi":"10.1152/ajpgi.00220.2024","DOIUrl":"10.1152/ajpgi.00220.2024","url":null,"abstract":"<p><p>Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A leading to the accumulation of globotriaosylceramide (Gb₃) and subsequent increase in globotriaosylsphingosine (lyso-Gb₃) in different cells and organs, including the gastrointestinal (GI) tract. GI symptoms represent some of the earliest manifestations of FD and significantly impact quality of life. The origin of these symptoms is complex, and the exact mechanisms remain poorly understood. Here, we sought to determine whether lyso-Gb₃ contributes to the pathophysiology of GI symptoms associated with FD by examining its effects on mouse colonic ion transport and motility ex vivo using Ussing chambers and organ baths, respectively. Lyso-Gb₃ significantly increased colonic baseline short-circuit current (<i>I</i>_sc). This increase in <i>I</i>_sc was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1, suggesting that the increase in <i>I</i>_sc is Cl^- ion independent. This response was also insensitive to inhibition by the neurotoxin, tetrodotoxin. In addition, pretreatment with lyso-Gb₃ did not significantly influence subsequent responses to either veratridine or capsaicin implying that the response to lyso-Gb₃ does not involve the enteric nervous system. In terms of colonic motility, lyso-Gb₃ did not significantly influence colonic tone, spontaneous contractility, or cholinergic-induced contractions. These data suggest that lyso-Gb₃ significantly influences ion transport in mouse colon, but that accumulation of Gb₃ may be a prerequisite for the more pronounced disturbances in GI physiology characteristic of FD.<b>NEW & NOTEWORTHY</b> Fabry disease-associated lyso-Gb₃ significantly influences mouse colonic ion transport in a Cl^- ion-independent manner.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G810-G817"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456090","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":"Rise in plasma bile acids following hypoabsorptive bariatric surgeries predicts beneficial metabolic and homeostatic outcomes in male rats.","authors":"Paulette Mukorako, Audrey-Anne Lavoie, Jocelyn Trottier, Natacha Lemoine, Laurent Biertho, Stéfane Lebel, Julie Plamondon, André Tchernof, David H St-Pierre, André Marette, Olivier Barbier, Denis Richard","doi":"10.1152/ajpgi.00289.2023","DOIUrl":"10.1152/ajpgi.00289.2023","url":null,"abstract":"<p><p>This study was designed to investigate the effects of three hypoabsorptive bariatric surgeries, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S), on bile acids (BAs) and to assess whether the changes in BA plasma levels were associated with the metabolic and homeostatic effects of the surgeries. Male Wistar rats, either fed a high- (HF) or a low-fat (LF) diet, were divided into seven groups: RYGB HF, BPD-DS HF, SADI-S HF, sleeve-gastrectomy (SG) HF, sham-operated (Sham) HF, Sham LF, and Sham HF-pair-weighed to BPD-DS (Sham HF-PW). The rats were treated for 56 days. The results demonstrate the ability of RYGB, BPD-DS, and SADI-S to raise plasma levels of BAs, whose elevations were likely due to changes in gene expression of transporters, enzymes, and receptors in the liver and small intestine. This increase, most notably of the secondary BAs (deoxycholic acid, ursodeoxycholic acid, and lithocholic acid), was negatively associated with body weight gain, fat gain, and fasting insulin levels, and positively with plasma peptide tyrosine-tyrosine (PYY). Plasma BAs also correlated positively with the fecal levels of <i>Clostridium</i>, <i>Sutterella</i>, and <i>Enterobacteriaceae</i> and negatively with Clostridiales_f_g_2, <i>Christensenellaceae</i>, Ruminococcaceae_g_2, <i>Oscillibacter</i>, and <i>Oscillospira</i>. In addition, they are associated positively with the short-chain fatty acid (SCFA) levels of propionate, butyrate, isobutyrate, valerate, and isovalerate. Altogether, the present study emphasizes the ability of RYGB, BPD-DS, and SADI-S to induce circulating BA elevations that predict the beneficial consequences of those hypoabsorptive bariatric surgeries on energy and glucose homeostasis and circulating levels of PYY. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are linked to significant fat losses and metabolic health improvements.<b>NEW & NOTEWORTHY</b> The study emphasizes the ability of RYGB, BPD-DS, and SADI-S to induce elevated circulating bile acids levels and changes in the gene expression of transporters, enzymes and receptors in the liver and small intestine, predicting positive effects on energy and glucose homeostasis as well as PYY levels. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are also linked to significant fat losses and metabolic health improvements. These findings provide valuable insights into the mechanisms underlying the positive effects of these surgical interventions.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G832-G846"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456094","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":"Alterations in cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation.","authors":"Michael Momoh, Sudiksha Rathan-Kumar, Andreanna Burman, Monica E Brown, Francisca Adeniran, Cynthia Ramos, James R Goldenring, Joseph T Roland, Izumi Kaji","doi":"10.1152/ajpgi.00091.2024","DOIUrl":"10.1152/ajpgi.00091.2024","url":null,"abstract":"<p><p>Functional loss of the motor protein myosin Vb (MYO5B) induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, namely, microvillus inclusion disease (MVID). Utilizing the MVID model mice <i>Vil1-Cre^ERT2;Myo5b^flox/flox</i> (MYO5BΔIEC) and <i>Vil1-Cre^ERT2;Myo5b^flox/G519R</i> [MYO5B(G519R)], we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in the MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observations in vivo, RNA sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, we reported that lysophosphatidic acid (LPA) signaling ameliorated epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrated that the highly soluble LPA receptor (LPAR)5-preferred agonist Compound-1 improved sodium transporter localization and absorptive function and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on the intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for the treatment of MVID symptoms induced by different point mutations in MYO5B.<b>NEW & NOTEWORTHY</b> This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, previously unexplored functions of MYO5B. The alterations may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID) intestines. To examine the therapeutic potential of progenitor-targeted treatments, the effects of the LPAR5-preferred agonist Compound-1 were investigated utilizing several MVID model mice and enteroids. Our observations suggest that Compound-1 may provide a therapeutic approach for treating MVID.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G877-G899"},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferential Neurogenesis of Nitrergic Neurons in the Myenteric Plexus of the DSS-induced Colitis Mouse Colon Causes Colonic Dysmotility in Colitis.","authors":"Kana Miyata, Takeshi Yamamoto, Ryo Kato, Shusaku Hayashi, Makoto Kadowaki","doi":"10.1152/ajpgi.00219.2023","DOIUrl":"https://doi.org/10.1152/ajpgi.00219.2023","url":null,"abstract":"<p><p>The enteric nervous system (ENS) continues to be exposed to various disturbances throughout life, which causes apoptosis in the ENS. Therefore, it is assumed that neurogenesis is induced to maintain the neuronal network in the adult ENS. However, these underlying mechanisms are largely unknown. We aimed to investigate adult neurogenesis in the DSS-induced colitis mouse colon.</p><p><strong>Methods: </strong>male C57BL/6N mice (12-week-old) were administered 2% DSS in their drinking water for 8 days. After DSS treatment, cross-sections and longitudinal muscle and myenteric plexus preparations from the colon were used for immunohistochemistry. The segments of colons were mounted in organ baths and then exposed to a voltage-gated sodium channel activator veratridine.</p><p><strong>Results: </strong>in the motility study, veratridine-induced colonic contractions were significantly suppressed in DSS-induced colitis mice compared to normal mice. Immunohistochemical analyses revealed that the proportion of nitrergic neurons per ganglion was significantly increased in the colons of DSS-induced colitis mice compared to normal mice. Furthermore, the proportion of Sox2 (new-born neuron marker)-positive neurons per ganglion was not significantly different between normal mice and DSS-induced colitis mice, whereas the proportion of Sox2-positive nitrergic neurons to Sox2-positive neurons per ganglion was significantly increased in the colons of DSS-induced colitis mice compared to normal mice. In addition, NOS inhibitor significantly enhanced veratridine-induced colonic contractions in DSS-induced colitis mice compared with normal mice.</p><p><strong>Conclusions: </strong>these findings suggested that colitis caused an imbalance in the enteric neural circuit composed of excitatory neurons and inhibitory neurons in the myenteric plexus of the colon, which resulted in colonic dysmotility.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724380","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":"Inhibition of Hedgehog Signaling Ameliorates Severity of Chronic Pancreatitis in Experimental Mouse Models.","authors":"Srikanth Iyer, Mohammad Tarique, Preeti Sahay, Sagnik Giri, Ejas P Bava, JiaShiung Guan, Tejeshwar Jain, Utpreksha Vaish, Xiuwen Jin, Sabrina Moon, David K Crossman, Vikas Dudeja","doi":"10.1152/ajpgi.00212.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00212.2024","url":null,"abstract":"<p><strong>Background and aims: </strong>Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults have been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when over-activated. The aim of this study is to explore the role of hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP.</p><p><strong>Methods: </strong>CP was induced in mice by repeated injections of L-arginine or Caerulein in two separate models. Mice were administered with the FDA approved pharmacological hedgehog pathway inhibitor, Vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease.</p><p><strong>Results: </strong>Our study shows that hedgehog signaling was over-activated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already established fibrosis. Additionally, inhibition of hedgehog signaling resulted in reversal of pancreatic stellate cell activation <i>ex vivo.</i> Conclusions: Findings from our study justify conducting clinical trials using Vismodegib against CP and thus, could lead to development of novel therapeutic strategy for the treatment of CP.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581808","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":"Intraduodenal fecal microbiota transplantation ameliorates gut atrophy and cholestasis in a novel parenteral nutrition piglet model.","authors":"Chandrashekhara Manithody, Christine Denton, Shaurya Mehta, Jasmine Carter, Kento Kurashima, Ashlesha Bagwe, Marzena Swiderska-Syn, Miguel Guzman, Sherri Besmer, Sonali Jain, Matthew McHale, Kamran Qureshi, Mustafa Nazzal, Yasar Caliskan, John Long, Chien-Jung Lin, Chelsea Hutchinson, Aaron C Ericsson, Ajay Kumar Jain","doi":"10.1152/ajpgi.00012.2024","DOIUrl":"10.1152/ajpgi.00012.2024","url":null,"abstract":"<p><p>Total parenteral nutrition (TPN) provides lifesaving nutritional support intravenously; however, it is associated with significant side effects. Given gut microbial alterations noted with TPN, we hypothesized that transferring fecal microbiota from healthy controls would restore gut-systemic signaling in TPN and mitigate injury. Using our novel ambulatory model (US Patent: US 63/136,165), 31 piglets were randomly allocated to enteral nutrition (EN), TPN only, TPN + antibiotics (TPN-A), or TPN + intraduodenal fecal microbiota transplant (TPN + FMT) for 14 days. Gut, liver, and serum were assessed through histology, biochemistry, and qPCR. Stool samples underwent 16 s rRNA sequencing. Permutational multivariate analysis of variance, Jaccard, and Bray-Curtis metrics were performed. Significant bilirubin elevation in TPN and TPN-A versus EN (<i>P</i> < 0.0001) was prevented with FMT. IFN-G, TNF-α, IL-β, IL-8, and lipopolysaccharide (LPS) were significantly higher in TPN (<i>P</i> = 0.009, P = 0.001, <i>P</i> = 0.043, <i>P</i> = 0.011, <i>P</i> < 0.0001), with preservation upon FMT. Significant gut atrophy by villous-to-crypt ratio in TPN (<i>P</i> < 0.0001) and TPN-A (<i>P</i> = 0.0001) versus EN was prevented by FMT (<i>P</i> = 0.426 vs. EN). Microbiota profiles using principal coordinate analysis demonstrated significant FMT and EN overlap, with the largest separation in TPN-A followed by TPN, driven primarily by Firmicutes and Fusobacteria. TPN-altered gut barrier was preserved upon FMT; upregulated cholesterol 7 α-hydroxylase and bile salt export pump in TPN and TPN-A and downregulated fibroblast growth factor receptor 4, EGF, farnesoid X receptor, and Takeda G Protein-coupled Receptor 5 (TGR5) versus EN was prevented by FMT. This study provides novel evidence of prevention of gut atrophy, liver injury, and microbial dysbiosis with intraduodenal FMT, challenging current paradigms into TPN injury mechanisms and underscores the importance of gut microbes as prime targets for therapeutics and drug discovery.<b>NEW & NOTEWORTHY</b> Intraduodenal fecal microbiota transplantation presents a novel strategy to mitigate complications associated with total parenteral nutrition (TPN), highlighting gut microbiota as a prime target for therapeutic and diagnostic approaches. These results from a highly translatable model provide hope for TPN side effect mitigation for thousands of chronically TPN-dependent patients.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G640-G654"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}