Gastroenterology
Volume 137, Issue 2 , Pages 415-418, August 2009

Infection, Inflammation, and Homeostasis in Inflammatory Bowel Disease

  • Lyn Sue Kahng

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprint to: Lyn Sue Kahng, MD, Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, 840 S. Wood Street, Chicago, Illinois 60612

Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, Illinois

published online 29 June 2009.

Article Outline

 

See “Increased short- and long-term risk of inflammatory bowel disease after Salmonella or Campylobacter gastroenteritis” by Gradel KO, Nielsen HL, Schønheyder HC, et al, on page 495; and “Salmonella induces flagellin- and MyD88-dependent migration of bacteria-capturing dendritic cells into the gut lumen” by Arques JL, Hautefort I, Ivory K, et al, on page 579.

The intestinal tract contains hundreds of different species of commensal bacteria and their phages, outnumbering our own cells by at least an order of magnitude. In recent years, our understanding of the importance of the intestinal microbiota has greatly expanded to include its roles in nutritional homeostasis and maintenance of normal immunologic function. This is an extremely exciting time as researchers elucidate the connections between bacteria, both commensal and pathogenic, and a variety of pathologies ranging from obesity to functional bowel disorders. Indeed, these topics are among several featured in a recent special issue of Gastroenterology.1 Although much remains unknown, including the factors controlling the structure of this population, its distribution, and its diversity between individuals, we are poised to learn a great deal as the human microbiome project moves forward.2

Among the most rapidly advancing areas of research are those related to the etiology and pathogenesis of inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). These disorders are due likely to a derangement of the delicate balance between microbial flora and the host immune system, where an aberrantly aggressive response to commensals may occur.3 For example, IBD predominantly affects portions of the gut with the highest concentrations of bacteria; genetically engineered mouse models of chronic IBD require the presence of bacteria for mice to develop inflammation, and IBD patients may improve with antibiotic treatment or diversion of the fecal stream. Cloning of IBD susceptibility genes also implicates the immune system: the NOD2/CARD15 susceptibility gene for CD encodes an intracellular receptor for muramyl dipeptide and a number of studies suggest loss of CARD15 function in this disease.4 Genes involved in the interleukin (IL)-23 (IL23/TH17) pathway and autophagy (ATG16L1 and IRGM) are candidates recently identified in genome-wide association studies of IBD,5, 6 Supportive data are already emerging for their role in IBD and, interestingly, the autophagy proteins may differentiate the diseases pathophysiologically as they are associated with CD and not UC.7, 8

On the bacterial side, it has long been questioned whether specific culprit flora may precipitate the development of IBD and/or persistently colonize patients; additionally, whether and how an abnormal immunologic milieu may alter gut flora is not known. For instance, Mycobacterium avium subspecies paratuberculosis was cultured from patients in the 1980s; however, despite a number of studies, the etiologic relationship remains controversial.9 An adherent and invasive Escherichia coli strain has been characterized in CD patients, and the B2+D phylogenetic group of E coli was also recently found to be over-represented in IBD patients.10, 11 The advent of large-scale sampling of bacterial communities has now allowed culture-independent studies demonstrating that microbial populations in IBD patients vary from those in healthy controls. For example, Frank et al12 performed rRNA sequencing and phylogenetic analysis on samples from surgically obtained tissue in CD and UC patients as well as non-IBD controls.12 Although this group did not find an individual bacterial species enriched to suggest it was an etiologic agent for IBD, a subset of the IBD patients had microbiotas that clustered separately from those of controls and the remaining IBD patients, and that were depleted for Bacteroides and Lachnospiraceae. Presence of the variant microbiota was correlated with abscesses in CD patients and younger age and may be a marker for more severe disease, although causation could not be addressed in this study.

In the work described above, a convincing role for common conventional pathogens in the development of IBD has not yet been established. In this issue of Gastroenterology, Arques et al13 and Gradel et al14 present 2 very different studies related to the complexity of events during bacterial infection and its possible etiologic relationship to both UC and CD. The work from Gradel et al is an epidemiologic study conducted in 2 Danish counties from 1991 through 2003. The authors utilized a study cohort of 13,148 patients exposed to Salmonella or Campylobacter gastroenteritis, and 26,216 control patients, who were followed for a mean of 7.5 years and up to 15 years. Among the patients who were exposed to Salmonella/Campylobacter gastroenteritis, there was a significant increase in IBD incidence over the first year postinfection, with a continuation of this trend so that by the end of the study period 1.2% of exposed versus 0.5% of unexposed patients carried a diagnosis of IBD. The study benefited from the comprehensive registry and long-term follow-up of patients, and builds on prior, more short-term studies that suggested an increased risk of IBD after these infections.15, 16, 17 Although the authors point out the challenges in assessing patients diagnosed with IBD in the short term—for example, similarities in endoscopic appearance between infectious colitis and IBD, or the likelihood of more detailed investigations in patients with more severe illness—the incidence of IBD in the exposed versus control patients was increased in the long term as well, although it is not yet understood how this might occur pathophysiologically.

The study by Arques et al presents data that extend our understanding of the early mucosal immune response to Salmonella infection in mice. Utilizing both oral infection and introduction of bacteria into isolated intestinal loops, the authors found evidence of transepithelial bacterial sampling as well as dendritic cell (DC) migration into the intestinal lumen in response to infection. Their reference strain was noninvasive S enterica serovar Typhimurium lacking Salmonella pathogenicity island 1 (SL1344-ΔSPI1). At 5 hours postinfection, the researchers detected CD11c+ cells containing GFP-labeled Salmonella in the gut lumen. Subsequently, a more detailed analysis utilizing flow cytometry and additional markers revealed that the Salmonella-containing cells were a specific subpopulation of DCs, CD11c+CX3CR1+ MHCII+CD11b−CD8α−, that are specific to the small intestine. DC migration was dependent upon the presence of bacterial-associated flagellin as well as the SPI2 pathogenicity island, as intraluminal DC migration was not induced significantly in response to ΔSPI1-ΔfliCΔfljB and ΔSPI1-ΔssrA strains, nor in response to purified flagellin. DC migration was also not elicited by E coli K12, and furthermore was minimal in MyD88 mutant mice lacking this adaptor molecule central to Toll-like receptor (TLR) signaling pathways. The DCs internalized bacteria as observed by confocal microscopy and recovery of the bacteria after purification of the DCs; however, the DCs were not observed to migrate back across the mucosa when labeled with diI and injected into fresh ileal loops. We still have much to learn about DCs, which sample bacterial antigens, monitor the environment, and coordinate the appropriate responses of the immune system through the actions of discrete DC subsets with specific addresses and functions. Arques et al have demonstrated that they can also undergo wholesale migration into the gut lumen in response to specific bacterial stimuli.

These 2 disparate studies present an opportunity to speculate further about how infection with common bacterial pathogens may predispose some patients to later development of IBD. First, the susceptible immunologic substrate may respond differently to these bacteria. CX3CR1 deficiency in DCs reduces their ability to sample luminal bacteria and take up pathogens, and the early phase of infection with a Salmonella type 3 secretion system 1 mutant required DCs for invasion across the epithelium.18, 19 DCs from IBD patients seem to be phenotypically distinct and have increased expression of TLR2 and TLR4, as well as the activation marker CD40.20 Although polarization of the immune response depends on the interaction between epithelial cells and DC, which normally promotes a TH2 type response, in CD patients, the DCs are predisposed to drive TH1 responses.21 Analysis of monocyte-derived DCs from CD patients also suggests that NOD2 mutations affect their baseline states and responses to Gram-negative bacteria.22 Finally, the ATG16L1 variant associated with CD has been found to be defective in capturing internalized Salmonella in autophagosomes.7 Thus, patients with IBD or a predisposition to it may have functionally different responses to infection when compared with healthy patients.

Of particular interest is the recently-identified TH17 T-cell subset, which is important in antimicrobial function and seems to play a critical role in IBD as well as other chronic inflammatory disorders. It has recently been found that phagocytosis of infected apoptotic cells by DCs can induce the IL-6 and transforming growth factor-β required to direct a TH17 response. In vivo, TH17 cells were induced by Citrobacter rodentium infection causing significant apoptosis, but not by infection with a mutant that fails to induce apoptosis.23 In patients, IL-17 mRNA is elevated in IBD mucosa, and IL-23 stimulation leads to distinct responses in CD4+ lamina propria cells from CD versus UC patients: Those from UC have significantly up-regulated IL-17, whereas interferon-γ is up-regulated in those from CD patients.24 Thus, responses to apoptotic cells infected by specific pathogens may be significant drivers of a TH17 response that is differentially perturbed in the 2 types of IBD.

Bacterial infection itself may alter the composition of the gut flora. Soon after birth, the intestine is colonized by bacteria and in the first year of life acquires a fairly stable microbiota characteristic for the individual.25 The protective role of the flora is well-known, particularly in instances such as that of antibiotic-induced Clostridium difficile infection or, in mouse models, the use of antibiotic pretreatment to facilitate colonization by pathogens.26 In the absence of antibiotics, shifts in the microbiota have also been documented in children with acute diarrheal illnesses.27 Changes in murine intestinal flora in response to Salmonella infection have been reported; these could be detected at 3 days postinfection, before the onset of diarrhea, and could even occur in response to a lower inoculum of bacteria that did not cause overt enteritis. Host interaction and virulence determinants were crucial to this shift; full induction of the changes required both SPI1 and SPI2.28

Finally, alterations in gut flora may also occur in response to the cytokine milieu that results from the infection. An interesting study has demonstrated recently that mice deficient in the T-bet transcription factor and RAG2 developed spontaneous colitis in which elevated tumor necrosis factor levels were central to pathogenesis. The mice also contained a colitogenic gut flora that was transmissible to wild-type mice; however, the colitis in the latter instance was not associated with increases in tumor necrosis factor and thus seems to be mechanistically different. Although specific alterations in the gut flora of these mice have not yet been delineated, the disease responded to metronidazole treatment. Thus, the authors hypothesized that T-bet deficiency engendered shifts in the intestinal microbial population; this pathologic community of bacteria could then cause disease through mechanisms that may differ depending on the immunologic background of the host.29

Recent studies from 2 groups also describe the role of inflammation in affecting the microbial composition of the gut flora: Lupp et al30 showed that inflammation led to a reduction in the numbers of bacteria as well as a shift in their distribution toward aerotolerant bacteria, whether the inflammation resulted from infection, DSS treatment, or colitis in the IL-10−/− mouse. Stecher et al31 found that inflammation caused by S typhimurium suppresses and alters the indigenous microbiota; however, the microbiota could outcompete an avirulent Salmonella strain and restrict its colonization efficiency. Nonetheless, the colonization resistance to the avirulent strain could be overcome by inflammation, caused either through mixed infection with wild-type Salmonella or by using mice with T-cell–induced colitis.31 Thus, this pathogen could trigger an inflammatory response that enhances its own colonization.

It is, therefore, possible that certain patients may have aberrant responses to acute bacterial infection that trigger dysfunctional regulation of the IL-23/TH17 pathway. Inflammation caused by the infection could also cause an altered microbiota that is restituted back to baseline over time in healthy patients, yet a subset of patients may have an abnormal response with more longstanding shifts in gut flora and the development of frank IBD (Figure 1). The next several years will be highly interesting as researchers further dissect specific signaling pathways in IBD and the mucosal response to bacteria, as well as the ways in which the gut microbial flora is maintained or perturbed in health and disease.

  • View full-size image.
  • Figure 1. 

    Infection by a pathogen causes mucosal inflammation that then resolves. The inflammation in turn may lead to a shifted gut flora that likewise returns to baseline over time. An aberrant genetic background may influence or interfere with appropriate responses and restoration of homeostasis.

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References 

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 Conflicts of interest The author discloses no conflicts.

PII: S0016-5085(09)00988-3

doi:10.1053/j.gastro.2009.06.019

Refers to article:

  • Editorial Accompanies this ArticleLinking Article with CGH Increased Short- and Long-Term Risk of Inflammatory Bowel Disease After Salmonella or Campylobacter Gastroenteritis , 09 April 2009

    Kim O. Gradel, Hans L. Nielsen, Henrik C. Schønheyder, Tove Ejlertsen, Brian Kristensen, Henrik Nielsen
    Gastroenterology August 2009 (Vol. 137, Issue 2, Pages 495-501)

  • Editorial Accompanies ArticleAdditional Online Content Available Salmonella Induces Flagellin- and MyD88-Dependent Migration of Bacteria-Capturing Dendritic Cells Into the Gut Lumen , 17 April 2009

    Juan L. Arques, Isabelle Hautefort, Kamal Ivory, Eugenio Bertelli, Marì Regoli, Simon Clare, Jay C.D. Hinton, Claudio Nicoletti
    Gastroenterology August 2009 (Vol. 137, Issue 2, Pages 579-587.e2)

Gastroenterology
Volume 137, Issue 2 , Pages 415-418, August 2009

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