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Oral Contraceptives and HRT a Risk Factor for Inflammatory Bowel Disease new
      #213003 - 09/13/05 01:22 PM

Reged: 12/09/02
Posts: 7798
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Risk Factors for Inflammatory Bowel Disease in the General Population

L. A. García Rodríguez; A. González-Pérez; S. Johansson; M.-A. Wallander

Background: The aetiology of inflammatory bowel disease remains largely unknown.

Aim: We performed a comprehensive assessment of potential risk factors associated with the occurrence of inflammatory bowel disease.

Methods: We identified a cohort of patients 20–84 years old between 1995 and 1997 registered in the General Practitioner Research Database in the UK. A total of 444 incident cases of IBD were ascertained and validated with the general practitioner. We performed a nested case–control analysis using all cases and a random sample of 10 000 frequency-matched controls.

Results: Incidence rates for ulcerative colitis, Crohn's disease, and indeterminate colitis were 11, 8, and 2 cases per 100 000 person-years, respectively. Among women, we found that long-term users of oral contraceptives were at increased risk of developing UC (OR: 2.35; 95% CI: 0.89–6.22) and CD (OR: 3.15; 95% CI: 1.24–7.99). Similarly, long-term users of HRT had an increased risk of CD (OR: 2.60; 95% CI: 1.04–6.49) but not UC. Current smokers experienced a reduced risk of UC along with an increased risk of CD. Prior appendectomy was associated with a decreased the risk of UC (OR: 0.37; 95% CI: 0.14–1.00).

Conclusions: Our results support the hypothesis of an increased risk of inflammatory bowel disease associated with oral contraceptives use and suggest a similar effect of hormone replacement therapy on CD. We also confirmed the effects of smoking and appendectomy on inflammatory bowel disease.

L. A. García Rodríguez*, A. González-Pérez*, S. Johansson, M.-A. Wallander

*Centro Espańol de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain;

AstraZeneca R&D Mölndal, Sweden;
Section of Preventive Cardiology, Göteborg University, Sweden;
Department of Public Health and Caring Science, Uppsala University, Sweden

Aliment Pharmacol Ther. 2005;22(4):309-315.

©2005 Blackwell Publishing

To read this article in full, please click here:

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Colonoscopic Surveillance in Inflammatory Bowel Disease new
      #218946 - 10/11/05 01:33 PM

Reged: 12/09/02
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From Current Opinion in Gastroenterology

Colonoscopic Surveillance in Inflammatory Bowel Disease

Thomas A Ullman, Mount Sinai School of Medicine, New York, New York

Curr Opin Gastroenterol. 2005;21(5):585-588. ©2005 Lippincott Williams & Wilkins

Posted 09/28/2005

Thomas A Ullman

Abstract and Introduction
Purpose of Review: To describe recent findings in the literature aimed at decreasing systematic error in dysplasia surveillance in inflammatory bowel disease.
Recent Findings: Despite great promise, colonoscopic surveillance in inflammatory bowel disease has yet to be demonstrated to reduce colorectal cancer mortality. In part, this stems from a number of inherent systematic troubles, including low rates of observer agreement among pathologists; lack of consensus on the natural history of dysplasia, particularly low-grade dysplasia; the patchy nature of dysplasia, which leads to sampling error caused by insufficient biopsy by endoscopists; and incomplete patient follow-up. Recent publications that have focused on defining better the natural history of different levels of dysplasia and improving dysplasia identification at the time of colonoscopy may aid in overcoming the flaws of surveillance. The key recent findings include conflicting evidence on the relative danger of flat low-grade dysplasia, the safety of treating polypoid low-grade dysplasia as a benign adenoma in the absence of flat dysplasia in the rest of the colon or the surrounding mucosa, and preliminary support of chromoendoscopy to target dysplasia better during colonoscopy and to limit unnecessary nontargeted biopsies.
Summary: These and other advances stand a reasonable chance of making surveillance a more accurate tool to discriminate between patients with chronic colitis likely to progress to advanced pathology and those less likely to do so. Such advances may result in effective surveillance in which both colorectal cancer mortality and unnecessary colectomy may be limited.

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Carbon Monoxide Eases Ulcerative Colitis new
      #239575 - 01/18/06 04:12 PM

Reged: 12/09/02
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Carbon Monoxide Eases Bowel Condition

MONDAY, Dec. 12 (HealthDay News) -- Carbon monoxide helps soothe a common form of inflammatory bowel disease called ulcerative colitis by shutting down the inflammation that causes the condition, a new study found.

University of Pittsburgh researchers used low concentrations of inhaled carbon monoxide to ease inflammatory bowel disease symptoms in mice. The carbon monoxide inhibited production of a protein called interleukin-12 (IL-12), which is normally produced during infection and helps activate immune cells that attack invading pathogens.

However, chronic production of IL-12 in the gut results in inflammation that causes ulcerative colitis. Inhibiting production of IL-12 prevents such inflammation, the researchers said.

The researchers are now trying to learn exactly how carbon monoxide inhibits IL-12.

Carbon monoxide is most widely known as a toxic air pollutant, but the body does produce small amounts of it as a normal byproduct of metabolism. High does of carbon monoxide are deadly because it robs the body of oxygen. However, recent studies have shown that low concentrations of carbon monoxide act as an anti-inflammatory, the researchers said.

The study findings appear in the Dec. 19 issue of the Journal of Experimental Medicine.

SOURCE: Dec. 19, 2005, Journal of Experimental Medicine news release
Copyright © 2005 ScoutNews LLC. All rights reserved.

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Viagra May Help Crohn's Disease new
      #249989 - 03/04/06 12:50 PM

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Crohn's Disease Etiology Questioned

By Jeff Minerd, MedPage Today Staff Writer
Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine
February 23, 2006
Also covered by: BBC, Forbes

LONDON, Feb. 23 - The exaggerated immune response that is considered part and parcel of Crohn's disease may have been exaggerated, reported investigators here.

In fact, Crohn's therapies aimed at reducing chronic inflammation may be doing more harm than good, reported Anthony W. Segal, F.R.S., and colleagues of University College London here in the February 25 issue of The Lancet.

Not only that, they suggested that one aspect of this weak response-sluggish blood flow in reaction to bacterial invaders-may be improved by Viagra (sildenafil).

Crohn's disease and colitis, known collectively as inflammatory bowel diseases, affect approximately 1.4 million Americans, including some 140,000 children under the age of 18, according to the Crohn's and Colitis Foundation of America.

Compared with 13 healthy controls, 13 patients with Crohn's disease produced abnormally low levels of neutrophils and the inflammatory cytokine interleukin 8 in response to experimental wounds and abrasions (with sandpaper) the researchers made at various sites on the body.

Neutrophil production was 79% lower than normal in the rectum (P=.0003) and 50% of normal in the skin (P<.0001). IL-8 levels were 63% lower in the rectum (P=.003) and 45% lower in the skin (P<.0001), the investigators reported.

To assess response to the presence of bacteria, the researchers injected heat-killed Escherichia coli under the skin of study participants. Healthy controls showed a vigorous inflammatory response, characterized by redness, swelling, and increased blood flow.

While superficially similar, the responses of Crohn's patients were characterized by sluggish increases in blood flow. Blood flow was reduced by 77% compared with controls in patients with colonic disease (P=.0003) and by 50% compared with controls in patients with ileal disease (P=.01).

Oral administration of 50 mg of Viagra to Crohn's patients after the bacterial injection markedly increased blood flow, bringing it up to normal or near-normal in half of the individuals within 30 minutes, the investigators said.

The researchers also tested three patients with ulcerative colitis, but the responses of these patients were more similar to the control participants than to the patients with Crohn's disease, suggesting that ulcerative colitis has a different etiology than Crohn's, the authors said.

The authors believe that in Crohn's disease, reduced or delayed recruitment of neutrophils to sites at which bacteria penetrate the intestinal wall might lead to the persistence of bacteria and other organic debris in the tissue. The body may respond to this buildup of bacteria by secreting inflammatory molecules, which accumulate and lead to the chronic inflammation typical of Crohn's.

"Causation of Crohn's disease by failure of the acute inflammatory response would fit very well with the so-called hygiene hypothesis, in which the increased incidence of the disease has been attributed to improved standards of sanitation," the authors wrote, noting that incidence of the disease rose greatly in the latter part of the 20th century.

"These findings provide hope for the development of more effective therapies for Crohn's disease," the authors said. Current treatments are immunosuppressive, but although they reduce symptoms by dampening the proposed secondary inflammation, they might actually accentuate the underlying immunodeficiency.

A more successful treatment approach might be to introduce IL-8 or other proinflammatory stimuli directly into acute lesions, either by direct enteral administration or through synthesis by genetically modified gut organisms, they proposed.

"Agents that increase blood flow, such as long-acting phosphodiesterase-5 inhibitors or other vasodilatatory or proinflammatory drugs, might be useful in healing or preventing lesions in Crohn's disease," they concluded.

Primary source: The Lancet
Source reference:
Marks DJB et al. Defective acute inflammation in Crohn's disease: a clinical investigation. The Lancet. 2006; 367:668-678.

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Novel Compound Targets Mucosal Healing in Crohn's new
      #266198 - 05/29/06 02:19 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

LOS ANGELES, May 23 — A novel treatment that targets mucosal protection and healing rather than inflammation led to fast and significant efficacy in patients with moderate to severe Crohn's disease, researchers said here.

At the highest tested dose, teduglutide, an analog of the naturally occurring human peptide glucagon like peptide-2 (GLP-2), elicited a response at two weeks in more than 50% of patients, reported Alan L. Buchman, M.D., of Northwestern University in Chicago at Digestive Disease Week sessions here. The agent was self injected subcutaneously daily.

At eight weeks more than 60% of patients randomized to 0.20 mg/kg daily had more than a 100-point drop in the Crohn's Disease Activity Index (CDAI). The response rate was similar in the placebo group (57%). Moreover, the clinical remission rate, defined as a CDAI of less than 150 points, was more than 50% for patients in the 0.20 mg/kg group.

The dose-ranging, proof of concept trial tested three dose regimens: 0.05 mg/kg/day; 0.10 mg/kg/day; and the 0.20 mg/kg/day dose.

"We still don't know maximum dose or maximum efficacy," said Dr. Buchman.

"We sent the bar very high in this trial," he said. "Our endpoint was complete remission by primary healing of the mucosa. Our secondary endpoint was reduction of inflammation." Inflammation was measured by surrogate markers, but Dr. Buchman did not report those data.

"Inflammatory bowel disease starts in the gut, so if you can heal the gut, you can probably heal the rest of the body," Dr. Buchman said, suggesting why teduglutide demonstrated such surprising efficacy.

Maria Abreu, M.D., of Mount Sinai in New York, said she, too was impressed with the results. The typical response with biologics is about 30%, said Dr. Abreu, so the teduglutide response was significantly better.

Dr. Buchman said it was not clear just how teduglutide works. For example, the compound has a short half life, just 2 hours, a very high absolute bioavailability (87%), and it reaches its median peak concentration in 20 minutes to an hour, he said.

He proposed a number of potential mechanisms of action including, stimulation of crypt cell proliferation, inhibition of enterocyte apoptosis and stimulation of mesenteric blood flow.

But, these effects are observed even when "we can no longer detect teduglutide," he said. "So, we can't detect it, yet we see the results."

In an interview, he predicted on the basis of some open-label data, that teduglutide would be durable. "In the open label study, we don't see any dose erosion, which is a problem with the biologics because after a time you need to increase dose amount or frequency in order to maintain response. We are not seeing that effect."

The study was funded by NPS Pharmaceuticals. Dr. Buchman said NPS plans to use these data will be used to design a phase III study.

Primary source: Digestive Disease Week
Source reference:
Buchman, AL et al. "Effect of Teduglutide on Patients with Moderate-Severe Crohn's Disease after 8 Weeks of Therapy: A Prospective, Double-Blind, Placebo Controlled Trial" Abstract 686c.

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Inflammatory Bowel Disease and Irritable Bowel Syndrome: Separate or Unified? new
      #354009 - 01/05/10 12:03 PM

Reged: 12/09/02
Posts: 7798
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Current Opinion in Gastroenterology

Inflammatory Bowel Disease and Irritable Bowel Syndrome: Separate or Unified?
Sylvie Bradesi, PhD, James A. McRoberts, Ph.D, Peter A. Anton, MD, Emeran A. Mayer, MD

Posted: 07/15/2003; Curr Opin Gastroenterol. 2003;19(4) © 2003 Lippincott Williams & Wilkins

Abstract and Introduction
Both irritable bowel syndrome and inflammatory bowel diseases share symptoms of altered bowel habits associated with abdominal pain or discomfort. Irritable bowel syndrome has been referred to as a functional bowel disorder, which is diagnosed by a characteristic cluster of symptoms in the absence of detectable structural abnormalities. Inflammatory bowel disease is a heterogeneous group of disorders characterized by various forms of chronic mucosal and/or transmural inflammation of the intestine. In this review, the authors discuss recent evidence suggesting several potential mechanisms that might play a pathophysiologic role in both syndromes. Possible shared pathophysiologic mechanisms include altered mucosal permeability, an altered interaction of luminal flora with the mucosal immune system, persistent mucosal immune activation, alterations in gut motility, and a role of severe, sustained life stressors in symptom modulation. It is proposed that similarities and differences between the two syndromes can best be addressed within the framework of interactions between the central nervous system and the gut immune system. Based on recent reports of low-grade mucosal inflammation in subpopulations of patients meeting current diagnostic criteria for irritable bowel syndrome, therapeutic approaches shown to be effective in inflammatory bowel disease, such as probiotics, antibiotics, and antiinflammatory agents, have been suggested as possible therapies for certain patients with irritable bowel syndrome.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) represent two conditions characterized by chronically recurring symptoms of abdominal pain, discomfort (urgency and bloating) and alterations in bowel habits. However, whereas IBD is characterized by inflammation or ulcerations in the small and/or large intestine, such "organic" changes have traditionally not been associated with IBS. IBD is usually classified as ulcerative colitis or Crohn disease, but it also includes forms of microscopic colitis, eg, histologic evidence of mucosal inflammation without macroscopic abnormalities. IBD is characterized by a constellation of patient-reported history and endoscopic, histopathologic, and radiologic findings, often with serologic correlates. Classic signs that reflect the inflammatory process within the gastrointestinal tract are rectal bleeding, diarrhea, fever, and weight loss, occasionally associated with extraintestinal manifestations. Interestingly, in the absence of complications, abdominal pain is not necessarily the most prominent symptom in IBD, despite extensive mucosal inflammation and presumably sensitization of peripheral visceral pain pathways. Genetic predisposition, environmental factors, infectious agents, altered gut epithelial permeability, and impaired immune responses have been incriminated in the still unclear cause of IBD.

By contrast, IBS, classified as functional (as opposed to organic) bowel disorder, is currently diagnosed on the basis of a characteristic cluster of symptoms in the absence of detectable structural abnormalities. As a matter of fact, according to the currently used symptom criteria (Rome criteria), once organic changes are detected, a diagnosis of a functional syndrome can no longer be made.[1] Because of the nonspecificity of the cardinal symptoms of abdominal pain or abdominal discomfort (the latter including bloating-type symptoms, a sensation of rectal urgency, or incomplete evacuation), the current diagnosis of IBS applies to a heterogeneous group of patients, even after attempts to define subgroups based on predominant bowel habit. Current theories to explain the pathophysiology of IBS include alteration in visceral perception, gastrointestinal motility and gut epithelial and immune function. Considerable evidence supports a role of psychosocial and physical (ie, gastroenteric infections) stressors as central and peripheral triggers, respectively, of first symptom onset or exacerbation.[2*] As reflected by an increasing number of publications on the subject, considerable interest in the putative role of low-grade chronic inflammation in the pathogenesis of IBS has recently emerged.[3] Enhanced responsiveness to psychosocial and physical stressors has been suggested as a plausible mechanism that could explain most clinical and experimental findings in IBS, and that is consistent with the majority of the reported physiologic alterations.[4]

Evidence of Mucosal Immune Activation in Patients Meeting Symptom Criteria for Inflammatory Bowel Diseases
Several recent independent studies have demonstrated alterations in the gut-associated immune system. Quantitative assessment in unselected patients with IBS have shown increased mast cell numbers in the ileum[5] and colonic mucosa.[6] Preliminary evidence suggests an increase of overall cellularity in the colonic mucosa[7] and a higher number of mast cells containing tryptase (known to have proinflammatory effects) in the colonic lamina propria of patients with IBS.[8] Additional preliminary results indicate a significant increase of inducible nitric oxide synthase (iNOS) expression in the colonic mucosa from unselected patients with IBS compared with control patients.[9] In the human colon, upregulation of iNOS has been implicated in inflammatory processes, and increased expression has been documented in IBD.[10] More recently, a study by Chadwick et al. [11*] demonstrated intestinal mucosal immune activation in 77 symptomatic patients meeting the Rome criteria (the authors did not specify Rome I vs II criteria). The study included patients with diarrhea, constipation, or both. In 38 of the patients (50%), a normal conventional histologic appearance was seen, but the immunohistologic results were abnormal (intraepithelial lymphocytes-IEL, lamina propria CD25+ and CD3+ lymphocytes). In 40% of patients, nonspecific microscopic inflammation was seen, whereas immunohistologic results showed similar increases in lymphocyte populations as in the first group. However, in contrast to the first group, they also showed increased numbers of neutrophils and mast cells. Ten percent of patients fulfilled the histologic and immunohistologic criteria for lymphocytic colitis. Even though the magnitude of changes in cell numbers was far less than observed in patients with IBD, the increased numbers of IEL, T cells, IL-2 receptor expressing cells, suppressor/cytotoxic T cells, and NK cells were consistent with an increased inflammatory cell presence in a subset of patients with altered bowel habits who met the symptom-based Rome criteria. Because a significant number of patients meeting the Rome criteria also met the histologic criteria for a diagnosis of lymphocytic colitis, the findings highlight a major problem with the way we currently diagnose IBS. By definition, the diagnosis of an organic disease such as lymphocytic colitis is inconsistent with a diagnosis of IBS. Furthermore, it is unclear whether the patients met the Rome criteria because of the presence of discomfort (urgency, bloating) relieved by bowel movements, or whether they reported abdominal pain. Using the current Rome criteria, a diagnosis of IBS can be made in any patient experiencing abdominal discomfort (for example, in the form of urgency or bloating-type symptoms), that is relieved by a bowel movement. In the absence of mucosal histology to rule out macroscopic or microscopic forms of colitis, such a symptom cluster is likely to include a wide range of syndromes with different causes and pathologic mechanisms.

Another study reported neuromuscular and inflammatory abnormalities in the small bowel of 10 patients (8 women; age range 24-55 years) with severe IBS symptoms.[12] Surprising for an IBS population, the symptoms apparently were severe and refractory enough to justify a laparoscopic full-thickness biopsy. The durations of IBS symptoms ranged from 2 to 30 years, and the predominant bowel habits included constipation, diarrhea, and alternating bowel habits. In this study, analysis of full-thickness biopsy specimens of the jejunum from IBS patients (diagnosis having been made on the basis of absence of detectable structural lesions and fulfillment of the Rome I criteria for IBS) showed several histopathologic abnormalities. The authors reported in most patients some neural degeneration in the ganglia of the myenteric plexus associated with infiltration of CD3+ T lymphocytes and longitudinal muscle hypertrophy. In some cases, IEL numbers were increased, and the numbers of interstitial cells of Cajal were also increased. There are two major problems with the reported findings. First is the absence of an appropriate control group. For example, the observed mucosal alterations in the proximal jejunum were compared with biopsy specimens obtained from the distal ileum during colonoscopy, and alterations in the jejunal wall were compared with findings obtained in tissues from deceased patients (of unspecified sex and age). Second, as admitted by the authors, the patients in this study represented a highly selected group with severe symptoms that were apparently refractory to current management. Even though it was stated that patients had normal or nonspecific changes on small intestinal manometry, it is conceivable that the patients had a mild or early form of chronic intestinal pseudoobstruction. Analogous to the comments made above about the nonspecificity of the Rome criteria to differentiate microscopic colitis from IBS, the same argument could be made for chronic intestinal pseudoobstruction.

Patients in another group, frequently discussed as evidence for a possible role of altered gut immune function in IBS, are those in whom IBS-like symptoms develop after a documented gastroenteric infection (so-called postinfectious IBS [PI-IBS] patients). A history of acute gastroenteritis caused by a variety of bacterial infections as well as parasitic infections was found to increase the risk of the development of persistent IBS symptoms. The risk factors associated with PI-IBS include female gender, duration of the acute illness episode, and a major stressful life event at the time of the infection. Patients with PI-IBS have been reported to show changes in gut motility (eg, reduced rectal compliance) and epithelial function and an increase in enterochromaffin cells.[13, 14] In addition, mucosal immune parameters in these patients exhibit changes that include altered macrophage (CD68) and T lymphocyte (CD3, CD4, CD8) populations and increased expression of IL-1 mRNA.[15] Some of these changes, as well as symptoms of diarrhea, were shown to persist for more than a year in some cases, suggesting chronic immune system activation.[15] Although the mechanisms involved in the ongoing inflammation after clearance of the infectious agent remain unclear, it has been suggested that a subset of IBS patients may have a genetic predisposition to inflammatory dysregulation. Preliminary evidence suggests a reduced frequency of the high producer allele for the antiinflammatory cytokines IL-10 and TGF-, suggesting a reduced production of these cytokines in patients with IBS compared with healthy control subjects.[16] Several important questions have to be addressed before the existence of a distinct pathophysiologic entity of PI-IBS can be confirmed. (1) Even though persistence of low-grade inflammation has been described in individuals who continued to be symptomatic, a causal role of these mucosal changes with IBS symptoms has not been demonstrated.[14, 15] Preliminary reports from a therapeutic trial with an antiinflammatory agent in PI-IBS did not demonstrate any effect on symptoms.[17] (2) There is currently no evidence of visceral hypersensitivity in this patient group, and the reported lower volume thresholds for discomfort simply reflect a reduced rectal compliance. (3) It is unclear whether patients who report their first onset of IBS symptoms after an enteric infection have a history of other intestinal or extraintestinal functional syndromes (such as dyspepsia or chronic constipation) or anxiety disorders. In this case, the persistence of bowel symptoms may simply be a reactivation of a preexisting functional syndrome.

Tibble et al. [18**] compared a large population of patients with altered bowel habits meeting the Rome I criteria for IBS and patients with different organic diseases of the intestine, including IBD, cancer, infectious diarrhea, and celiac disease. They observed that markers for intestinal inflammation, such as fecal calprotectin levels, were elevated in the majority of patients with organic gastrointestinal conditions and decreased in the majority of patients with IBS. The sensitivity and specificity of fecal calprotectin levels for organic intestinal disease were 89% and 79%, respectively. However, the authors observed a significant number of IBS patients whose fecal calprotectin levels were above a normal cutoff value, suggesting some degree of inflammation.

Taken together, the above findings are most consistent with the concept that in a subset of patients meeting the current diagnostic criteria for IBS, chronic low-grade immune activation may be associated with chronic changes in gut motor and secretory function resulting in chronic abdominal discomfort associated with altered bowel habits. However, a causal relationship between visceral hypersensitivity and chronic immune activation has not been demonstrated.

Altered Immune System and Inflammation in Inflammatory Bowel Diseases
Classic histopathologic inspection of tissue from patients with IBD reveals vasodilatation, venocongestion, edema, infiltration of large numbers of inflammatory cells (lymphocytes as well as macrophages and monocytes), and architectural disarray, often with mucosal erosions and/or frank ulcerations. Although the causative triggers remain unclear, the role of a persistent and likely dysregulated mucosal immune response is central to the pathogenesis of IBD. However, it remains unclear whether the persistent inflammation, an intrinsic feature of IBD, reflects a primary aberration in mucosal response or results from an inappropriate persistent stimulation. Accumulating evidence indicates that excessive activation of immunoinflammatory responses in IBD may be initiated by luminal flora. In this regard, recent data showed no difference in the overall composition of mucosal flora in patients with IBD and control subjects but demonstrated a higher concentration of mucosa-associated bacteria in patients with IBD.[19] The authors suggest that the changes in the concentrations of mucosal flora in IBD are not secondary to inflammation but result from a host-specific altered immunoinflammatory mucosal response to "self-flora" in susceptible individuals. The role of genetic factors continues to be explored, with disease susceptibility associated with genetic markers for particular subsets of IBD patients. Recent studies using genome-wide screening provided the first link between NOD2 mutations and the clinical characterization of Crohn disease.[20, 21] NOD proteins are thought to be cytosolic receptors for bacterial signals, and NOD2 is expressed in monocytes and activates nuclear factor kB (NF-kB). However, the mechanisms by which NOD2 mutations contribute to Crohn disease need further investigation. It has been hypothesized that different concentrations of bacteria in the ileum relative to the colon may contribute to the association between NOD2 mutations and ileal disease. A genetic background was also identified in ulcerative colitis associated with HLA genes and regions of the chromosomes 3, 7, and 12.[22] In a recent review, Ardizzone et al. [23**] compiled the genetic factors recently involved in the pathogenesis of IBD. Considering the central role of cytokines in modulating intestinal inflammation, several studies have focused on cytokine genes, looking for mutations or polymorphisms and expression dysregulation.[24] In Crohn disease, an increased expression of T-helper-1 (Th1) cytokines was initially described, whereas an atypical Th2 response was associated with ulcerative colitis, but this assessment is now thought to be too simplistic. Cytokine gene-regulated differences between and within the diseases are clearly more complex. Advances in the understanding of the immune response in IBD have stimulated the development of new therapeutic agents directed against key players in the inflammatory process. A range of therapeutic strategies to block the biosynthesis or action of proinflammatory cytokines, acting directly or though targeting immunoregulatory cytokines, has been developed.[25]

Among specific targets, tumor necrosis factor- (TNF-) was among the first mucosal cytokines identified as critical in the development and amplification of mucosal inflammation in IBD.[26] Recent clinical trials showed that anti-TNF- antibodies provide marked clinical benefits in some patients with Crohn disease: a translational insight that has now become commonplace in IBD clinical therapy.[27, 28] An inhibitor of mitogen-activated protein kinase (MAPK) appears to be another candidate in novel therapeutic strategies. A beneficial effect of CNI-1493 (MAPK inhibitor) in patients with severe Crohn disease was recently described.[29] A better characterization of the molecular signaling pathways involved in the activation of key immune and inflammatory cells will indubitably provide new targets for the development of therapeutic agents for IBD.

What Unifies and Separates Irritable Bowel Syndrome and Inflammatory Bowel Diseases
Possible Role of Failure to Downregulate Immune Response
A comparison of published data on the activation of the gut-associated mucosal immune system in IBS and IBD reflects both the similarities and the differences in the altered immune response observed in these disorders. However, the triggering factor initiating the inflammatory response remains unclear. In IBS, an immune response to infection,[30] a disinhibition of the immune system during chronic sustained stress (Fig. 1), or a combination of both are plausible mechanisms that could result in the initial immune activation. The persistence of low-grade inflammation after pathogen clearance or after resolution of the psychosocial stressor, in a subset of individuals, may be related to an inability to efficiently downregulate the inflammatory response. This inability may be related to genetic factors or to early programming of antiinflammatory systems, such as the hypothalamic-pituitary-adrenal (HPA).[31*] For example, a hyporesponsive HPA axis in the Lewis rat has been shown to be associated with exaggerated immune responses to various stimuli, including chemically induced colitis.[32] The most recent available data on IBD increasingly emphasize the role of immunogenetics in the predisposition, modulation, and perpetuation of the disease.[33] The abnormal amplification and persistence of inflammation leading to tissue injuries likely reflects the continuing presence of the driving stimulus and self-reinforcing activation of mucosal inflammatory cells mediated by increased expression of cytokines.

Figure 1. Brain-gut immune interactions in irritable bowel syndrome and inflammatory bowel disease: effect of chronic stress on the mucosal immune system. Acute stress causes increases in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of the two branches of the autonomic nervous system (ANS), the sympathetic nervous system (SNS), and the parasympathetic (vagal) system. In patients with irritable bowel syndrome, the peripherally acting products of each of these pathways (cortisol, CORT; norepinephrine, NE; acetylcholine, Ach) can inhibit the mucosal immune system, especially Th1-type responses. This results in a temporary shift toward Th2 cytokine responses (IL-4 and others) that are not as strongly inhibited and that can further inhibit Th1 responses. In patients with inflammatory bowel diseases, the corticotropin-releasing factor (CRF) response may be blunted, leading to diminished CORT and NE release. These changes favor the production of Th1 cytokines and the proliferation of macrophages, natural killer (NK) cells, and cytotoxic T cells (Tc). TNF, which is produced by activated macrophages but can also be released by activated mast cells, stimulates the production of IL-1 (in the Th1 pathway) and IL-6 (by lymphoid and nonlymphoid tissues). With chronic stress in both types of patients, the shift to a Th1 response becomes predominant, with positive feedback loops developing between the gut and the brain. The restraints on immune cell proliferation and activation are compromised by blunting of the HPA axis response due to downregulation of pituitary CRF1 receptors, decreased vagal tone, and downregulation of 2-adrenergic receptors (2-AR) on Th1 immune cells by chronically elevated catecholamines. Circulating levels of TNF-, IL-1, and IL-6 increase to concentrations that synergistically stimulate CRF production in the PVN of the hypothalamus. In irritable bowel syndrome, TNF and IL-1 sensitize primary afferent terminals through long-lasting effects on gene expression, including the expression of neurokinin receptors. Locally acting mast cell products (tryptase and histamine) and proinflammatory compounds (PGE2) can also sensitize primary afferents. Both IFN (Th1 cytokine), which is produced by NK cells in response to TNF, and IL-4 (a Th2 cytokine) have been shown to decrease mucosal barrier function by increasing epithelial permeability,[54,55] thus perpetuating a local inflammatory response by allowing entry of bacteria and bacterial products. Subjective pain responses to peripheral sensitization of visceral afferents in irritable bowel syndrome and inflammatory bowel diseases are likely to be modulated differentially by endogenous pain modulation pathways. DMN, dorsal motor nucleus of the vagus; ACTH, adrenocorticotropin hormone.
Increased Permeability
For both syndromes, histologic and functional alterations of the mucosal barrier have been recently reported.[11*, 12, 24, 25] Small intestinal permeability is abnormal in a wide variety of conditions affecting the small intestine, including celiac disease, Crohn disease, and intestinal infections.[18**] Interestingly, gut permeability assessed by the lactulose/mannitol ratio is significantly elevated in PI-IBS patients.[15] This functional alteration of the intestinal barrier function may be a cause or consequence of inflammation, and a direct link between increased intestinal permeability and the exaggerated immune activation in IBD still needs to be confirmed. In addition to a causative role of peripheral factors, gut permeability changes in animal models have also been reported in response to various stressors. For example, in a rat model of chronic stress, an increase in intestinal epithelial permeability, associated with an increase in mucosal neutrophils and mast cells, has been demonstrated.[34**] In this model, the combination of stress-induced increases in intestinal permeability, allowing easier access of antigens to gut-associated macrophages and dendritic cells, together with stress-induced changes in HPA axis responsiveness and cytokine profiles, resulted in the development of colitis, without any additional chemical or immunologic manipulations. Rats with a history of aversive early life events were more susceptible to these stress-induced changes in gut permeability,[35*] possibly related to early programming of the HPA axis.[31*]

Changes in Luminal Flora
A change in intestinal microflora has been implicated, in association with genetic factors, as a putative mechanism responsible for the initiation and persistence of inflammation in IBD. Indeed, it has been suggested that the failure to maintain immunologic tolerance toward the indigenous microflora leads to a disease-associated dysregulation of the gut-associated immune system. Direct and indirect evidence of altered flora of the large and small intestine has been reported in IBS patients. For example, Balsari et al. [36] observed a decrease in coliforms, lactobacilli, and, to some extent, bifidobacteria in a small group of IBS patients. More recently, preliminary evidence of an alteration of bacterial concentration in colonic biopsy specimens from IBS patients has been reported.[37] Indirect evidence for bacterial overgrowth of the small intestine (in the form of altered hydrogen breath test results) has been reported in patients with IBS, and a recent randomized controlled trial found evidence that antibiotic treatment was beneficial for IBS symptoms of bloating and discomfort.[38] Based on the concept of altered interactions between the colonic flora and the gut-associated immune system, probiotics have been proposed as an alternative strategy for the treatment of several gastrointestinal diseases, including IBD[39] and more recently IBS.[40, 41] However, the reported results are conflicting, and only a small number of double-blind controlled clinical trials support a beneficial health effect in IBD or IBS.[42] The epithelium has recently been recognized as playing an important role in innate immune responses in response to intestinal microorganisms.[43, 44] It expresses a variety of receptors (Toll-like receptor) involved in the recognition of a spectrum of microbial products. This recognition capability may enable an appropriate cytokine and chemokine secretion in response to changes in luminal flora.

Influence of Sustained Psychosocial Stressors on Mucosal Immune System Activation
Even though stress has been less recognized as a factor in the natural history of IBD, considerable evidence supports a prominent role for it in the pathophysiology and clinical presentation of both IBD and IBS symptoms.[45] Patients with IBS seem to have a greater reactivity to stress than do control subjects or IBD patients. Yet, sustained psychologic stressors have been associated with the onset and exacerbation of symptoms in both IBS and IBD.[46-48] The development of persistent IBS symptoms after acute gastroenteritis has been associated with major life events around the time of infection.[14] Similarly, for IBD, a wide range of clinical studies indicates a strong link between sustained psychosocial stressors and IBD activity.[49] Levels of long-term perceived stress have been shown to correlate with changes in mucosal appearance and relapse in ulcerative colitis.[50*] Further evidence of an influence of stress on inflammatory processes comes from animal studies showing a modulation of the immune function at different levels, including immune cell distribution, cytokine profiles, or susceptibility to infection in naďve or colitic animals.[51] In view of the established concept of an altered immune response in IBD patients, and the suspected low-grade inflammation in some patients meeting the symptom criteria for IBS, it is reasonable to consider a bidirectional model of brain-gut interactions as an important determinant of gut-associated immune activation in both disorders.

Chronic Inflammation and Alteration of Sensory-Motor Functions of the Gastrointestinal Tract
Despite the common assumption that chronic gut mucosal inflammation is associated with sensory-motor dysfunction of the gastrointestinal tract in inflammatory as well as functional intestinal disorders, the relationship between chronic inflammation and the generation of gastrointestinal symptoms remains unclear. The development of IBS-like symptoms in some patients with quiescent ulcerative colitis was suggested as an indication of the role of inflammation on altered sensory and motor function.[8] The concept of long-lasting postinflammatory changes in gut motility is supported by the observation of altered anorectal and colonic motility in patients in remission from ulcerative colitis and Crohn disease.[52] However, chronic abdominal pain and visceral hypersensitivity-classic features in patients with IBS-do not appear to be a hallmark of ulcerative colitis or Crohn disease.[53] One may speculate that various patient populations with different degrees of intestinal inflammation (patients with IBD and PI-IBS, and possibly small subsets of those with IBS) do not necessarily experience pain and discomfort from these mucosal changes. Whereas the effects of the immune activation are likely to affect enteric nervous system circuits and smooth muscle function, altering intestinal compliance and reflex activity and producing such symptoms as diarrhea and urgency, the effects on visceral perception are less predictable. An important variable in symptom generation is the differences in the ability of the brain and its endogenous pain inhibitory pathways to counteract the changes in peripheral viscerosensory pathways.

The recent observation of an activated immune system in some IBS patients associated with persistent low-grade mucosal inflammation provides evidence for the reconsideration of the symptom-criteria-based diagnosis of functional bowel disorders. The development and use of biologic markers identifying low-grade inflammation would improve the characterization of subsets of IBS patients in whom peripheral mechanisms may participate in specific symptom genesis and could be considered in the choice of the therapy.

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Mayer EA, Collins SM: Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology 2002, 122:2032-2048.
* Comprehensive review of evidence for peripheral and central mechanisms contributing to symptom generation in IBS.
Spiller RC: Neuropathology of IBS? Gastroenterology 2002, 123:2144-2147.
Mayer EA, Naliboff BD, Chang L, et al.: V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2001, 280:G519-G524.
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Barbara G, Cottrell G, Grady E, et al.: Expression and release of mast cell tryptase in irritable bowel syndrome (IBS). Gastroenterology 2002, 122:A276.
O'Sullivan MA, Clayton N, Wong T: Increased inos and nitrotyrosine expression in irritable bowel syndrome. Gastroenterology 2000, 118:A702.
Miller MJ, Sandoval M: Nitric oxide: III. A molecular prelude to intestinal inflammation. Am J Physiol Gastrointest Liver Physiol 1999, 276:G795-G799.
Chadwick VS, Chen W, Shu D, et al.: Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002, 122:1778-1783.
* Interesting paper showing evidence for mucosal immune activation in patients who also meet the current diagnostic criteria for IBS.
Tornblom H, Lindberg G, Nyberg B, et al.: Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002, 123:1972-1979.
Gwee KA, Collins SM, Marshall JS, et al.: Evidence of inflammatory pathogenesis in post-infectious irritable bowel syndrome. Gastroenterology 1998, 114:A758.
Gwee KA, Leong YL, Graham C, et al.: The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999, 44:400-406.
Spiller RC, Jenkins D, Thornley JP, et al.: Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000, 47:804-811.
Chan J, Gonsalkorale WM, Perrey C, et al.: IL-10 and TGF-b genotypes in irritable bowel syndrome: evidence to support an inflammatory component? Gastroenterology 2000, 118:A184.
Dunlop S, Jenkins D, Naesdal J, et al.: Randomised double-blind placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Gastroenterology 2002, 122:A60.
Tibble JA, Sigthorsson G, Foster R, et al.: Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002, 123:450-460.
** Large clinical study comparing biologic markers that may be useful to differentiate inflammatory from functional disorders of the gut. The results suggest that mucosal inflammation and increased small intestinal permeability are not found in the majority of IBS patients.
Swidsinski A, Ladhoff A, Pernthaler A, et al.: Mucosal flora in inflammatory bowel disease. Gastroenterology 2002, 122:44-54.
Ahmad T, Armuzzi A, Bunce M, et al.: The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology 2002, 122:854-866.
Cuthbert AP, Fisher SA, Mirza MM, et al.: The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 2002, 122:867-874.
Satsangi J, Parkes M, Louis E, et al.: Two-stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 1996, 14:199-202.
Ardizzone S, Porro GB: Inflammatory bowel disease: new insights into pathogenesis and treatment. J Intern Med 2002, 252:475-496.
** Comprehensive and extensive review of the mechanisms associated with the development of IBD and the new therapeutic approaches in IBD.
Laroux FS, Grisham MB: Immunological basis of inflammatory bowel disease: role of the microcirculation. Microcirculation 2001, 8:283-301.
Van Montfrans C, Peppelenbosch M, Te Velde AA, et al.: Inflammatory signal transduction in Crohn's disease and novel therapeutic approaches. Biochem Pharmacol 2002, 64:789-795.
Kollias G, Kontoyiannis D: Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. Cytokine Growth Factor Rev 2002, 13:315-321.
Hommes DW, van de Heisteeg BH, van der Spek M, et al.: Infliximab treatment for Crohn's disease: one-year experience in a Dutch academic hospital. Inflamm Bowel Dis 2002, 8:81-86.
Ardizzone S, Colombo E, Maconi G, et al.: Infliximab in treatment of Crohn's disease: the Milan experience. Dig Liver Dis 2002, 34:411-418.
Hommes DW, Peppelenbosch MP, van Deventer SJ: Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets. Gut 2003, 52:144-151.
Collins SM, Piche T, Rampal P: The putative role of inflammation in the irritable bowel syndrome. Gut 2001, 49:743-745.
Matthews SG: Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 2002, 13:373-380.
* Excellent summary of evidence supporting the concept that prenatal aversive events are able to permanently alter the responsiveness of the HPA axis in the offspring.
Million M, Tache Y, Anton P: Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. Am J Physiol Gastrointest Liver Physiol 1999, 276:G1027-G1036.
Podolsky DK: The current future understanding of inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2002, 16:933-943.
Soderholm JD, Yang PC, Ceponis P, et al.: Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 2002, 123:1099-1108.
** First report demonstrating that chronic stress without additional peripheral insults to the gut can result in the development of colitis in the rat. The involved mechanisms include a stress-induced increase in intestinal permeability.
Soderholm JD, Yates DA, Gareau MG, et al.: Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 2002, 283:G1257-G1263.
* Interesting study showing that early life stress can program an organism to show altered stress responses as an adult. The reported greater propensity of affected animals to the development of increased intestinal permeability during stress, together with previous reports on altered motility and perceptual responses to stress, emphasize the importance of early life events in programming the stress responsiveness of the adult animal.
Balsari A, Ceccarelli A, Dubini F, et al.: The fecal microbial population in the irritable bowel syndrome. Microbiologica 1982, 5:185-194.
Swdsinski A, Khilkin M, Ortner M, et al.: Alteration of bacterial concentration in colonic biopsies from patients with irritable bowel syndrome (IBS). Gastroenterology 1999, 116:A1.
Pimentel M, Chow EJ, Lin HC: Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2003, 98:412-419.
Gionchetti P, Rizzello F, Venturi A, et al.: Probiotics in infective diarrhoea and inflammatory bowel diseases. J Gastroenterol Hepatol 2000, 15:489-493.
Sen S, Mullan MM, Parker TJ, et al.: Effect of Lactobacillus plantarum 299v on colonic fermentation and symptoms of irritable bowel syndrome. Dig Dis Sci 2002, 47:2615-2620.
Madden JA, Hunter JO: A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. Br J Nutr 2002, 88 (Suppl 1): S67-S72.
Marteau PR, de Vrese M, Cellier CJ, et al.: Protection from gastrointestinal diseases with the use of probiotics. Am J Clin Nutr 2001, 73 (Suppl 2): S430-S436.
Cario E, Podolsky DK: Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 2000, 68:7010-7017.
Cario E, Rosenberg IM, Brandwein SL, et al.: Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol 2000, 164:966-972.
Mayer EA: The neurobiology of stress and gastrointestinal disease. Gut 2000, 47:861-869.
Monnikes H, Tebbe JJ, Hildebrandt M, et al.: Role of stress in functional gastrointestinal disorders: evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Dig Dis 2001, 19:201-211.
Levy RL, Cain KC, Jarrett M, et al.: The relationship between daily life stress and gastrointestinal symptoms in women with irritable bowel syndrome. J Behav Med 1997, 20:177-193.
LeResche L, Dworkin SF: The role of stress in inflammatory disease, including periodontal disease: review of concepts and current findings. Periodontol 2000 2002, 30:91-103.
Levenstein S, Prantera C, Varvo V, et al.: Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 2000, 95:1213-1220.
Hart A, Kamm MA: Mechanisms of initiation and perpetuation of gut inflammation by stress. Aliment Pharmacol Ther 2002, 16:2017-2028.
* Comprehensive review of the mechanisms by which stress can alter intestinal physiologic functions. Identification of the different mediators involved in the brain-gut-immune axis contributing to the initiation, perpetuation, and reactivation of gut inflammation.
Collins SM, McHugh K, Jacobson K, et al.: Previous inflammation alters the response of the rat colon to stress. Gastroenterology 1996, 111:1509-1515.
Annese V, Bassotti G, Napolitano G, et al.: Gastrointestinal motility disorders in patients with inactive Crohn's disease. Scand J Gastroenterol 1997, 32:1107-1117.
Chang L, Munakata J, Mayer EA, et al.: Perceptual responses in patients with inflammatory and functional bowel disease. Gut 2000, 47:497-505.
Madara JL, Stafford J: Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest 1989, 83:724-727.
Colgan SP, Resnick MB, Parkos CA, et al.: IL-4 directly modulates function of a model human intestinal epithelium. J Immunol 1994, 153:2122-2129.
Authors and Disclosures
Sylvie Bradesi, PhD*; James A. McRoberts, Ph.D*; Peter A. Anton, MD*; Emeran A. Mayer, MD*

CNS: Center of Neurovisceral Sciences & Women's Health, Division of Digestive Diseases and Brain Research Institute, Departments of Medicine*, Physiology, and Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, USA

Reprint Address
Emeran A. Mayer, MD, CNS: Center of Neurovisceral Sciences and Women's Health, VAGLAHS, Bldg.115/CURE, Room 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA;

Abbreviation Notes
HPA: hypothalamic-pituitary-adrenal; IBD: inflammatory bowel diseases; IBS: irritable bowel syndrome; IELs: intraepithelial lymphocytes; iNOS: inducible nitric oxide synthase; MAPK: mitogen-activated protein kinase; PI-IBS: postinfectious irritable bowel syndrome; Th1: T helper 1; TNF-

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Red meat may raise odds for ulcerative colitis, but oily fish could be protective new
      #356594 - 03/11/10 01:22 PM

Reged: 12/09/02
Posts: 7798
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Fatty Acids in Diet Linked to Bowel Disease Risk

Red meat may raise odds for ulcerative colitis, but oily fish could be protective, study shows

THURSDAY, July 23 (HealthDay News) -- Consuming too much of a common polyunsaturated fatty acid could be a contributing factor in an estimated 30 percent of all cases of ulcerative colitis, researchers say.

In a new study, participants who had the highest intake of linoleic acid had more than double the chance of developing the painful inflammation and blistering of the bowels as did those whose diet contained the least of the acid. The report is published online in Gut.

Red meat and some cooking oils and margarines are among the many dietary sources of linoleic acid.

However, the research also found that consuming lots of omega 3 fatty acids can cut the chance of developing ulcerative colitis by more than three quarters. Oily fish such as salmon and mackerel, flaxseed and certain dairy products are rich in omega 3, also known as docosahexanoic acid.

The European study, which looked at the dietary habits of more than 200,000 people in five countries, found that ulcerative colitis occurred about equally in men and women and at an average age of 60. The data analysis took into account other possible causes of the condition, including smoking, age, caloric intake and aspirin use.

The body converts linoleic acid to arachidonic acid, a component of the cell membranes in the bowel, and it then can turn into various chemicals that inflame tissue, according to information in a news release from the journal's publisher. People with ulcerative colitis have been found to have high levels of these chemicals in their bowel tissue.

Having ulcerative colitis, which is a chronic condition, puts a person at a higher risk of developing bowel cancer.

SOURCE: BMJ Specialist Journals, news release, July 22, 2009

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Accutane may cause ulcerative colitis new
      #357631 - 04/09/10 01:38 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

NEW YORK (Reuters Health) - Adding to evidence that the acne drug isotretinoin may lead to bowel disease in some users, a new study finds that patients on the medication were four times more likely than non-users to develop ulcerative colitis within a year.

Reporting in the American Journal of Gastroenterology, researchers say that the risk of any one isotretinoin user developing ulcerative colitis is "likely quite small."

However, the findings do strengthen the evidence of a cause-and-effect relationship between the acne drug and inflammatory bowel disease (IBD) -- a group of digestive disorders that includes ulcerative colitis and Crohn's disease.

Isotretinoin, which is used to treat severe acne, is probably best known by the brand-name Accutane. That drug was taken off the market last year in the face of competition from generic alternatives -- though in pulling the medication, maker Roche Pharmaceuticals also cited costs from defending personal-injury lawsuits.

Earlier this year, the company was ordered to pay $25 million in damages to a former Accutane user who claimed that the drug caused his IBD.

The company has maintained that there is no strong evidence that the acne drug triggers IBD. Between 1997 and 2002, 83 cases of IBD among isotretinoin users were reported to the U.S. Food and Drug Administration, but that does not prove that the drug itself is to blame.

For the new study, Dr. Seth D. Crockett and colleagues at the University of North Carolina Chapel Hill tried to test the cause-and-effect relationship.

Using a database of information from 87 U.S. health insurance plans, the researchers identified 8,189 people -- mostly adults -- who'd been diagnosed with IBD. They then compared each of those individuals with up to three other health plan members the same age and sex with no history of IBD.

Of the nearly 8,200 IBD patients, Crockett's team found, 24 had used isotretinoin in the year before diagnosis; and of the nearly 22,000 controls, 36 had used the acne drug over a one-year period.

Overall, the researchers found, isotretinoin users were roughly four times more likely than non-users to have ulcerative colitis. There was no association, however, between isotretinoin use and Crohn's disease.

The researchers also found that the risk of ulcerative colitis tended to climb in tandem with patients' daily dose of the drug -- which strengthens the case for a cause-and-effect relationship. There was no evidence that severe acne itself was linked to IBD risk.

Still, the findings do not definitively prove that isotretinoin was the cause of some patients' ulcerative colitis, and the researchers say that further studies are needed to confirm their results.

If the acne drug does lead to ulcerative colitis in some cases, the absolute risk of that happening to any one patient are probably quite small, Crockett and his colleagues point out. But, they add, patients with severe acne should be aware of the possible link between isotretinoin and IBD before they are prescribed the drug.

The biological mechanism by which isotretinoin might contribute to IBD is not clear, but some researchers have speculated that the drug may affect immune function in the intestines. Both Crohn's disease and ulcerative colitis are thought to involve abnormal immune system activity.

As for why isotretinoin was linked to ulcerative colitis, but not Crohn's, in this study, Crockett and his colleagues point out that while the two disorders are related, they are distinct and have different immune-system-related features.

SOURCE: here 4a.html American Journal of Gastroenterology, online March 30, 2010.

© Thomson Reuters 2010 All rights reserved.

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Olive Oil May Protect Against Ulcerative Colitis new
      #358398 - 05/05/10 10:32 AM

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Study finds diet rich in oleic acid may prevent development of ulcerative colitis

SATURDAY, May 1 (HealthDay News) -- Increasing your intake of olive oil may help protect against ulcerative colitis, a new study finds.

Ulcerative colitis is an inflammatory bowel disease that causes ulcers in the lining of the rectum and colon, resulting in abdominal pain, diarrhea and weight loss. This study found that people whose diet was rich in oleic acid were far less likely to develop ulcerative colitis.

Oleic acid is a monosaturated fatty acid found in foods such as olive oil, peanut oil, grapeseed oil, butter and some margarines.

This study included more than 25,000 people, aged 40-65, in Norfolk, U.K. who were recruited between 1993 and 1997. None of the participants had ulcerative colitis at the start of the study. By 2002, 22 participants had developed ulcerative colitis. The researchers compared the diets of these people to those who didn't develop the disease and found that those with the highest intake of oleic acid were 90 percent less likely to develop ulcerative colitis.

"Oleic acid seems to help prevent the development of ulcerative colitis by blocking chemicals in the bowel that aggravate the inflammation found in the illness," study leader Dr. Andrew Hart, of the University of East Anglia's School of Medicine, said in a news release.

"We estimate that around half the cases of ulcerative colitis could be prevented if larger amounts of oleic acid were consumed. Two-to-three tablespoons of olive oil per day would have a protective effect," he said.

The study was presented Saturday at the Digestive Disease Week conference in New Orleans.

-- Robert Preidt

SOURCE: University of East Anglia, news release, May 1, 2010

Last Updated: May 03, 2010

Copyright © 2010 HealthDay. All rights reserved.

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Infants' antibiotic use tied to IBD risk new
      #361863 - 11/03/10 01:42 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Infants' antibiotic use tied to bowel disease risk

By Amy Norton

NEW YORK ' Fri Oct 29, 2010 11:39am EDT

NEW YORK (Reuters Health) - Babies treated with antibiotics for middle-ear and other infections may have increased odds of developing inflammatory bowel disease later in childhood, a small study suggests.

Canadian researchers found that among 36 children with either ulcerative colitis or Crohn's disease -- the two main forms of inflammatory bowel disease (IBD) -- 58 percent had been prescribed at least one course of antibiotics in the first year of life.

In contrast, only 39 percent of 360 IBD-free children studied for comparison had taken antibiotics during their first year.

The findings, published in the American Journal of Gastroenterology, do not prove that early antibiotic use causes IBD in some children. But they support the theory that factors affecting the early-life balance of "good" and "bad" bacteria in the intestines may contribute to IBD.

Both colitis and Crohn's disease are marked by chronic inflammation in the intestines, leading to symptoms like abdominal pain and diarrhea. The conditions are thought to arise from an immune-system overreaction that injures the body's own intestinal tissue, but the underlying reasons for the aberrant immune response are unclear.

There is a genetic component to IBD, since the conditions can run in families. However, experts believe that environmental triggers -- such as diet, an infection, or exposure to tobacco smoke - likely combine with genetic susceptibility to cause IBD in some people.

The new study appears to be the first to draw a connection between confirmed early antibiotic use and childhood IBD, according to the researchers.

The design of the study does not, however, allow any conclusions about cause-and-effect, senior researcher Dr. Charles N. Bernstein, of the University of Manitoba in Winnipeg, told Reuters Health in an e-mail.

Larger studies, as well as lab research into the effects of common antibiotics on different types of intestinal bacteria, are still needed, he said.

In theory, early antibiotic use could create an imbalance in the potentially beneficial and potentially harmful bacteria that establish residence in the gut during the first year of life. If the composition of these intestinal "microflora" is altered, the immune system may begin to react abnormally to some of the bacteria.

For the current study, Bernstein and his colleagues analyzed medical records for 36 children diagnosed with either ulcerative colitis or Crohn's between 1996 and 2008, at an average age of 8. Each child was compared with 10 IBD-free children of the same age, sex and area of residence.

The researchers found that children with IBD were more likely to have been prescribed an antibiotic during the first year of life -- most commonly for middle-ear infections, but also for respiratory and other types of infection.

Overall, antibiotic use in infancy was linked to a tripling of the risk of IBD relative to children who had no antibiotic prescriptions in their first year of life.

While that relative increase in risk is large, any one child's absolute risk of developing IBD from antibiotic use -- if the medications are, in fact, to blame -- would be small, according to Bernstein.

In the U.S., it's estimated that just over 1 million people have IBD, with new cases diagnosed at a rate of 10 per 100,000 people each year.

It is still possible that factors other than the antibiotics themselves explain the link between early use of the medications and IBD risk. One alternative, according to Bernstein, is that certain conditions for which antibiotics are used -- like middle-ear infections -- are related to IBD risk.

However, he added, the biological mechanisms that would underlie such a connection are not clear.

For now, Bernstein said, the findings offer a reminder "to avoid indiscriminate use of antibiotics when we can." Parents should be aware that antibiotics are often unnecessary for respiratory infections; in fact, many are caused by viruses and do not even respond to antibiotics, which target bacteria, he said.

As for the middle-ear infections so common in infancy, about 80 percent of children get better without antibiotics, according to the American Academy of Pediatrics. In its treatment guidelines, the academy says that infants and children without severe symptoms can often wait 48 to 72 hours before starting antibiotics to see if the infection improves on its own.

SOURCE: American Journal of Gastroenterology, online October 12, 2010.

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