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Review
. 2021 Sep 7:9:703310.
doi: 10.3389/fcell.2021.703310. eCollection 2021.

Bacterial Translocation as Inflammatory Driver in Crohn's Disease

Raquel Linares  1 , Rubén Francés  1   2   3 , Ana Gutiérrez  2   3   4 , Oriol Juanola  5   6
Affiliations
Review

Bacterial Translocation as Inflammatory Driver in Crohn's Disease

Raquel Linares et al. Front Cell Dev Biol. .

Abstract

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host-microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.

Keywords: Crohn’s disease; NOD2; anti-TNF-α; bacterial translocation; dysbiosis; inflammatory response; intestinal permeability.

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Conflict of interest statement

AG has served as speaker, consultant, or advisory member for, or received research funding from MSD, ABBVIE, TAKEDA, KERN PHARMA, PFIZER, OTSUKA, SHIRE, and JANSSEN, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Bacterial translocation in Crohn’s disease. Intestinal tolerogenic mechanisms are altered in Crohn’s disease leading to sustained inflammatory status. Integrity of the epithelial barrier is altered due to reduced expression of tight junction proteins. Increased populations of Enterobacteriaceae and pathogens, as well as reduced Bacteroidetes, Firmicutes, and populations of bacteria producing short chain fatty acids define intestinal dysbiosis in CD. Paneth cells display alterations in the production and secretion of antimicrobial peptides that can be explained by the gene status (NOD2). Translocating bacteria or its products can activate antigen presenting cells as macrophages and dendritic cells. Gene variants in ATG16L1 and NOD2 are associated with abnormalities in the secretion of antimicrobial peptides by Paneth cells and altered function of intestinal DCs and macrophages. Dendritic cells express higher levels of CD40 leading to increased interactions with T-lymphocytes and production of proinflammatory cytokines. Low regulatory T-lymphocyte differentiation will favor Th1 and Th17 subsets that will further produce proinflammatory cytokines. Neutrophils and eosinophils will be recruited to the site of infection and further contribute to induce an inflammatory environment in the attempt to eliminate translocating bacteria. AMPs, antimicrobial peptides; IgA, Immunoglobulin A; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor; IELs, intraepithelial lymphocytes; ILCs, innate lymphoid cells; SCFAs, short chain fatty acids; TJPs, tight-junction proteins; TREG, regulatory T-cells. This figure has been created using the BioRender platform.
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References

    1. Aden K., Rehman A., Waschina S., Pan W. H., Walker A., Lucio M., et al. (2019). Metabolic Functions of Gut Microbes Associate With Efficacy of Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases. Gastroenterology 157 1279–1292.e11. - PubMed
    1. Ahern P. P., Schiering C., Buonocore S., McGeachy M. J., Cua D. J., Maloy K. J., et al. (2010). Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33 279–288. 10.1016/j.immuni.2010.08.010 - DOI - PMC - PubMed
    1. Ainsworth M. A., Bendtzen K., Brynskov J. (2008). Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn’s disease. Am. J. Gastroenterol. 103 944–948. 10.1111/j.1572-0241.2007.01638.x - DOI - PubMed
    1. Alexander J. W., Boyce S. T., Babcock G. F., Gianotti L., Peck M. D., Dunn D. L., et al. (1990). The process of microbial translocation. Ann. Surg. 212 496–510; discussion1–2. - PMC - PubMed
    1. Al-Sadi R., Guo S., Ye D., Rawat M., Ma T. Y. (2016). TNF-α modulation of intestinal tight junction permeability is mediated by NIK/IKK-α axis activation of the canonical NF-κB pathway. Am. J. Pathol. 186 1151–1165. 10.1016/j.ajpath.2015.12.016 - DOI - PMC - PubMed