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Crohn's Disease Forum » Books, Multimedia, Research & News » Bacterial Infections: New and Emerging Enteric Pathogens


03-15-2010, 04:37 PM   #1
David in Seattle
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Bacterial Infections: New and Emerging Enteric Pathogens

Abstract

Purpose of review The aim of this review is to highlight recent advances in knowledge of bacterial enteric infections. We focus on understanding of enterohemorrhagic Escherichia coli O157:H7 and Campylobacter jejuni infections, and to link these acute events with long-term consequences in a susceptible host, including irritable bowel syndrome and chronic inflammatory bowel diseases.
Recent findings Enterohemorrhagic E. coli and C. jejuni are zoonotic infections that are acquired from exposure to tainted food (undercooked hamburger and chicken, respectively) and contaminated drinking water. Noninvasive E. coli O157:H7 elaborates Shiga-like toxins and protein effectors that are injected, via a molecular syringe that is encoded by a bacterial type 3 secretion system, into infected eukaryotic cells. Less is known about the precise virulence properties of enteroinvasive Campylobacter strains, but both enteric pathogens are able to disrupt polarized epithelial monolayers resulting in increased uptake of macromolecules and antigens.
Summary An improved understanding of the epidemiology, pathobiology and mechanisms underlying infectious enterocolitides will provide the basis for developing new intervention strategies including, for example, the use of probiotics, to interrupt the infectious process.
Introduction

The past year has brought major advances in our understanding of the gut microbiota in settings of both health[1,2] and disease.[3••,4] Technological advances in molecular genetics and bioinformatics have yielded novel insights regarding the intestinal microbiome. For example, even short courses of oral antibiotics provided to healthy adult volunteers impact on the composition of the colonic microflora for several months after the cessation of therapy[5,6] that can predispose them to an intercurrent bacterial infection.[7] Similarly, acute enteric infections alter composition of the normal resident commensal microbiota.[8] This disruption in the composition of the gut microbiome, termed dysbiosis, may be improved by the ingestion of probiotics,[9] which are defined as exogenous live organisms that – when taken in sufficient amounts – have a beneficial effect on the host. Increasing evidence also points to long-term chronic consequences of acute infectious insults, including the development of postinfectious irritable bowel syndrome (IBS)[10] and chronic inflammatory bowel diseases (IBD).[11,12]

Emerging Pathogens

It has been stated that there are roughly 1400 recognized species of human pathogens.[13] More than half of these are zoonotic infections arising from contamination by exposure to birds, bats, and ruminants. Of these, some 177 organisms are considered as emerging or reemerging human pathogens. It is clear, however, that this is likely to underestimate the number and range of pathogens that can infect people. Potential pitfalls in the identification of enteric pathogens include the timing of collecting fecal samples (that is, the infection can clear even though symptoms persist), the use of antimicrobial agents or other compounds that inhibit the growth of an organism, the choice of culture medium and the atmospheric condition of the culture. In addition, it is simply not possible to successfully culture the range of organisms known to colonize mucosal surfaces. The use of molecular technologies, that are increasingly accessible to the diagnostic microbiology laboratory, serves to identify novel microbes that are not able to be cultured using currently available laboratory culture facilities and methodologies.[14,15]

Rather than providing a general overview, this review will focus on two Gram-negative enteric bacterial pathogens with vast human morbidity worldwide:[16•] enterohemorrhagic Escherichia coli O157:H7 and Campylobacter jejuni.
03-15-2010, 04:38 PM   #2
David in Seattle
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Enterohemorrhagic Escherichia coli

E. coli of the serotype O157:H7 was first isolated in the 1980s from outbreaks of hemorrhagic colitis related to the ingestion of contaminated and undercooked hamburger meat. Since that time, it has become clear that the organism asymptomatically colonizes the intestine of a variety of ruminants,[17] including cattle. Some cattle excrete large numbers of the organism, perhaps related to bacterial colonization of the rectum.[18•] Fecal contamination of undercooked ground hamburger meat[19] and vegetables, nonchlorinated drinking and swimming water, and exposure to the organism by contact with animals housed in petting zoos[20] are all described methods of acquisition of the infection.

Diarrhea-associated hemolytic-uremic syndrome, which is characterized by the triad of acute renal failure, thrombocytopenia and microangiopathic hemolytic anemia, is due to systemic toxemia from the Shiga-like toxins elaborated by E. coli O157:H7[21] and other EHEC serogroups (e.g. O26, O113).[22•] Hemolytic uremic syndrome is a systemic complication of intestinal disease arising in up to 10% of patients infected with E. coli O157:H7, particularly affecting young children and the elderly, and is the most common cause of acute renal failure in children. Antibiotics may worsen the progression of systemic complications of EHEC infection, so the diagnosis should be sought actively,[23] particularly in the setting of an otherwise unexplained community outbreak of acute bloody diarrhea.

In addition to the phage encoded Shiga-like toxins, the genome of E. coli O157:H7 contains a pathogenicity island referred to as the locus of enterocyte effacement (LEE). Similar to other enteric pathogens, characterized by intimate attachment to eukaryotic cells and effacement of surface-exposed microvilli, including E. albertii,[24] enteropathogenic E. coli, rabbit diarrheagenic E. coli (RDEC-1 and RDEC-2) and the mouse-specific enteric pathogen Citrobacter rodentium, the LEE locus in these bacteria encodes a molecular syringe that injects multiple prokaryotic effector proteins into the cytosol of infected host eukaryotic cells.[25] These effectors then induce protean effects, including the alteration of signal transduction cascades, nuclear transcription, mitochondrial function, and the integrity of intercellular tight junctions.[26,27] Injected protein effectors also alter the architecture of the cytoskeleton by recruiting F-actin, and related structural proteins, to pedestals below intimately adherent bacteria.[28,29] These effectors are virulence determinants, because even though EHEC causes bloody diarrhea and hemorrhagic colitis the organisms are not typically invasive like other dysentery-producing bacteria such as enteroinvasive E. coli, Yersinia, Clostridium difficile, Shigella, Salmonella and Campylobacter species.[30]

The resident commensal microbial flora is an important factor protecting against EHEC infection, as evidenced by more severe gut and systemic disease in germ-free mice infected orally with E. coli O157:H7 strains originally isolated from affected patients.[31] In addition, Shiga-like toxin production by EHEC is inhibited in the cecum of gnotobiotic rats when either a human microbiota or conditioned medium derived from a complex mixture of human-derived microbes is administered.[32]

Probiotic agents might serve to restore dysbiosis and disrupted signal transduction cascades. For instance, EHEC subvert interferon-γ induced activation of the Jak-STAT (signal transducer and activator of transcription)1 cascade that normally turns on the transcription of more than 500 genes employed in the host response to infection. In reductionist models of infection, selected probiotic strains are able to restore both STAT1 signaling[33] and integrity of the epithelial barrier,[34] but only if provided as live organisms in advance of challenge with the pathogen. As a result, beneficial microbes should now be considered for further evaluation as a potential agent for use in the prevention of EHEC infection; such as in an outbreak setting.

Campylobacter Infections

C. jejuni and C. coli are microaerophilic, spiral-shaped bacteria that asymptomatically colonize birds, including chickens.[35,36] Campylobacter infections are a leading cause of acute infectious diarrhea resulting in up to 14% of cases worldwide. In a study of 100 000 persons in Sweden, C. jejuni was isolated in 56% of cases of enteritis.[12] Ingestion of undercooked poultry and cross-contaminated foodstuffs results in a spectrum of acute diarrheal disease, ranging from watery diarrhea to dysentery and a mesenteric adenitis syndrome mimicking acute appendicitis. Complications arising from Campylobacter infections include the Guillain Barrι syndrome,[37] an immune-mediated radiculopathy arising due to molecular mimicry and antibody cross-reactivity of the lipo-oligosaccharide antigens of specific bacterial serogroups and gangliosides of neural cells.[38]

The mechanisms by which C. jejuni causes intestinal disease are the subject of active investigation. The genomes of several strains have now been sequenced and the findings published. The C. jejuni isolates are of interest because of their low G+C content, lack of typical pathogenicity islands, absence of genes encoding for classical enterotoxins, and lack of plasmids encoding genes promoting bacterial invasion. Nevertheless, the organism is able to invade and replicate in infected epithelia,[39••] activate the innate immune system via Toll-like receptor (TLR)-2[40] and TLR-4,[41] and disrupt the integrity of the epithelial barrier.[42] Such studies will direct future research aimed at developing a vaccine for use in the prevention of diarrhea caused by C. jejuni infection.[43]

The role of Campylobacters other than C. jejuni has also been the subject of investigation. For instance, it is clear that the selective media employed in many diagnostic microbiology laboratories result in a reduced ability to identify C. upsaliansis in stool samples obtained from individuals with acute diarrhea.[44] Antibodies against C. concisus are detected more frequently in children with Crohn disease compared with children with symptoms related to the gastrointestinal tract, but no evidence of chronic bowel inflammation.[45] The authors note that the site of intestinal biopsy acquisition (large bowel versus small intestine, adjacent to ulcers and sites of inflamed mucosa, and from the overlying mucus layer) is likely to heavily influence rates of isolation of viable organisms even when employing appropriate culture media and ambient temperature and oxygen levels for culture of fastidious organisms.
03-15-2010, 04:39 PM   #3
David in Seattle
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Postinfectious Irritable Bowel Syndrome

An outbreak of dysentery in Walkerton, Ontario, Canada in May 2000 due to contamination of a town water supply that was not properly chlorinated was caused by both EHEC O157:H7 and C. jejuni infections. At least 2300 residents were infected, 27 developed hemolytic-uremic syndrome and there were seven reported deaths. After at least 2 years of follow-up, the subsequent risk of developing symptoms of IBS was dramatically increased (odds ratio 4.8, 95% confidence intervals: 3.4–6.8), compared with community age-matched and sex-matched controls.[46] In a Danish population-based cohort study, acute infection with either Campylobacter or Salmonella increased the risk in exposed individuals of developing IBD (hazard ratio 2.9, 95% CI: 2.2–3.9) over the entire observation period of 15 years.[47••] Similar findings have been reported in children in the United States and Italy, a third of whom had an initial documented Campylobacter infection.[48] Probiotics could well have a protective role in this clinical setting by acting to alter enteric neural and muscular dysfunction and the low-grade inflammatory responses that appear to mediate chronic IBS-related symptoms after an acute intercurrent bacterial infection.[49]

Conclusion

Undoubtedly, there are many more unrecognized microbial pathogens awaiting identification. There is an ongoing need to identify novel pathogens, because knowledge of the underlying cause of an illness is of benefit to the affected individual, their healthcare provider and to society as a whole. Such knowledge serves to direct, as appropriate, healthcare and public health policy measures, and increases the pressure to develop new antimicrobial[50] and vaccine strategies.[51,52] Constituents of the commensal intestinal microbiota and exogenous agents, such as probiotics and prebiotics (defined as nondigestible oligosaccharides used as substrate in the colon by resident Bifidiobacteria and lactic acid-producing organisms), can both serve to restore gut homeostasis.[53] In the future, probiotics are likely to garner increasing attention as a novel approach to prevent intercurrent infections and dysbiosis in the composition of the human colonic microflora.[54]
03-15-2010, 05:45 PM   #4
D Bergy
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Thanks David,

You have given me a couple of new pathogens to put on my suspect list, and reinforced my suspicion that a strain of E-Coli may be involved.

I eat this stuff up.

Dan
03-15-2010, 05:56 PM   #5
Misty-Eyed
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haha I'm currently writing a paper on the overview of Crohn's diease at uni. It's a literature review. It's really amazing what kind of research goes on these days. It's such a vast subject that's it's hard to fit it all into 10,000 words! And my supervisor wants to publish it in a medical journal. Eeeeek.

Do you have a link of where this was published?
03-15-2010, 05:58 PM   #6
Misty-Eyed
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haha I'm currently writing a paper on the overview of Crohn's diease at uni. It's a literature review. It's really amazing what kind of research goes on these days. It's such a vast subject that's it's hard to fit it all into 10,000 words! And my supervisor wants to publish it in a medical journal. Eeeeek.

Do you have a link of where this was published?
03-15-2010, 06:05 PM   #7
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Opps didn't mean to double post.
03-15-2010, 08:16 PM   #8
Shenk
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This is what scares me. With all the colonoscopies they are doing now. They are not always sterlized properly.

I had mild IBS until they did a colonscopy and then, several years later.....forget it.

I don't know if there is a link or not, but no one knew that cancer could be caused by viruses.
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