NSAIDS, Small Bowel and Leaky Gut

Indomethacin_Indocin_Leaky_Gut Jeffrey Dach MDNSAIDS, Small Bowel and Leaky Gut  by Jeffrey Dach MD

Sarah has a PhD degree in Nursing and works on a medical team  in a University Medical Center.   She arrives in my office with complaints of chronic fatigue and generalized muscle and joint pain (fibromyalgia), loose stools, hair loss, depression, anxiety and generally poor health.  For the past three years, Sarah has been taking every day 300 mg of Indocin (Indomethacin), for chronic muscle and joint pain.  NSAIDS are Non-Steroidal Anti-inflammatory drugs commonly taken to relieve pain from arthritis and other inflammatory conditions. Because of possible adverse effects, precautions are advised.

NSAIDs LIST

Generic Name Brand Names
Aspirin Made by several companies
Ibuprofen Motrin®, Advil®, Motrin IB®
Naproxen Naprosyn®, Aleve®
Nabumetone Relafen®

NORMAL Intestinal Brush Border

Normal Intestinal Brush Border_surface leaky gut jeffrey dach

Above Image: Normal Brush Border.  Left Panel Scanning elecron microscope showing finger like villi. Each one has micro-villi (at right panel)  Courtesy of Colorado State

Normal Small Bowel Brush Border

Above Image  Green arrows point to normal intestinal brush border courtesy of  Wallace Gastroenterology. 2011 (9)             .

Short term use of NSAIDs is usually well tolerated. However long term use causes adverse side effects such as gastric ulceration and GI bleeding.  NSAID-induced upper gastrointestinal bleeding is a common cause of hospital admission.(15)  About 16,500 people die every year from NSAID induced gastrointestinal bleeding according to Micheal Wolfe in the New England Journal. (21

The least understood, and more universal adverse effect is NSAID induced damage to the small bowel intestinal brush border, with increased intestinal permeability and “Leaky Gut”.(12,14)

NSAID Damage to Intestinal Brush Border

NSAID Damage to Small Bowel Brush Border Leaky Gut Jeffrey DAch MD

Above image:  Red Arrows point to damaged villi intestinal brush border after NSAID administration to mouse. Courtesy of Wallace Gastroenterology. 2011 NSAID DAMAGE to SMALL Bowel brush border Fig 4. (9) 

All the conventional NSAIDs are associated with small intestinal inflammation.  However, aspirin and nabumetone (Relafen) seem to spare the small bowel.(3)  Intestinal permeability increased significantly following NSAID drug administration to experimental animals (4)

The altered intestinal permeability allows the mucosa to be exposed to bacterial toxins with bacterial invasion of the mucosa.  This may explain NSAID induced intestinal perforations, strictures, and bleeding from the small intestine.(5)

A literature review showed all studies in agreement that NSAIDs increase intestinal permeability in the human within 24 h of ingestion. (7)

Administration of NSAIDs in a mouse model causes progressive increase in intestinal permeability, marked increase in gram-negative bacterial numbers, and frank intestinal ulceration.(8)

Proton pump inhibitor antacid drugs are frequently given with NSAIDS, thinking this will protect the patient.  Studies show the opposite effect.  PPI drugs actually exacerbate NSAID-induced intestinal damage, accompanied by alterations in intestinal microbial populations.(9,20)

Bovine Colostrum

Bovine colostrum, available over-the-counter may prevent NSAID-induced gastrointestinal damage in humans.(10) (22)
See: Leaky Gut Treatment with Colostrum

Leaky Gut Syndrome: A Modern Epidemic with an Ancient Solution? by Douglas A. Wyatt Center for Nutritional Research

Glutamine

Taking Glutamine supplements prior to using NSAID drugs is a preventive measure which inhibits small bowel damage. (18)

A more complete treatment program for “Leaky Gut” is listed in this article:Treatment of Intestinal Permeability Defects Leaky Gut Corey Resnick Natural Medicine Journal 2010 (24)

Diagnostic Testing

Faecal calprotectin (a non-degraded neutrophil cytosolic protein) is as a method for diagnosing NSAID enteropathy.(13)

The urine test for Lactulose/ Mannitol Ratio is a useful test of Intestinal Permeability and Leaky Gut (23)

Another easy home kit test for leaky gut is the 13C-Sucrose Breath Leaky Gut Test. (25)

Worsens Cardiovascular Disease

In patients with established cardiovascular disease, NSAIDs are associated with increased mortality and hospitalization because of acute myocardial infarction and heart failure. (16)

Renal Disease from NSAIDS

NSAIDs may induce a variety of kidney problems, such as acute interstitial nephritis, nephrotic syndrome with acute renal failure,  chronic renal insufficiency, and papillary necrosis. (17)

Mitochondrial Damage

In an animal model, there was mitochondrial damage in the cells of the intestinal brush border within an hour of  NSAID (indomethacin) administration. Electron microscopy showed  mitochondrial damage following NSAID (indomethacin) compatible with uncoupling of oxidative phosphorylation and inhibition of electron transport.  (19)

NSAIDS increases Heart Attacks

Update 2017:  Sondergaard, Kathrine B., et al. “Non-steroidal Anti-inflammatory Drug use is associated with increased risk of Out-of-hospital Cardiac Arrest: A nationwide Case-Time-Control study.” European Heart Journal-Cardiovascular Pharmacotherapy (2016): pvw041.

Articles with Related Interest:

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Omega 3 Fish Oil : Buy Green Lipped Mussel Oilon Amazon

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Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
954-792-4663
http://www.jeffreydachmd.com/
http://www.drdach.com/
http://www.naturalmedicine101.com/
http://www.truemedmd.com/ http://www.bioidenticalhormones101.com

____________________________________

Links and References

1) http://www.thedailybeast.com/articles/2014/04/21/research-shows-link-between-nsaid-use-and-gut-disease.html
Research Shows Link Between NSAID Use and Gut Disease  4/21/14

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2) http://www.aafp.org/afp/2009/1215/p1371.html
NSAID Prescribing Precautions
AMANDA RISSER, MD MPH; DEIRDRE DONOVAN, MD; JOHN HEINTZMAN, MD; and TANYA PAGE, MD, Oregon Health and Science University, Portland, Oregon
Am Fam Physician. 2009 Dec 15;80(12):1371-1378.

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3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727292/
Gut. Oct 1998; 43(4): 506–511.
Intestinal permeability and inflammation in patients on NSAIDs
G Sigthorsson, J Tibble, J Hayllar, I Menzies, A Macpherson, R Moots, D Scott, M Gumpel, and I Bjarnason Department of Medicine, King’s College School of Medicine and Dentistry, London, UK

All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel.

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4) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434083/
Gut. 1986 Nov;27(11):1292-7.
Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine.
Bjarnason I, Williams P, Smethurst P, Peters TJ, Levi AJ.
Intestinal permeability was estimated in healthy subjects after ingestion of aspirin (1.2+1.2 g), ibuprofen (400+400 mg) and indomethacin (75+50 mg) at midnight and an hour before starting a 51chromium labelled ethylenediaminetetraacetate absorption test. Intestinal permeability increased significantly from control levels following each drug and the effect was related to drug potency to inhibit cyclooxygenase. Intestinal permeability increased to a similar extent after oral and rectal administration of indomethacin showing that the effect is systemically mediated. Prostaglandin E2 decreased intestinal permeability significantly but failed to prevent the indomethacin induced increased intestinal permeability. These studies show that non-steroidal anti-inflammatory drugs disrupt the intestinal barrier function in man and suggest that the morphological correlates of the damage may reside at the level of the intercellular junctions.

Intestinal permeability was estimated in healthy subjects after ingestion of aspirin (1.2+1.2 g), ibuprofen (400+400 mg) and indomethacin (75+50 mg) at midnight and an hour before starting a 51chromium labelled ethylenediaminetetraacetate absorption test. Intestinal permeability increased significantly from control levels following each drug and the effect was related to drug potency to inhibit cyclooxygenase. Intestinal permeability increased to a similar extent after oral and rectal administration of indomethacin showing that the effect is systemically mediated. Prostaglandin E2 decreased intestinal permeability significantly but failed to prevent the indomethacin induced increased intestinal permeability. These studies show that non-steroidal anti-inflammatory drugs disrupt the intestinal barrier function in man and suggest that the morphological correlates of the damage may reside at the level of the intercellular junctions.

5) http://www.ncbi.nlm.nih.gov/pubmed/3324305
Scand J Rheumatol Suppl. 1987;64:55-62.
The pathogenesis and consequence of non steroidal anti-inflammatory drug induced small intestinal inflammation in man.  Bjarnason I1, Zanelli G, Smith T, Smethurst P, Price AB, Gumpel MJ, Levi AJ.
Non steroidal anti-inflammatory drugs (NSAID’s) have recently been shown to cause small intestinal inflammation in the majority of patients receiving these on a regular basis for more than one year. The development of inflammation is preceded by an NSAID effect to increase small intestinal permeability. Increased intestinal permeability is shown to be related to drug potency to inhibit cyclooxygenase and the effect is systemically mediated rather than a local irritant one. More recently, increased intestinal permeability due to NSAID’s has been reduced by concomitant prostaglandin administration, showing that prostaglandins are essential for maintaining intestinal integrity in man. It is proposed that altered intestinal permeability allows the mucosa to be exposed to bacterial degradation products or other toxins and together with reduced chemotaxic response and altered neutrophil function due to NSAID’s, this series of events leads to bacterial invasion of the mucosa which is evident by the techniques of 111Indium leucocyte scans and faecal collections. The consequence of such inflammation is that it may explain intestinal perforations and strictures which are occasionally seen in subjects on NSAID’s. Most patients with NSAID-induced small intestinal inflammation may be bleeding from the intestine, loosing protein and some have ileal dysfunction. The small intestine may be a greater source of morbidity than the stomach, in patients receiving NSAID’s.

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6) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727292/
Gut. 1998 Oct;43(4):506-11.
Intestinal permeability and inflammation in patients on NSAIDs.
Sigthorsson G1, Tibble J, Hayllar J, Menzies I, Macpherson A, Moots R, Scott D, Gumpel MJ, Bjarnason I.
The frequency with which non-steroidal anti-inflammatory drugs (NSAIDs) increase small intestinal permeability and cause inflammation is uncertain.
AIMS:To examine small intestinal permeability and inflammation in a large number of patients on long term NSAIDs.
METHODS:Sixty eight patients receiving six different NSAIDs for over six months underwent combined absorption-permeability tests at three different test dose osmolarities (iso-, hypo-, and hyperosmolar). Two hundred and eighty six patients on 12 different NSAIDs underwent indium-111 white cell faecal excretion studies to assess the prevalence and severity of intestinal inflammation.
RESULTS:The iso- and hyperosmolar tests showed significant malabsorption of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose. Intestinal permeability changes were significantly more pronounced and frequent with the hypo- and hyperosmolar as opposed to the iso-osmolar test. Sequential studies showed that four and nine patients (of 13) developed inflammation after three and six months treatment with NSAIDs, respectively. There was no significant difference (p>0.1) in the prevalence (54-72%) or severity of intestinal inflammation in the 286 patients taking the various NSAIDs apart from those on aspirin and nabumetone, these having no evidence of intestinal inflammation. There was no significant correlation between the inflammatory changes and age, sex, dose of NSAID, length of disease, or NSAID ingestion.
CONCLUSIONS:Intestinal permeability test dose composition is an important factor when assessing the effects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel.

7) http://www.ncbi.nlm.nih.gov/pubmed/19148789
J Gastroenterol. 2009;44 Suppl 19:23-9.
Intestinal permeability in the pathogenesis of NSAID-induced enteropathy. Bjarnason I1, Takeuchi K. 1Department of Gastroenterology, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK.

The pathogenesis of nonsteroidal antiinflammatory drug (NSAID)-induced small bowel disease suggests that increased intestinal permeability is the central mechanism that translates biochemical damage to tissue damage. The purpose of this review is to summarize studies on the effect of NSAIDs to increase intestinal permeability in humans and methods for limiting this effect.
METHODS:A Medline search was made for papers that described measurements of increased intestinal permeability in humans.
RESULTS:Virtually all studies agree that all conventional NSAIDs increase intestinal permeability in the human within 24 h of ingestion and that this is equally evident when they are taken long term. Various methods have been tried to limit the damage. The most promising agents are coadministration of synthetic prostaglandins, micronutrients, pre-NSAIDs, and COX-2 selective agents. However, their efficacy in preventing the development of NSAID enteropathy in the long term has not been studied in detail, and, in the case of COX-2 selective agents, small bowel damage is comparable to that which is seen with conventional NSAIDs.
CONCLUSIONS:NSAID enteropathy is associated with significant morbidity and occasionally mortality. There are no proven effective ways of preventing this damage. Because increased intestinal permeability appears to be a central mechanism in the pathogenesis of NSAID enteropathy, it becomes a potential therapeutic target for prevention. At present there are a number of ways to limit the increased permeability, but additional studies are required to assess if this approach reduces the prevalence and severity of NSAID enteropathy.

8) http://www.ncbi.nlm.nih.gov/pubmed/8978349
Gastroenterology. 1997 Jan;112(1):109-17.
Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation.
Reuter BK1, Davies NM, Wallace JL.
The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains poorly understood. The aim of this study was to examine the relative importance of the three suggested components of the pathogenesis of NSAID enteropathy, namely, epithelial permeability, enteric bacterial numbers, and enterohepatic recirculation, using an NSAID derivative (nitrofenac) that does not cause small intestinal damage.
METHODS:Rats were given diclofenac or nitrofenac at 12-hour intervals. Epithelial permeability to [51Cr]-ethylenediaminetetraacetic acid and enteric bacterial numbers were determined after 1-4 doses of the drugs. Serum levels and biliary excretion of the two drugs were determined by high-performance liquid chromatography.
RESULTS:Diclofenac caused a progressive increase in epithelial permeability, marked increases in enteric gram-negative bacterial numbers, and frank intestinal ulceration. Nitrofenac caused similar changes in intestinal permeability after a single dose but no further increase with repeated administration. Moreover, nitrofenac had no effect on enteric bacterial numbers and did not cause frank ulceration. Unlike diclofenac, nitrofenac did not undergo extensive enterohepatic recirculation. Two other NSAIDs that do not undergo enterohepatic recirculation (nabumetone and aspirin) also did not modify enteric bacterial numbers or cause intestinal ulceration.
CONCLUSIONS:Enterohepatic recirculation of NSAIDs is of paramount importance in the pathogenesis of enteropathy caused by these drugs, whereas suppression of prostaglandin synthesis is relatively unimportant.

Image from this article NSAID DAMAGE to SMALL Bowel brush border Figure 4

PPI-induced exacerbation of NSAID enteropathy is transferrable via intestinal microflora. (A) Germ-free mice colonized by intestinal flora from PPI-treated rats developed more severe naproxen-induced small intestinal damage than germ-free mice colonized by intestinal flora from vehicle-treated rats (*P < .05). (B) In the mice colonized with intestinal flora from vehicle-treated

9) http://www.gastrojournal.org/article/S0016-5085%2811%2900926-7/fulltext

http://www.ncbi.nlm.nih.gov/pubmed/21745447
Gastroenterology. 2011 Oct;141(4):1314-22, 1322.e1-5. doi: 10.1053/j.gastro.2011.06.075. Epub 2011 Jul 13.
Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis.
Wallace JL1, Syer S, Denou E, de Palma G, Vong L, McKnight W, Jury J, Bolla M, Bercik P, Collins SM, Verdu E, Ongini E.
1Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used classes of drugs, with the former frequently coprescribed to reduce gastroduodenal injury caused by the latter. However, suppression of gastric acid secretion by PPIs is unlikely to provide any protection against the damage caused by NSAIDs in the more distal small intestine.
METHODS:Rats were treated with antisecretory doses of omeprazole or lanzoprazole for 9 days, with concomitant treatment with anti-inflammatory doses of naproxen or celecoxib on the final 4 days. Small intestinal damage was blindly scored, and changes in hematocrit were measured. Changes in small intestinal microflora were evaluated by denaturing gradient gel electrophoresis and reverse-transcription polymerase chain reaction.
RESULTS:Both PPIs significantly exacerbated naproxen- and celecoxib-induced intestinal ulceration and bleeding in the rat. Omeprazole treatment did not result in mucosal injury or inflammation; however, there were marked shifts in numbers and types of enteric bacteria, including a significant reduction (∼80%) of jejunal Actinobacteria and Bifidobacteria spp. Restoration of small intestinal Actinobacteria numbers through administration of selected (Bifidobacteria enriched) commensal bacteria during treatment with omeprazole and naproxen prevented intestinal ulceration/bleeding. Colonization of germ-free mice with jejunal bacteria from PPI-treated rats increased the severity of NSAID-induced intestinal injury, as compared with mice colonized with bacteria from vehicle-treated rats.
CONCLUSIONS:PPIs exacerbate NSAID-induced intestinal damage at least in part because of significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be a viable option for reducing the incidence and severity of NSAID enteropathy.

2001  Bovine Colostrum Preventive

10)http://www.ncbi.nlm.nih.gov/pubmed/11352778

Clin Sci (Lond). 2001 Jun;100(6):627-33.
Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability.
Playford RJ1, MacDonald CE, Calnan DP, Floyd DN, Podas T, Johnson W, Wicks AC, Bashir O, Marchbank T.
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics but cause gastrointestinal injury. Present prophylactic measures are suboptimal and novel therapies are required. Bovine colostrum is a cheap, readily available source of growth factors, which reduces gastrointestinal injury in rats and mice. We therefore examined whether spray-dried, defatted colostrum could reduce the rise in gut permeability (a non-invasive marker of intestinal injury) caused by NSAIDs in volunteers and patients taking NSAIDs for clinical reasons. Healthy male volunteers (n=7) participated in a randomized crossover trial comparing changes in gut permeability (lactulose/rhamnose ratios) before and after 5 days of 50 mg of indomethacin three times daily (tds) per oral with colostrum (125 ml, tds) or whey protein (control) co-administration. A second study examined the effect of colostral and control solutions (125 ml, tds for 7 days) on gut permeability in patients (n=15) taking a substantial, regular dose of an NSAID for clinical reasons. For both studies, there was a 2 week washout period between treatment arms. In volunteers, indomethacin caused a 3-fold increase in gut permeability in the control arm (lactulose/rhamnose ratio 0.36+/-0.07 prior to indomethacin and 1.17+/-0.25 on day 5, P<0.01), whereas no significant increase in permeability was seen when colostrum was co-administered. In patients taking long-term NSAID treatment, initial permeability ratios were low (0.13+/-0.02), despite continuing on the drug, and permeability was not influenced by co-administration of test solutions. These studies provide preliminary evidence that bovine colostrum, which is already currently available as an over-the-counter preparation, may provide a novel approach to the prevention of NSAID-induced gastrointestinal damage in humans.

2014

Japanese honeysuckle

11) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901675/
PLoS One. 2014 Jan 24;9(1):e86117. doi: 10.1371/journal.pone.0086117. eCollection 2014.
Flos Lonicera ameliorates obesity and associated endotoxemia in rats through modulation of gut permeability and intestinal microbiota.
Wang JH1, Bose S2, Kim GC3, Hong SU4, Kim JH4, Kim JE5, Kim H3.
Increasing evidence has indicated a close association of host-gut flora metabolic interaction with obesity. Flos Lonicera, a traditional herbal medicine, is used widely in eastern Asia for the treatment of various disorders. The aim of this study was to evaluate whether unfermented or fermented formulations of Flos Lonicera could exert a beneficial impact to combat obesity and related metabolic endotoxemia.
METHODS:Obesity and metabolic endotoxemia were induced separately or together in rats through feeding a eight-week high fat diet either alone (HFD control group) or in combination with a single LPS stimulation (intraperitoneal injection, 0.75 mg/kg) (LPS control group). While, the mechanism of action of the Lonicera formulations was explored in vitro using RAW 264.7 and HCT 116 cell lines as models.
RESULTS:In cell-based studies, treatment with both unfermented Flos Lonicera (UFL) and fermented Flos Lonicera (FFL) formulations resulted in suppression of LPS-induced NO production and gene expression of vital proinflammatory cytokines (TNF-α, COX-2, and IL-6) in RAW 264.7 cells, reduced the gene expression of zonula occludens (ZO)-1 and claudin-1, and normalized trans epithelial electric resistance (TEER) and horseradish peroxidase (HRP) flux in LPS-treated HCT-116 cells. In an animal study, treatment of HFD as well as HFD+LPS groups with UFL or FFL resulted in a notable decrease in body and adipose tissue weights, ameliorated total cholesterol, HDL, triglyceride, aspartate transaminase and endotoxin levels in serum, reduced the urinary lactulose/mannitol ratio, and markedly alleviated lipid accumulation in liver. In addition, exposure of HFD as well as HFD+LPS groups with UFL or FFL resulted in significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and ratio of Bacteroidetes and Firmicutes.
CONCLUSION:This evidence collectively demonstrates that Flos Lonicera ameliorates obesity and related metabolic endotoxemia via regulating distribution of gut flora and gut permeability.

2013)

12) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789478/#__ffn_sectitle
Recent Advances in NSAIDs-Induced Enteropathy Therapeutics: New Options, New Challenges. Yun Jeong Lim and Hoon Jai Chun
Gastroenterol Res Pract. 2013; 2013: 761060.

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Single stool faecal calprotectin concentration

13) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727647/
Gut. Sep 1999; 45(3): 362–366.
PMCID: PMC1727647
High prevalence of NSAID enteropathy as shown by a simple faecal test   J Tibble, G Sigthorsson, R Foster, D Scott, M Fagerhol, A Roseth, and I Bjarnason

BACKGROUND—The diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of 111In labelled white cells.
AIMS—To assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy.
METHODS—Single stool faecal calprotectin concentrations were compared with the four day faecal excretion of 111In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs.
RESULTS—The four day faecal excretion of 111In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables.
CONCLUSIONS—Assay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.

14) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065426/
BMC Med. 2011; 9: 24.

‘Gut health’: a new objective in medicine?
Stephan C Bischoffcorresponding author1
1Institute of Nutritional Medicine, University of Hohenheim, Fruwirthstr. 12, Stuttgart, D 70599, Germany

15) http://www.ncbi.nlm.nih.gov/pubmed/15144234
Drug Saf. 2004;27(6):411-20.
Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents.
Laporte JR1, Ibáñez L, Vidal X, Vendrell L, Leone R.

The relative gastrointestinal toxicity of NSAIDs in normal clinical practice is unknown. The aim of this study was to estimate the risk of upper gastrointestinal bleeding associated with NSAIDs and analgesics, with special emphasis on those agents that have been introduced in recent years.
All incident community cases of upper gastrointestinal bleeding from a gastric or duodenal lesion in patients aged >18 years of age (4309 cases). After secondary exclusions, 2813 cases and 7193 matched controls were included in the analysis.
SETTING:Eighteen hospitals in Spain and Italy with a total study experience of 10,734,897 person-years.
MAIN OUTCOME MEASURE:Odds ratios of upper gastrointestinal bleeding for each drug, with adjustment for potential confounders. For each individual drug the reference category was defined as those not exposed to the drug.
RESULTS:The incidence of upper gastrointestinal bleeding was 401.4 per million inhabitants aged >18 years. Thirty-eight percent of cases were attributable to NSAIDs. Individual risks for each NSAID were dose dependent. Ketorolac was associated with the highest risk estimate (24.7; 95% CI 8.0, 77.0). For newer NSAIDs, the risks were as follows: aceclofenac 1.4 (95% CI 0.6, 3.3), celecoxib 0.3 (95% CI 0.03, 4.1), dexketoprofen 4.9 (95% CI 1.7, 13.9), meloxicam 5.7 (95% CI 2.2, 15.0), nimesulide 3.2 (95% CI 1.9, 5.6) and rofecoxib 7.2 (95% CI 2.3, 23.0). The risk was significantly increased in patients with a history of peptic ulcer and/or upper gastrointestinal bleeding, and in those taking antiplatelet drugs.
CONCLUSIONS:NSAID-induced upper gastrointestinal bleeding is a common cause of hospital admission. Apart from the patient’s history of peptic ulcer, its risk depends on the particular drug and its dose, and on concomitant treatments. Our results do not confirm that greater selectivity for COX-2 confers less risk of upper gastrointestinal bleeding.

16) http://www.ncbi.nlm.nih.gov/pubmed/19171810
Arch Intern Med. 2009 Jan 26;169(2):141-9. doi: 10.1001/archinternmed.2008.525.
Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure.
Gislason GH1, Rasmussen JN, Abildstrom SZ, Schramm TK, Hansen ML, Fosbøl EL, Sørensen R, Folke F, Buch P, Gadsbøll N, Rasmussen S, Poulsen HE, Køber L, Madsen M, Torp-Pedersen C.
Accumulating evidence indicates increased cardiovascular risk associated with nonsteroidal anti-inflammatory drug (NSAID) use, in particular in patients with established cardiovascular disease. We studied the risk of death and hospitalization because of acute myocardial infarction and heart failure (HF) associated with use of NSAIDs in an unselected cohort of patients with HF.
METHODS:We identified 107,092 patients surviving their first hospitalization because of HF between January 1, 1995, and December 31, 2004, and their subsequent use of NSAIDs from individual-level linkage of nationwide registries of hospitalization and drug dispensing by pharmacies in Denmark. Data analysis was performed using Cox proportional hazard models adjusted for age, sex, calendar year, comorbidity, medical treatment, and severity of disease, and propensity-based risk-stratified models and case-crossover models.
RESULTS:A total of 36,354 patients (33.9%) claimed at least 1 prescription of an NSAID after discharge; 60,974 (56.9%) died, and 8970 (8.4%) and 39,984 (37.5%) were hospitalized with myocardial infarction or HF, respectively. The hazard ratio (95% confidence interval) for death was 1.70 (1.58-1.82), 1.75 (1.63-1.88), 1.31 (1.25-1.37), 2.08 (1.95-2.21), 1.22 (1.07-1.39), and 1.28 (1.21-1.35) for rofecoxib, celecoxib, ibuprofen, diclofenac, naproxen, and other NSAIDs, respectively. Furthermore, there was a dose-dependent increase in risk of death and increased risk of hospitalization because of myocardial infarction and HF. Propensity-based risk-stratified analysis and case-crossover models yielded similar results.
CONCLUSIONS:NSAIDs are frequently used in patients with HF and are associated with increased risk of death and cardiovascular morbidity. Inasmuch as even commonly used NSAIDs exerted increased risk, the balance between risk and benefit requires careful consideration when any NSAID is given to patients with HF.

17) http://www.ncbi.nlm.nih.gov/pubmed/7631049
Semin Nephrol. 1995 May;15(3):228-35.
Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs.
Kleinknecht D

Nonsteroidal anti-inflammatory drugs (NSAIDs) may induce a variety of acute and chronic renal lesions. Acute interstitial nephritis can follow the use of nearly all NSAIDs, but the number of reported cases is low. Most of these patients are elderly and develop a nephrotic syndrome with acute renal failure while taking NSAID for months. Renal biopsy shows acute tubulo-interstitial lesions with minimal changes in the glomeruli. The renal signs usually improve after discontinuing the drug, with or without steroid therapy, but chronic renal insufficiency or even end-stage renal disease (ESRD) are possible hazards. There is evidence that interstitial nephritis results mainly from a delayed hypersensitivity response to NSAID, and nephrotic syndrome results from changes in glomerular permeability mediated by prostaglandins and other hormones. Nephrotic syndrome without interstitial nephritis may occur, as well as immune-complex glomerulopathy, in a small subset of patients receiving NSAIDs. Patients taking NSAID for months or years may develop papillary necrosis, chronic interstitial nephritis, or even ESRD. Case-control studies suggest that patients at risk are older men who suffer from chronic heart disease and renal hypoperfusion. Impaired medullary circulation and direct toxicity due to a drug metabolite seem to play a critical role in inducing interstitial fibrosis, which can be facilitated by a sustained production of some growth factors and cytokines.

18) http://www.ncbi.nlm.nih.gov/pubmed/15128285
Clin Sci (Lond). 2004 Sep;107(3):281-9.
Oral glutamine attenuates indomethacin-induced small intestinal damage.
Basivireddy J1, Jacob M, Balasubramanian KA.
The use of NSAIDs (non-steroidal anti-inflammatory drugs), although of great therapeutic value clinically, is limited by their tendency to cause mucosal damage in the gastrointestinal tract. In the small intestine, the effects these drugs have been shown to produce include inhibition of cyclo-oxygenase, mitochondrial dysfunction and free radical-induced oxidative changes, all of which contribute to the mucosal damage seen. Glutamine is a fuel preferentially used by enterocytes and is known to contribute to maintaining the integrity of these cells. In the present study, we investigated the effect of glutamine on indomethacin-induced changes in the small intestinal mucosa. Rats were given 2% glutamine or glutamic acid or isonitrogenous amino acids, glycine or alanine, in the diet for 7 days. Indomethacin was then administered orally at a dose of 40 mg/kg of body weight. After 1 h, the small intestine was removed and used for the measurement of parameters of oxidative stress and mitochondrial and BBM (brush border membrane) function. Evidence of oxidative stress was found in the mucosa of the small intestine of drug-treated rats, as indicated by significantly increased activity of xanthine oxidase (P < 0.001) and myeloperoxidase (P < 0.001), with corresponding decreases in the levels of several free radical scavenging enzymes and alpha-tocopherol (P < 0.001 in all cases). Levels of products of peroxidation were also significantly elevated (P < 0.001 for all the parameters measured). In addition, oxidative stress was evident in isolated intestinal mitochondria and BBMs (P < 0.001 for all the parameters measured), with associated alterations in function of these organelles (P < 0.001 for all the parameters measured). Supplementation of the diet with glutamine or glutamic acid prior to treatment with indomethacin produced significant amelioration in all the effects produced by the drug in the small intestine (P < 0.001 for all the parameters measured). Glycine and alanine were found to be much less effective in these respects.

19)http://gut.bmj.com/content/41/3/344.long

http://www.ncbi.nlm.nih.gov/pubmed/9378390
Gut. 1997 Sep;41(3):344-53.
Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine.
Somasundaram S1, Rafi S, Hayllar J, Sigthorsson G, Jacob M, Price AB, Macpherson A, Mahmod T, Scott D, Wrigglesworth JM, Bjarnason I.
The “topical” effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage.
AIM:To examine the possible mechanism of the “topical” phase of damage in the small intestine.
METHODS:Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode.
RESULTS:The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the “topical” phase of NSAID induced damage.
CONCLUSION:Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the “topical” phase of damage induction.

Here, we show directly by a subcellular marker enzyme technique that intestinal mitochondria and brush border are affected within one hour of indomethacin administration. Electron microscopy shows dose dependent mitochondrial changes that are indicative of uncoupling of oxidative phosphorylation or inhibition of electron transport.

20)  http://www.hindawi.com/journals/mi/2013/258209/
http://www.ncbi.nlm.nih.gov/pubmed/23576851
Current perspectives in NSAID-induced gastropathy.
Sinha M1, Gautam L, Shukla PK, Kaur P, Sharma S, Singh TP.
1Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most highly prescribed drugs in the world. Their analgesic, anti-inflammatory, and antipyretic actions may be beneficial; however, they are associated with severe side effects including gastrointestinal injury and peptic ulceration. Though several approaches for limiting these side effects have been adopted, like the use of COX-2 specific drugs, comedication of acid suppressants like proton pump inhibitors and prostaglandin analogs, these alternatives have limitations in terms of efficacy and side effects. In this paper, the mechanism of action of NSAIDs and their critical gastrointestinal complications have been reviewed. This paper also provides the information on different preventive measures prescribed to minimize such adverse effects and analyses the new suggested strategies for development of novel drugs to maintain the anti-inflammatory functions of NSAIDs along with effective gastrointestinal protection.

21) Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs NSAIDS Micheal Wolfe NEJM 1999

22) Bovine Colostrum – Leaky Gut Modern Epidemic Ancient Solution Colostrum Douglas A. Wyatt Twonsend Letter 2014

23) Testing for intestinal Permeability – Intestinal Permeability Test Lactulose Mannitol Ratio Genova Diagnostics

(24) Treatment of Intestinal Permeability Defects Leaky Gut Corey Resnick Natural Medicine Journal 2010

(25)  Testing for Leaky Gut:    13C-Sucrose Breath Leaky Gut Test

13C-Sucrose Breath Leaky Gut Test Kits are available directly from:
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Lactulose/Mannitol Intestinal Permeability Test Kits are available (through retail website sellers) from:
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26) Leaky Gut Autoimmune Diseases Allesio Fasano Clin Review Allergy Immunology 2011

Jeffrey Dach MD
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