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Autophagy: a new target or an old strategy for the treatment of Crohn's disease?

Abstract

In the past 5 years much progress has been made in understanding the molecular basis of Crohn's disease, a multifactorial chronic inflammatory disease of the gastrointestinal tract. Data suggest that hampered autophagy—the major lysosomal pathway for recycling of cytoplasmic material—might contribute to an increased susceptibility to Crohn's disease. Consequently, intense investigations have started to evaluate the potential value of autophagy as a therapeutic target and as a highly needed diagnostic tool. Interestingly, as well as the promising introduction of direct autophagic modulators, several drugs already used in the treatment of Crohn's disease might exert at least part of their effect through the regulation of autophagy. However, whether this phenomenon contributes to or rather counteracts their therapeutic use, remains to be determined and might prove to be highly compound-specific. Here we review the complex and emerging role of autophagy modulation in the battle against Crohn's disease. Moreover, we discuss the potential benefits and deleterious effects of autophagic regulation by both new and clinically used drugs.

Key Points

  • Crohn's disease is a multifactorial chronic inflammatory disease of the gastrointestinal tract for which the exact causative mechanism is still unknown

  • Current treatment options for Crohn's disease are far from successful in all patients, indicating the urgent need for more efficient diagnostic and therapeutic strategies

  • Polymorphisms in autophagy-related genes have been associated with the incidence of Crohn's disease

  • Autophagy is an important regulator of both innate and adaptive immune and/or inflammatory responses and is an appealing target to restore and normalize the imbalanced inflammatory responses in Crohn's disease

  • Several compounds currently used in treatment of Crohn's disease, such as anti-TNF agents, thiopurines and curcumin, have been shown to affect autophagy or might benefit from combinatory autophagy stimulation (for example, with sirolimus)

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Figure 1: Immunological regulation by autophagy.

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Acknowledgements

This work of the authors is supported by project grants from the Fund for Scientific Research Flanders (FWO-Vlaanderen, G072810N, G058412N and G060713N to P. Agostinis) and from GOA grants (GOA/11/015 to S. Vermeire and GOA/11/2010-2015 to P. Agostinis).

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K. Nys contributed to all aspects of the preparation of this manuscript. S. Vermeire contributed to researching data, discussion of content and reviewing/editing the manuscript before submission. P. Agostinis contributed to discussion of content and reviewing/editing the manuscript before submission.

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Correspondence to Séverine Vermeire.

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Nys, K., Agostinis, P. & Vermeire, S. Autophagy: a new target or an old strategy for the treatment of Crohn's disease?. Nat Rev Gastroenterol Hepatol 10, 395–401 (2013). https://doi.org/10.1038/nrgastro.2013.66

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