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Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.
Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
(2019) Gastroenterology 156: 1041-1051.e4
MeSH Terms: Anastomosis, Surgical, Animals, Anticholesteremic Agents, Bariatric Surgery, Bile Acids and Salts, Blood Glucose, Cholestyramine Resin, Diet, High-Fat, Gallbladder, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose Tolerance Test, Ileum, Insulin Resistance, Intestines, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Signal Transduction, Verrucomicrobia, Weight Loss
Show Abstract · Added January 4, 2019
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward.
Reddy IA, Smith NK, Erreger K, Ghose D, Saunders C, Foster DJ, Turner B, Poe A, Albaugh VL, McGuinness O, Hackett TA, Grueter BA, Abumrad NN, Flynn CR, Galli A
(2018) PLoS Biol 16: e2006682
MeSH Terms: Animals, Bariatric Surgery, Behavior, Animal, Bile, Choice Behavior, Cocaine, Dopamine, Gallbladder, Ileum, Male, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Nucleus Accumbens, Reward, Signal Transduction
Show Abstract · Added January 4, 2019
The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine. Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation. These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.
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16 MeSH Terms
The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1.
Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, Schumacher MA, Hamilton KE, Lau KS, Shroyer NF, Frey MR
(2017) Cell Death Differ 24: 855-865
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Communication, Cell Count, Cell Differentiation, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Regulation, HT29 Cells, Humans, Ileum, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Paneth Cells, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, ErbB-3, Receptors, G-Protein-Coupled, Stem Cell Niche, Stem Cells
Show Abstract · Added October 16, 2018
Paneth cells (PCs), a secretory population located at the base of the intestinal crypt, support the intestinal stem cells (ISC) with growth factors and participate in innate immunity by releasing antimicrobial peptides, including lysozyme and defensins. PC dysfunction is associated with disorders such as Crohn's disease and necrotizing enterocolitis, but the specific pathways regulating PC development and function are not fully understood. Here we tested the role of the neuregulin receptor ErbB3 in control of PC differentiation and the ISC niche. Intestinal epithelial ErbB3 knockout caused precocious appearance of PCs as early as postnatal day 7, and substantially increased the number of mature PCs in adult mouse ileum. ErbB3 loss had no effect on other secretory lineages, but increased expression of the ISC marker Lgr5. ErbB3-null intestines had elevated levels of the Atoh1 transcription factor, which is required for secretory fate determination, while Atoh1 cells had reduced ErbB3, suggesting reciprocal negative regulation. ErbB3-null intestinal progenitor cells showed reduced activation of the PI3K-Akt and ERK MAPK pathways. Inhibiting these pathways in HT29 cells increased levels of ATOH1 and the PC marker LYZ. Conversely, ErbB3 activation suppressed LYZ and ATOH1 in a PI3K-dependent manner. Expansion of the PC compartment in ErbB3-null intestines was accompanied with elevated ER stress and inflammation markers, raising the possibility that negative regulation of PCs by ErbB3 is necessary to maintain homeostasis. Taken together, our data suggest that ErbB3 restricts PC numbers through PI3K-mediated suppression of Atoh1 levels leading to inhibition of PC differentiation, with important implications for regulation of the ISC niche.
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MeSH Terms
Does Diverting Loop Ileostomy Improve Outcomes Following Open Ileo-Colic Anastomoses? A Nationwide Analysis.
Hawkins AT, Dharmarajan S, Wells KK, Krishnamurty DM, Mutch MG, Glasgow SC
(2016) J Gastrointest Surg 20: 1738-43
MeSH Terms: Aged, Aged, 80 and over, Anastomosis, Surgical, Anastomotic Leak, Colon, Digestive System Surgical Procedures, Female, Humans, Ileostomy, Ileum, Male, Middle Aged, Reoperation, Risk Factors, Treatment Outcome
Show Abstract · Added September 27, 2016
BACKGROUND - Anastomotic leak is one of the most feared complications of gastrointestinal surgery. Surgeons routinely perform a diverting loop ileostomy (DLI) to protect high-risk colo-rectal anastomoses.
STUDY DESIGN - The NSQIP database was queried from 2012 to 2013 for patients undergoing open ileo-colic resection with and without a DLI. The primary outcome was the development of any anastomotic leak-including those managed operatively and non-operatively. Secondary outcomes included overall complication rate, return to the OR, readmission, and 30-day mortality.
RESULTS - Four thousand one hundred fifty-nine patients underwent open ileo-colic resection during the study period. One hundred eighty-six (4.5 %) underwent a DLI. Factors associated with the addition of a DLI included emergency surgery, pre-operative sepsis, and IBD. There were 197 anastomotic leaks (4.7 %) with 100 patients requiring reoperation (2.4 %). DLI was associated with a decrease in anastomotic leaks requiring reoperation (DLI vs no DLI: 0 (0 %) vs 100 (2.5 %); p = 0.02) and with increased readmission (OR 1.93; 95 % CI 1.30-2.85; p = 0.001).
CONCLUSION - DLI is rarely used for open ileo-colic resection. There were no serious leaks requiring reoperation in the DLI group. A DLI was associated with an almost two-fold increase in the odds of readmission. Surgeons must weigh the reduction in serious leak rate with postoperative morbidity when considering a DLI for open ileo-colic resection.
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15 MeSH Terms
Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development.
Fung CM, White JR, Brown AS, Gong H, Weitkamp JH, Frey MR, McElroy SJ
(2016) PLoS One 11: e0146542
MeSH Terms: Animals, Apoptosis, Birth Weight, Cell Proliferation, Female, Fetal Growth Retardation, Gene Expression, Goblet Cells, Humans, Ileum, Infant, Newborn, Mice, Inbred C57BL, Organ Size, Paneth Cells, Pregnancy
Show Abstract · Added April 11, 2016
Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation.
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15 MeSH Terms
Bombesin Preserves Goblet Cell Resistin-Like Molecule β During Parenteral Nutrition but Not Other Goblet Cell Products.
Busch RA, Heneghan AF, Pierre JF, Neuman JC, Reimer CA, Wang X, Kimple ME, Kudsk KA
(2016) JPEN J Parenter Enteral Nutr 40: 1042-9
MeSH Terms: Animals, Bombesin, Goblet Cells, Hormones, Ectopic, Ileum, Immunity, Innate, Interleukin-13, Interleukin-4, Male, Mice, Mice, Inbred ICR, Mucin-2, Paneth Cells, Parenteral Nutrition, Trefoil Factor-3
Show Abstract · Added August 2, 2016
INTRODUCTION - Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule β (RELMβ). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN-induced defects.
METHODS - Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 µg tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMβ by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay.
RESULTS - Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMβ (P < .01). BBS supplementation significantly increased ileal RELMβ to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS.
CONCLUSION - PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMβ during PN but not other goblet cell products measured.
© 2015 American Society for Parenteral and Enteral Nutrition.
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15 MeSH Terms
Identification of pathologic features associated with "ulcerative colitis-like" Crohn's disease.
James SD, Wise PE, Zuluaga-Toro T, Schwartz DA, Washington MK, Shi C
(2014) World J Gastroenterol 20: 13139-45
MeSH Terms: Adult, Colitis, Ulcerative, Colon, Colonic Pouches, Crohn Disease, Female, Humans, Ileum, Intestinal Mucosa, Male, Middle Aged, Neutrophils, Predictive Value of Tests, Proctocolectomy, Restorative, Retrospective Studies, Risk Factors, Severity of Illness Index, Treatment Outcome, Young Adult
Show Abstract · Added April 12, 2016
AIM - To identify pathologic features associated with this "ulcerative colitis (UC)-like" subgroup of Crohn's disease (CD).
METHODS - Seventeen subjects diagnosed as having UC who underwent proctocolectomy (RPC) from 2003-2007 and subsequently developed CD of the ileal pouch were identified. UC was diagnosed based on pre-operative clinical, endoscopic, and pathologic studies. Eighteen patients who underwent RPC for UC within the same time period without subsequently developing CD were randomly selected and used as controls. Pathology reports and histological slides were reviewed for a wide range of gross and microscopic pathological features, as well as extent of disease. The demographics, gross description and histopathology of the resection specimens were reviewed and compared between the two groups.
RESULTS - Patients with "UC-like" CD were on average 13 years younger than those with "true" UC (P < 0.01). More severe disease in the proximal involved region and active ileitis with/without architectural distortion were observed in 6 of 17 (35%) and 7 of 17 (41%) "UC-like" CD cases, respectively, but in none of the "true" UC cases (P < 0.05). Active appendicitis occurred in 8 of 16 (50%) "UC-like" CD cases but in only two (11%) "true" UC cases (P < 0.05). Conspicuous lamina propria neutrophils were more specific for "UC-like" CD (76% vs 22%, P < 0.05). In addition, prominent lymphoid aggregates tended to be more common in "UC-like" CD (P = 0.07). The "true" UC group contained a greater number of cases with severe activity (78% vs 47%). Therefore, the features more commonly seen in "UC-like" CD were not due to a more severe disease process. Crohn's granulomas and transmural inflammation in non-ulcerated areas were absent in both groups.
CONCLUSION - More severe disease in the proximal involved region, terminal ileum involvement, active appendicitis, and prominent lamina propria neutrophils may be morphological factors associated with "UC-like" CD.
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19 MeSH Terms
Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis.
Coursodon-Boyiddle CF, Snarrenberg CL, Adkins-Rieck CK, Bassaganya-Riera J, Hontecillas R, Lawrence P, Brenna JT, Jouni ZE, Dvorak B
(2012) Am J Physiol Gastrointest Liver Physiol 303: G744-51
MeSH Terms: Animals, Animals, Newborn, Diet, Enterocolitis, Necrotizing, Female, Gene Expression Regulation, Ileum, Lipids, Lythraceae, Mucin-2, Neuropeptides, Plant Oils, Pregnancy, RNA, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Seeds, Trefoil Factor-3
Show Abstract · Added July 11, 2013
Pomegranate seed oil (PSO), which is the major source of conjugated linolenic acids such as punicic acid (PuA), exhibits strong anti-inflammatory properties. Necrotizing enterocolitis (NEC) is a devastating disease associated with severe and excessive intestinal inflammation. The aim of this study was to evaluate the effects of orally administered PSO on the development of NEC, intestinal epithelial proliferation, and cytokine regulation in a rat model of NEC. Premature rats were divided into three groups: dam fed (DF), formula-fed rats (FF), or rats fed with formula supplemented with 1.5% of PSO (FF + PSO). All groups were exposed to asphyxia/cold stress to induce NEC. Intestinal injury, epithelial cell proliferation, cytokine production, and trefoil factor 3 (Tff3) production were evaluated in the terminal ileum. Oral administration of PSO (FF+PSO) decreased the incidence of NEC from 61 to 26%. Feeding formula with PSO improved enterocyte proliferation in the site of injury. Increased levels of proinflammatory IL-6, IL-8, IL-12, IL-23, and TNF-α in the ileum of FF rats were normalized in PSO-treated animals. Tff3 production in the FF rats was reduced compared with DF but not further affected by the PSO. In conclusion, administration of PSO protects against NEC in the neonatal rat model. This protective effect is associated with an improvement of intestinal epithelial homeostasis and a strong anti-inflammatory effect of PSO on the developing intestinal mucosa.
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19 MeSH Terms
Absence of gastrointestinal pathogens in ileum tissue resected for necrotizing enterocolitis.
Ullrich T, Tang YW, Correa H, Garzon SA, Maheshwari A, Hill M, Matta P, Krishnan MK, Weitkamp JH
(2012) Pediatr Infect Dis J 31: 413-4
MeSH Terms: Animals, Bacteria, Enterocolitis, Necrotizing, Female, Humans, Ileum, Infant, Infant, Newborn, Male, Multiplex Polymerase Chain Reaction, Parasites, Reverse Transcriptase Polymerase Chain Reaction, Viruses
Show Abstract · Added February 27, 2014
Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in premature infants and has been linked with viral antigens in as much as 40% of cases in single-center cohorts. We examined 28 tissue sections from surgically resected ileum from 27 preterm infants with NEC from 2 separate institutions for 15 common bacterial, viral, and parasitic gastrointestinal pathogens using multiplex reverse transcriptase polymerase chain reaction amplification and suspension array detection methods. We did not detect infectious enteritis pathogens in any of the NEC tissues and conclude that gastrointestinal pathogens are a rare cause of NEC.
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13 MeSH Terms
In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs.
Lau KS, Juchheim AM, Cavaliere KR, Philips SR, Lauffenburger DA, Haigis KM
(2011) Sci Signal 4: ra16
MeSH Terms: Animals, Apoptosis, Benzamides, Blotting, Western, Cell Proliferation, Cluster Analysis, Diphenylamine, Discriminant Analysis, Dose-Response Relationship, Drug, Duodenum, Ileum, Least-Squares Analysis, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Models, Biological, Phosphoproteins, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Time Factors, Tumor Necrosis Factor-alpha
Show Abstract · Added November 15, 2013
Cellular responses to external stimuli depend on dynamic features of multipathway network signaling; thus, cell behavior is influenced in a complex manner by the environment and by intrinsic properties. Methods of multivariate systems analysis have provided an understanding of these convoluted effects, but only for relatively simplified examples in vitro. To determine whether such approaches could be successfully used in vivo, we analyzed the signaling network that determines the response of intestinal epithelial cells to tumor necrosis factor-α (TNF-α). We built data-driven, partial least-squares discriminant analysis (PLSDA) models based on signaling, apoptotic, and proliferative responses in the mouse small intestinal epithelium after systemic exposure to TNF-α. The extracellular signal-regulated kinase (ERK) signaling axis was a critical modulator of the temporal variation in apoptosis at different doses of TNF-α and of the spatial variation in proliferation in distinct intestinal regions. Inhibition of MEK, a mitogen-activated protein kinase kinase upstream of ERK, altered the signaling network and changed the temporal and spatial phenotypes consistent with model predictions. Our results demonstrate the dynamic, adaptive nature of in vivo signaling networks and identify natural, tissue-level variation in responses that can be deconvoluted only with quantitative, multivariate computational modeling. This study lays a foundation for the use of systems-based approaches to understand how dysregulation of the cellular network state underlies complex diseases.
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26 MeSH Terms