Gastroenterology
Volume 132, Issue 2 , Pages 481-483, February 2007

In the Beginning Was Helicobacter pylori: Roles for Microbes in Other Intestinal Disorders

published online 31 January 2007.

Article Outline

 

The 2005 Nobel Prize in Medicine for Marshall and Warren marked a milestone in the establishment of Helicobacter pylori as the causative agent of ulcer disease. The skepticism of the gastrointestinal (GI) community during the early days, the validation of Barry Marshall as a suitable model for studying Koch’s postulates, and the eventual widespread acceptance of the bacterial etiology of peptic ulcers is now part of scientific lore. The key question is: Are there sequels to the story, and if so, are we prepared to accept them? Although studies with germ-free animals during the past 2 decades show clearly that the bacteria in our gut are integral to the development and maintenance of a healthy digestive system, could this dynamic interaction be subject to imbalances that lead to other forms of GI pathology? New and emerging research suggests that microbial mischief may be underfoot in disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colorectal cancer, and perhaps, even obesity. Surprisingly, the miscreants may not be the classic pathogens that are armed with the familiar toxins and virulence factors, but rather, the normal intestinal flora.

There is indisputable evidence that the enteric microflora are crucial in the initiation and reactivation of IBD, both Crohn’s disease and ulcerative colitis. A vast literature supports this statement and has been recently reviewed.1 Although no specific bacteria are indicted in this process, the major findings that support a role for the intestinal flora include the following: numerous animal models of chronic intestinal inflammation fail to develop colitis in the absence of intestinal flora; many of the mutated genes associated with Crohn’s disease are involved in detection of and response to microbial antigens; and altered responses to intestinal flora are seen ranging from loss of tolerance to failure to clear invading bacteria. In fact, the first identified gene to be associated with Crohn’s disease was CARD15 (caspase recruitment domain family member 15, also known as NOD2), which binds muramyl dipeptide present in the cell wall of essentially all bacteria.2, 3, 4, 5 Most recently, mutations in the interleukin (IL)-23 receptor gene, required for effective responses to intestinal infection, were reported to be associated with Crohn’s disease.6 Several other genetic mutations4 associated with Crohn’s disease have been identified and future studies will undoubtedly uncover others. Ultimately, in the right genetic background, microbial antigens activate pathogenic T cells and intestinal inflammation ensues. Realizing that bacteria play a role in IBD begs the question of whether a lack of “good bugs” or a gain of “bad bugs” is responsible. Dr Balfour Sartor and colleagues began to address this point by monoassociating germ-free IL-10–deficient mice with different strains of commensal bacteria. They found that variable phenotypes of colitis occurred,5 suggesting that not all intestinal flora are equal and may define the pattern of disease. Although most of the focus has been on the role of commensal bacteria in IBD, some data suggest that unidentified bacterial pathogens are to blame. Supporting this hypothesis, a strain of Escherichia coli with enhanced adherence and invasive capability was recovered from a significant number of Crohn’s disease patients as compared with controls.7 These findings are consistent with the hypothesis that CARD15 mutations confer a defect in the ability to clear invasive bacteria. There is no doubt that time will clarify the role of bacterial in IBD.

Another intestinal disease entity to which bacteria contribute is IBS. Of patients meeting criteria for IBS, 25%–30% claim an antecedent episode of acute gastroenteritis. A recent study of a large cohort who experienced infection with either E coli 0157:H7 or Campylobacter jejuni following contamination of the municipal water supply in Walkerton, Ontario, Canada, found that a diagnosis of IBS based on Rome I criteria was made in 28% of those that self-reported gastroenteritis and 36% of individuals with clinically suspected gastroenteritis, compared with 10% of controls.8 This entity, now referred to as postinfectious IBS, demonstrates evidence of an activated immune response characterized by increased intestinal intraepithelial lymphocytes and intestinal permeability. Small intestinal bacterial overgrowth has also been postulated to underlie IBS.9 The hypothesis is that IBS patients have an underlying disorder of intestinal motility that allows overgrowth of intestinal flora in the small bowel; food is digested and gas produced in this location as opposed to the colon of non-IBS individuals. Some studies report a favorable response of IBS subjects to antibiotic treatment (reviewed by Lin9). However, a recently published animal study suggests that ingestion of the probiotic Lactobacillus acidophilus alleviates the abdominal pain associated with IBS by increasing the expression of μ-opioid and cannabinoid receptors in the intestinal epithelium.10 Future studies investigating these hypotheses and new therapeutic strategies in humans are eagerly awaited.

A major concern to gastroenterologists is high prevalence of colorectal cancer. Preventative strategies are lacking in large part due to the paucity of mechanistic insights, leaving us with expensive and cumbersome screening programs. Several studies suggest that the colonic microbiota play a role in the etiology of sporadic colorectal cancer; however, mechanistic insight began to emerge only recently. Two independent publications suggest that specific components of the intestinal bacterial flora, E coli and Enterococcus faecalis, induce DNA breaks in eukaryotic cells that then contribute to the development of sporadic colorectal cancer. Nougayrede et al11 found that 34% of E coli strains isolated from the stool of healthy individuals and 53% of extraintestinal pathogenic E coli strains carry a genomic island designated pks that encodes a polyketide–peptide hybrid cytotoxin that blocks mitosis resulting in megalocytosis. Ultimately, this gene cluster causes DNA double-strand breaks, resulting in genomic instability which may in turn predispose to the development of intestinal cancer. Interestingly, E coli Nissle 1917, a “probiotic” able to colonize the human intestine and used to treat IBD, harbors the pks island.

In this issue of Gastroenterology, Wang and Huycke provide evidence of yet another mechanism by which intestinal commensal bacteria may contribute to the development of sporadic colorectal cancer.12 In this paper, the authors show that the commensal bacterium Enterococcus faecalis produces uniquely high levels of extracellular superoxide that in turn stimulate macrophages to express cyclooxygenase (COX)-2, which ultimately promotes chromosomal instability in mammalian cells. Therefore, a product from commensal bacterium may be responsible for initiating tumorigenesis via paracrine effects of macrophages. Substantiating this hypothesis is the multitude of clinical trials demonstrating a chemoprotective effect of COX-2 inhibitors in sporadic colorectal cancer. An accompanying editorial by Frank Sinicrope in this issue of Gastroenterology elegantly examines this new finding in the context of known information. We look forward to studies that test these hypotheses using in vivo models.

Perhaps it should not be surprising that so many GI disorders have bacterial components of etiology. After all, intestinal cells have been communicating with the resident flora for thousands of years, and through an appreciation of their mutual biology have perfected a remarkably efficient digestive system. That this communication could go awry occasionally is understandable. Our best option is to listen in on the conversation and understand the relationship so that we may tweak this ecosystem when necessary. This appreciation of gut biology has now percolated through to the lay public. The general population is consuming probiotics in ever increasing amounts. The cover story of the August 13, 2006, issue of The New York Times Magazine highlighted Jeffrey Gordon’s work on “microbesity” and discussed the role of intestinal flora and even infectious pathogens in obesity. Could antibiotics hold the solution for obesity or is that just our fantasy of a quick fix for a very complex problem? This much, however, is certain: if a disorder stems from the gut, the microflora may be involved and we, as gastroenterologists will benefit from a better understanding of the players involved. So, what is the next horizon for microbes and GI disorders? No one can predict, but we at Gastroenterology look forward to publishing studies addressing such issues.

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References 

  1. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407
  2. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603
  3. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–606
  4. Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. Genetics of Crohn’s disease, an archetypal inflammatory barrier disease. Nat Rev Genet. 2005;6:376–388
  5. Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891–906
  6. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–1463
  7. Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127:412–421
  8. Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology. 2006;131:445–450
  9. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292:852–858
  10. Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med Adv. 2006;13:35–37
  11. Nougayrede JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science. 2006;313:848–851
  12. Wang X, Huycke MM. Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells. Gastroenterology. 2007;132:551–561

PII: S0016-5085(07)00015-7

doi:10.1053/j.gastro.2007.01.013

Gastroenterology
Volume 132, Issue 2 , Pages 481-483, February 2007

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