Unraveling the role of autophagy regulation in Crohn's disease: from genetic mechanisms to potential therapeutics

Abstract

Autophagy serves as the primary intracellular degradation mechanism in which damaged organelles and self-cytoplasmic proteins are transported to the lysosome for degradation. Crohn's disease, an idiopathic chronic inflammatory disorder of the gastrointestinal tract, manifests in diverse regions of the digestive system. Recent research suggests that autophagy modulation may be a new avenue for treating Crohn's disease, and several promising small-molecule modulators of autophagy have been reported as therapeutic options. In this review, we discuss in detail how mutations in autophagy-related genes function in Crohn's disease and summarize the modulatory effects on autophagy of small-molecule drugs currently used for Crohn's disease treatment. Furthermore, we delve into the therapeutic potential of small-molecule autophagy inducers on Crohn's disease, emphasizing the prospects for development in this field. We aim to highlight the significance of autophagy modulation in Crohn's disease, with the aspiration of contributing to the development of more efficacious treatments that can alleviate their suffering, and improve their quality of life.

Keywords: Autophagy; Autophagy-related genes; Crohn's disease; Small-molecule modulators.

Fig. 1

Overview of Crohn's disease. The etiology of Crohn's disease is related to genetic susceptibility, environmental factors, and gut microbiota. Genetic susceptibility is associated with autophagy-related genes, including ATG16L1, NOD2, IRGM, etc. Symptoms of Crohn's disease is determined by the site of onset, the intensity of inflammation, and the behavior of the disease, and can be classified into major symptoms and extraintestinal manifestations. Owing to the complexity of the underlying etiology, Crohn's disease is currently incurable, but it is possible to manage the patient's symptoms with medications and surgical procedures. The most used drugs in pharmacologic therapy fall into four categories: corticosteroids, immunomodulators, 5-ASA medications, and monoclonal antibody drugs

Fig. 2

ATG16L1 dysfunction and increased risk of Crohn's inflammation. At homeostasis in vivo (left panel), the dense granules produced by Paneth cells are enriched with AMP and immunomodulatory proteins that control the composition of the intestinal flora. Moreover, after sensing the gut microbiota via PRRs, ATG16L1 negatively regulates TRIF- and RICK-mediated pro-inflammatory cytokine responses to maintain gut homeostasis. In the ATG16L1 dysfunctional state (right panel), AMP production by Paneth cells is reduced. This leads to increased PRRs stimulation of macrophages and DCs, which are not well regulated by ATG16L1, resulting in intestinal dysbiosis

Fig. 3

Regulation of the immune system and autophagic processes by NOD2. The activation of NOD2 promotes the sensing of MDP and autophagy in macrophages and DCs, mediating bacterial clearance, reducing inflammation, maintaining immune balance, and consequently preserving intestinal barrier function

Fig. 4

Regulation of core autophagy by IRGM. IRGM controls core autophagy and exerts its anti-microbial activities through five discrete but convergent mechanisms. The regulation of the core autophagic process by IRGM can be categorized into five aspects. (1) IRGM stimulates the phosphorylation of key autophagy regulators. (2) IRGM promotes the co-assembly of ULK1 and Beclin 1. (3) IRGM promotes the interaction between NOD2 and ATG16L1. (4) IRGM binds to LC3 and transports STX17 to autophagosomes for lysosomal fusion. (5) IRGM induces TFEB nuclear expansion by interacting with calcineurin

Fig. 5

Other autophagy-related genes associated with Crohn's disease susceptibility. A Modulation of autophagy pathway. B Modulation of inflammatory pathway