scholarly journals The Nonsteroidal Anti-Inflammatory Drug Ketorolac Alters the Small Intestinal Microbiota and Bile Acids Without Inducing Intestinal Damage or Delaying Peristalsis in the Rat

2021 ◽  
Vol 12 ◽  
Author(s):  
Barbara Hutka ◽  
Bernadette Lázár ◽  
András S. Tóth ◽  
Bence Ágg ◽  
Szilvia B. László ◽  
...  
Keyword(s):  
Small Intestine ◽  
Bile Acids ◽  
Intestinal Microbiota ◽  
Intestinal Bacteria ◽  
Mucosal Inflammation ◽  
Intestinal Damage ◽  
Small Intestinal ◽  
Gi Transit ◽  
Anti Inflammatory ◽  
Conjugated Bile Acids

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce significant damage to the small intestine, which is accompanied by changes in intestinal bacteria (dysbiosis) and bile acids. However, it is still a question of debate whether besides mucosal inflammation also other factors, such as direct antibacterial effects or delayed peristalsis, contribute to NSAID-induced dysbiosis. Here we aimed to assess whether ketorolac, an NSAID lacking direct effects on gut bacteria, has any significant impact on intestinal microbiota and bile acids in the absence of mucosal inflammation. We also addressed the possibility that ketorolac-induced bacterial and bile acid alterations are due to a delay in gastrointestinal (GI) transit.Methods: Vehicle or ketorolac (1, 3 and 10 mg/kg) were given to rats by oral gavage once daily for four weeks, and the severity of mucosal inflammation was evaluated macroscopically, histologically, and by measuring the levels of inflammatory proteins and claudin-1 in the distal jejunal tissue. The luminal amount of bile acids was measured by liquid chromatography-tandem mass spectrometry, whereas the composition of microbiota by sequencing of bacterial 16S rRNA. GI transit was assessed by the charcoal meal method.Results: Ketorolac up to 3 mg/kg did not cause any signs of mucosal damage to the small intestine. However, 3 mg/kg of ketorolac induced dysbiosis, which was characterized by a loss of families belonging to Firmicutes (Paenibacillaceae, Clostridiales Family XIII, Christensenellaceae) and bloom of Enterobacteriaceae. Ketorolac also changed the composition of small intestinal bile by decreasing the concentration of conjugated bile acids and by increasing the amount of hyodeoxycholic acid (HDCA). The level of conjugated bile acids correlated negatively with the abundance of Erysipelotrichaceae, Ruminococcaceae, Clostridiaceae 1, Muribaculaceae, Bacteroidaceae, Burkholderiaceae and Bifidobacteriaceae. Ketorolac, under the present experimental conditions, did not change the GI transit.Conclusion: This is the first demonstration that low-dose ketorolac disturbed the delicate balance between small intestinal bacteria and bile acids, despite having no significant effect on intestinal mucosal integrity and peristalsis. Other, yet unidentified, factors may contribute to ketorolac-induced dysbiosis and bile dysmetabolism.

scholarly journals Small intestinal damage associated with the use of nonsteroidal anti-inflammatory drugs

2019 ◽  
Vol 47 (6) ◽  
pp. 559-567 ◽  
Author(s):  
A. E. Karateev ◽  
E. V. Moroz ◽  
E. V. Kryukov
Keyword(s):  
Small Intestine ◽  
Capsule Endoscopy ◽  
Mucosal Inflammation ◽  
Intestinal Damage ◽  
Short Term ◽  
Iron Deficient ◽  
Nsaid Enteropathy ◽  
Inflammatory Drugs ◽  
Small Intestinal ◽  
Anti Inflammatory

The use of nonsteroidal anti-inflammatory drugs (NSAID), even if short-term, may be associated to small intestinal complications, such as erosions, ulcers and chronic mucosal inflammation. Video capsule endoscopy allows for identification of such lesions in 20 to 55% of the patients who have taken nonselective NSAID for 2 to 4  weeks. The pathophysiology of NSAID-induced enteropathy is related to a reduced reparative potential of the mucosa and abnormalities of the microbial balance in the small intestine. In real world practice, NSAID enteropathy is commonly asymptomatic, and its manifestations, such as bleeding, perforation and ileus, are quite rare (about 0.3 episodes per 100  patient-years). The main manifestation of NSAID enteropathy is chronic iron deficient anemia. The use of rebamipide, sulfasalazine, mesalazine, and rifaximin has been discussed in the treatment of NSAID enteropathy, whereas its prevention implies preferential administration of coxibs, the use of rebamipide and probiotics.

FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321757 ◽  
Author(s):  
Song-Yang Zhang ◽  
Rosa J W Li ◽  
Yu-Mi Lim ◽  
Battsetseg Batchuluun ◽  
Huiying Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Small Intestine ◽  
Bile Acids ◽  
Insulin Action ◽  
Farnesoid X Receptor ◽  
Intestinal Microbiome ◽  
Dorsal Vagal Complex ◽  
Small Intestinal ◽  
The Brain ◽  
Conjugated Bile Acids

ObjectiveConjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown.DesignWe evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel.ResultsWe found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance.ConclusionOur findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.

scholarly journals Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage

PLoS ONE ◽  
2019 ◽  
Vol 14 (2) ◽  
pp. e0211436 ◽  
Author(s):  
Sunao Shimada ◽  
Tetsuya Tanigawa ◽  
Toshio Watanabe ◽  
Akinobu Nakata ◽  
Naoki Sugimura ◽  
...  
Keyword(s):  
Intestinal Permeability ◽  
Wheat Gluten ◽  
Intestinal Damage ◽  
Drug Induced ◽  
Inflammatory Drug ◽  
Small Intestinal ◽  
Anti Inflammatory

scholarly journals Observations on the nature and origin of lipids in the small intestine of the sheep

1968 ◽  
Vol 22 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Aileen M. Lennox ◽  
A. K. Lough ◽  
G. A. Garton
Keyword(s):  
Fatty Acids ◽  
Small Intestine ◽  
Fatty Acid ◽  
Bile Acids ◽  
Neutral Lipids ◽  
Intestinal Lumen ◽  
Total Lipids ◽  
Total Fatty Acids ◽  
Proportional Contribution ◽  
Conjugated Bile Acids

1. Total lipids were extracted from digesta obtained from the rumen, abomasum and upper small intestine (jejunum) of each of four slaughtered sheep. The lipids were fractionated into unesterified fatty acids, neutral lipids and phospholipids and the proportional contribution of each fraction to the total fatty acids was determined.2. The contribution made by phospholipids to the total fatty acids in the digesta showed a marked increase in the samples from the small intestine compared with those from the rumen and abomasum. This increase was apparently due to the presence of biliary phospholipids.3. Total lipids and conjugated bile acids were extracted from sheep bile, the lipids were fractionated and their fatty-acid composition was determined. Phospholipids predominated and these consisted mainly of phosphatidylcholine, together with some lysophosphatidylcholine.4. Both phospholipids contained significant amounts of unsaturated C18 components which could account, at least in part, for the previously reported increament to the proportion of these acids in the digesta when it enters the upper jejunum.5. The overall fatty acid compositions of the two biliary phospholipids were very similar and, in common with other naturally occurring phosphatidylcholines, the fatty acids present in position 2 of the phosphatidylcholine of bile were found to consist almost entirely of unsaturated components.6. Total lipids and conjugated bile acids were extracted from samples of digesta obtained from three sheep with cannulas in different positions in the jejunum. Analysis of the lipids indicated that biliary phospholipids, in particular phosphatidylcholine, underwent progressive hydrolysis in the intestinal lumen.7. The distribution of conjugated bile acids, unesterified fatty acids and phospholipids between the solid (particulate) and liquid (micellar) phases of the intestinal digesta was determined. These chyme constituents were, for the most part, associated with the particulate matter and thus, at any given time, it appears that only a small fraction of the total fatty acids is available for absorption in micellar form. It is suggested that the micellar solubilization of fatty acids may be facilitated by the presence of lysophosphatidylcholine.

Mo1031 PROTECTIVE ROLE OF THE PRO-RESOLVING LIPID MEDIATOR RESOLVIN D1 IN NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED SMALL INTESTINAL DAMAGE

2020 ◽  
Vol 158 (6) ◽  
pp. S-762
Author(s):  
Takuya Kuzumoto ◽  
Tetsuya Tanigawa ◽  
Hiroyuki Kitamura ◽  
Akira Higashimori ◽  
Yuji Nadatani ◽  
...  
Keyword(s):  
Protective Role ◽  
Lipid Mediator ◽  
Intestinal Damage ◽  
Resolvin D1 ◽  
Drug Induced ◽  
Inflammatory Drug ◽  
Small Intestinal ◽  
Anti Inflammatory

Isoliquiritigenin Ameliorates Indomethacin-Induced Small Intestinal Damage by Inhibiting NOD-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation

Pharmacology ◽  
2018 ◽  
Vol 101 (5-6) ◽  
pp. 236-245 ◽  
Author(s):  
Shiro Nakamura ◽  
Toshio Watanabe ◽  
Tetsuya Tanigawa ◽  
Sunao Shimada ◽  
Yuji Nadatani ◽  
...  
Keyword(s):  
Small Intestine ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Intestinal Damage ◽  
Protein Levels ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Small Intestinal ◽  
Receptor Family

Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro-caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1β into mature IL-1β, which is critical for the development of non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation. To induce enteropathy, mice were administered indomethacin by gavage with or without isoliquiritigenin pretreatment. Some mice received an intraperitoneal injection of recombinant murine IL-1β in addition to isoliquiritigenin and indomethacin. Indomethacin induced small intestinal damage and increased protein levels of cleaved caspase-1 and mature IL-1β in the small intestine. Treatment with 7.5 and 75 mg/kg isoliquiritigenin inhibited indomethacin-induced small intestinal damage by 40 and 56%, respectively. Isoliquiritigenin also inhibited the indomethacin-induced increase in cleaved caspase-1 and mature IL-1β protein levels, whereas it did not affect the mRNA expression of NLRP3, ASC, caspase-1, and IL-1β. Protection against intestinal damage in isoliquiritigenin-treated mice was completely abolished with exogenous IL-1β. NLRP3–/– and caspase-1–/– mice exhibited resistance to intestinal damage, and isoliquiritigenin treatment failed to inhibit the damage in NLRP3–/– and caspase-1–/– mice. Isoliquiritigenin prevents NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation.

Risk factors for severe nonsteroidal anti-inflammatory drug-induced small intestinal damage

2013 ◽  
Vol 45 (5) ◽  
pp. 390-395 ◽  
Author(s):  
Toshio Watanabe ◽  
Tetsuya Tanigawa ◽  
Yuji Nadatani ◽  
Yasuaki Nagami ◽  
Satoshi Sugimori ◽  
...  
Keyword(s):  
Risk Factors ◽  
Intestinal Damage ◽  
Drug Induced ◽  
Inflammatory Drug ◽  
Small Intestinal ◽  
Anti Inflammatory
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