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Review
. 2017 Feb 28:8:191.
doi: 10.3389/fimmu.2017.00191. eCollection 2017.

A Potential Role of Salmonella Infection in the Onset of Inflammatory Bowel Diseases

Bárbara M Schultz  1 , Carolina A Paduro  1 , Geraldyne A Salazar  1 , Francisco J Salazar-Echegarai  1 , Valentina P Sebastián  1 , Claudia A Riedel  2 , Alexis M Kalergis  3 , Manuel Alvarez-Lobos  4 , Susan M Bueno  5
Affiliations
Review

A Potential Role of Salmonella Infection in the Onset of Inflammatory Bowel Diseases

Bárbara M Schultz et al. Front Immunol. .

Abstract

Inflammatory bowel disease (IBD) includes a set of pathologies that result from a deregulated immune response that may affect any portion of the gastrointestinal tract. The most prevalent and defined forms of IBD are Crohn's disease and ulcerative colitis. Although the etiology of IBD is not well defined, it has been suggested that environmental and genetic factors contribute to disease development and that the interaction between these two factors can trigger the pathology. Diet, medication use, vitamin D status, smoking, and bacterial infections have been proposed to influence or contribute to the onset or development of the disease in susceptible individuals. The infection with pathogenic bacteria is a key factor that can influence the development and severity of this disease. Here, we present a comprehensive review of studies performed in human and mice susceptible to IBD, which supports the notion that infection with bacterial pathogens, such as Salmonella, could promote the onset of IBD due to permanent changes in the intestinal microbiota, disruption of the epithelial barrier and alterations of the intestinal immune response after infection.

Keywords: Crohn’s disease; Salmonella enterica serovar Typhimurium; gut microbiota; inflammatory bowel disease; innate immune response; ulcerative colitis; virulence factors.

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Figures

Figure 1
Figure 1
Normal intestinal epithelium versus altered intestinal epithelium observed in inflammatory bowel disease (IBD). (A) The normal intestine presents a high secretion of bactericidal molecules (defensins, REGIIIγ, and IgA) as mechanisms of defense against pathogenic bacteria. The commensal microbiota inhibits the access of pathogens to the epithelial barrier by competing for nutrients, maintaining homeostasis of the epithelial barrier, and supporting the host immune response. The commensal microbiota is composed of mainly Firmicutes and Bacteroidetes, and a lower percentage of Proteobacteria and Actinobacteria. They promote the secretion of mucus and antimicrobial peptides [short-chain fatty acid (SCFA), H2S] and the activation of some pathway of immune system such as the activation of macrophages and dendritic cells in lamina propria, and the production of cytokines such as IL-6, IL-23, and IL-12, which activates Th1 or Th17 cells to produce cytokines acting on intestinal epithelium. (B) The intestine of IBD patient has a deregulated response to commensal microbiota by a decrease in the secretion of antimicrobial peptides such as α-defensins and increase in REGIIIγ as compensatory effect; these effects have relation with defect in Paneth and goblet cells. IBD patients showed lower Firmicutes and Bacteroidetes but have increased amounts of Proteobacterias resulting in a decrease production of SCFA, mucus, and increased inflammation. The epithelium produces an abnormal amount of IgG against commensal microbiota instead IgA. Macrophages produce higher amounts of cytokines that overstimulate Th1 or Th17 cells, which secrete pro-inflammatory cytokines to epithelium.
Figure 2
Figure 2
Effect of Salmonella infection in inflammatory bowel disease (IBD) patients. In genetically susceptible to IBD patients, many parameters are disrupted. (A) Paneth cells have an impaired secretion of antimicrobial peptides showing a decrease in the amounts of α-defensins, as well as increased amounts of REGIIIγ, which is associated with impaired protection against pathogens. (B) Plasma cells have a polarized antibodies’ secretion to the production of IgG antibodies targeting the individual’s own microbiota. Beside this, the proportions of commensal microorganisms present are unbalanced related to a healthy host. Due to this imbalance, there is a decrease production of short-chain fatty acid (SCFA), which generates an increase in inflammation. Taken together, these effects generate an environment more vulnerable to further infection. Furthermore, (C) S. Typhimurium recruits neutrophils to the lumen, which generates ROS, producing tetrathionate in the intestinal lumen; this compound is used by Salmonella as electron acceptor, which gives advantage to S. Typhimurium over the microbiota. (D) Salmonella infection is produced by the entry through DCs interspersed in the epithelial barrier or M cells that recognize it through glycoprotein-2, accessing to the Peyer’s patches. (E) Salmonella can also get into the epithelial cells forming membrane ruffling or through disruptions of tight junctions caused by itself and in this case especially in inflamed epithelium of IBD patients. (F) In the basolateral side, Salmonella can be recognized by TLR5 stimulating an increased production of NF-κβ, which correlates with an enhanced recruitment of neutrophils, finally once within the epithelial cells, Salmonella blocks the autophagosome pathway avoiding its own degradation.
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