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Pathological mechanisms in Crohn’s disease via dysbiosis triggered by Paneth cell α-defensin misfolding

清水, 由宇 北海道大学

2020.12.25

概要

In the human intestinal tract, forty trillion of commensal bacteria construct complex ecosystem termed intestinal microbiota1 . The human intestinal microbiota is thought to possess approximately 10 million genes which are more than several hundred times larger than that of the host2 , and involved in many aspects of host physiology, that includes energy metabolism3 , immune system regulation4 , and nervous system development5 . Recently, associations with imbalance of the intestinal microbiota, termed dysbiosis, and many diseases, including chronic lifestyle diseases such as obesity and diabetes, immunological disorders, and nervous system diseases have been reported6 . a-Defensin, a major family of mammalian antimicrobial peptides, are known regulators of the intestinal microbiota. These ~ 4 kDa, basic peptides are characterized by evolutionally conserved Cys residue positions that are invariantly spaced to form disulfide bonds between CysI -CysVI, CysII-CysIV, and CysIII-CysV 7 . In the intestinal epithelium, a-defensin occur only in intracellular dense-core secretory granules of Paneth cells, one of the major terminally differentiated lineages of the small intestine. Paneth cells, which reside at the base of the crypts of Lieberkühn, release secretory granules that are rich in a-defensin, termed cryptdins (Crps) in mice and HD5 and HD6 in human, in response to bacteria and other stimuli at effective concentrations, thereby contributing to enteric innate immunity8‒13. Also, Paneth cell a-defensin contribute to regulating the composition of the intestinal microbiota in an activity-dependent manner in vivo as well as affecting development of host adaptive immunity14. Furthermore, oral administration of Crp4 prevents severe dysbiosis in mouse graft-versushost disease15,16, indicating that Paneth cell a-defensin secreted into the intestinal lumen contribute not only to innate immunity but also to maintenance of intestinal homeostasis by regulating the intestinal microbiota17,18.

Recently, a relationship has been revealed between the intestinal microbiota and the pathophysiology of Crohn’s disease (CD)19. CD is a chronic inflammatory bowel disease that may affect the entire gastrointestinal tract, especially the terminal ileum, with chronic inflammation and ulceration20. The number of patients with CD has been increasing continuously worldwide, including Europe, The Americas and Asia20‒22. Because CD typically appears in younger people in their teens and 20s and any radical treatments have yet to be developed, the patient’s quality of life could be diminished for a lifetime. Although a complete picture of CD pathogenesis is lacking, there is consensus that dysbiosis and dysregulated immune responses to the intestinal microbiota play important roles20. Moreover, both genetic factors consisting of more than 160 susceptibility loci23, as well as environmental factors such as overuse of antibiotics24 and adoption of “westernized diets”25 have been reported as CD risk factors, and these factors are suggested to induce pathophysiology of CD via dysbiosis26.

Evidence shows that certain Paneth cell defects are involved in CD onset and pathophysiology. Paneth cells continuously synthesize high levels of secretory proteins in the endoplasmic reticulum (ER) and are susceptible to ER stress, a failure of maintaining ER homeostasis induced by accumulation of misfolded proteins27. Excessive ER stress induces series of signal cascades termed unfolded protein response (UPR), and UPR manages to recover ER homeostasis by inducing suppression of protein translation, induction of ER chaperones which help refolding of the misfolded proteins, and degradation of the misfolded proteins via autophagy and activation of ubiquitin-proteasome system28. Several genes involved in resolution of ER stress affect CD susceptibility, and deletions or mutations of such gene. For example, UPR-related genes XBP129 and AGR230, autophagy-related genes ATG16L131, IRGM132, and LRRK233 cause Paneth cell abnormalities in granule morphology and cellular localization in mouse models. In CD patients with mutations in XBP129 and ATG16L131, Paneth cell abnormalities occur which are similar to those observed in genetically deficient mice. Moreover, several studies have identified relationships between ER stress in Paneth cells and disruptions of the intestinal microbiota in CD. The appearance rate of Paneth cells with abnormal granule morphology in CD patients is associated with dysbiosis that is characterized by reduction of diversity and decrease of anti-inflammatory bacteria such as Faecalibacterium34. CD patients positive for the ER stress marker GRP78 in Paneth cells harbor greater numbers of CD associated enteroinvasive Escherichia coli compared to patients that lack GPR78-positive Paneth cells35. Although these findings suggest the involvement of ER stress, Paneth cell dysfunction, and dysbiosis in CD pathophysiology, causal relationships between these factors remain to be demonstrated.

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