Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches

  • 투고 : 2021.05.01
  • 심사 : 2021.05.24
  • 발행 : 2021.07.01


The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.



This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology [Grant NRF-2019R1F1A1062070].


  1. Alatab, S., Sepanlou, S. G., Ikuta, K., Vahedi, H., Bisignano, C., Safiri, S., Sadeghi, A., Nixon, M. R., Abdoli, A., Abolhassani, H., Alipour, V., Almadi, M. A. H., Almasi-Hashiani, A., Anushiravani, A., Arabloo, J., Atique, S., Awasthi, A., Badawi, A., Baig, A. A. A., Bhala, N., Bijani, A., Biondi, A., Borzi, A. M., Burke, K. E., Carvalho, F., Daryani, A., Dubey, M., Eftekhari, A., Fernandes, E., Fernandes, J. C., Fischer, F., Haj-Mirzaian, A., Haj-Mirzaian, A., Hasanzadeh, A., Hashemian, M., Hay, S. I., Hoang, C. L., Househ, M., Ilesanmi, O. S., Jafari Balalami, N., James, S. L., Kengne, A. P., Malekzadeh, M. M., Merat, S., Meretoja, T. J., Mestrovic, T., Mirrakhimov, E. M., Mirzaei, H., Mohammad, K. A., Mokdad, A. H., Monasta, L., Negoi, I., Nguyen, T. H., Nguyen, C. T., Pourshams, A., Poustchi, H., Rabiee, M., Rabiee, N., Ramezanzadeh, K., Rawaf, D. L., Rawaf, S., Rezaei, N., Robinson, S. R., Ronfani, L., Saxena, S., Sepehrimanesh, M., Shaikh, M. A., Sharafi, Z., Sharif, M., Siabani, S., Sima, A. R., Singh, J. A., Soheili, A., Sotoudehmanesh, R., Suleria, H. A. R., Tesfay, B. E., Tran, B., Tsoi, D., Vacante, M., Wondmieneh, A. B., Zarghi, A., Zhang, Z. J., Dirac, M., Malekzadeh, R. and Naghavi, M. (2020) The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 5, 17-30.
  2. Andres, E., Fothergill, H. and Mecili, M. (2010) Efficacy of oral cobalamin (vitamin B12) therapy. Expert. Opin. Pharmacother. 11, 249-256.
  3. Arab, H. H., Al-Shorbagy, M. Y. and Saad, M. A. (2021) Activation of autophagy and suppression of apoptosis by dapagliflozin attenuates experimental inflammatory bowel disease in rats: targeting AMPK/mTOR, HMGB1/RAGE and Nrf2/HO-1 pathways. Chem. Biol. Interact. 335, 109368.
  4. Bhonde, M. R., Gupte, R. D., Dadarkar, S. D., Jadhav, M. G., Tannu, A. A., Bhatt, P., Bhatia, D. R., Desai, N. K., Deore, V., Yewalkar, N., Vishwakarma, R. A., Sharma, S., Kumar, S. and Dagia, N. M. (2008) A novel mTOR inhibitor is efficacious in a murine model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G1237-G1245.
  5. Billiau, A., Heremans, H., Vermeire, K. and Matthys, P. (1998) Immunomodulatory properties of interferon-gamma. An update. Ann. N. Y. Acad. Sci. 856, 22-32.
  6. Billmann-Born, S., Lipinski, S., Bock, J., Till, A., Rosenstiel, P. and Schreiber, S. (2011) The complex interplay of NOD-like receptors and the autophagy machinery in the pathophysiology of Crohn disease. Eur. J. Cell Biol. 90, 593-602.
  7. Boya, P., Reggiori, F. and Codogno, P. (2013) Emerging regulation and functions of autophagy. Nat. Cell Biol. 15, 713-720.
  8. Burada, F., Nicoli, E. R., Ciurea, M. E., Uscatu, D. C., Ioana, M. and Gheonea, D. I. (2015) Autophagy in colorectal cancer: an important switch from physiology to pathology. World J. Gastrointest. Oncol. 7, 271-284.
  9. Burns, A. J. (2007) Disorders of interstitial cells of Cajal. J. Pediatr. Gastroenterol. Nutr. 45, S103-S106.
  10. Cadwell, K., Liu, J. Y., Brown, S. L., Miyoshi, H., Loh, J., Lennerz, J. K., Kishi, C., Kc, W., Carrero, J. A., Hunt, S., Stone, C. D., Brunt, E. M., Xavier, R. J., Sleckman, B. P., Li, E., Mizushima, N., Stappenbeck, T. S. and Virgin, H. W., 4th (2008) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259-263.
  11. Callaghan, J. M., Khan, M. A., Alderuccio, F., van Driel, I. R., Gleeson, P. A. and Toh, B. H. (1993) Alpha and beta subunits of the gastric H+/K(+)-ATPase are concordantly targeted by parietal cell auto-antibodies associated with autoimmune gastritis. Autoimmunity 16, 289-295.
  12. Carneiro, F., Fonseca, E. and Sobrinho-Simoes, M. (1992) Epithelial degeneration induced by Helicobacter pylori. Hum. Pathol. 23, 1314-1315.
  13. Castano-Rodriguez, N., Kaakoush, N. O., Goh, K. L., Fock, K. M. and Mitchell, H. M. (2015) Autophagy in Helicobacter pylori infection and related gastric cancer. Helicobacter 20, 353-369.
  14. Chai, Y., Huang, Y., Tang, H., Tu, X., He, J., Wang, T., Zhang, Q., Xiong, F., Li, D. and Qiu, Z. (2017) Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome. Exp. Ther. Med. 13, 1187-1193.
  15. Chang, J., Leong, R. W., Wasinger, V. C., Ip, M., Yang, M. and Phan, T. G. (2017) Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology 153, 723-731.e1.
  16. Chen, H., Li, L., Hu, J., Zhao, Z., Ji, L., Cheng, C., Zhang, G., Zhang, T., Li, Y., Chen, H., Pan, S. and Sun, B. (2019) UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1. J. Exp. Clin. Cancer Res. 38, 297.
  17. Chen, L., Wang, J., You, Q., He, S., Meng, Q., Gao, J., Wu, X., Shen, Y., Sun, Y., Wu, X. and Xu, Q. (2018) Activating AMPK to restore tight junction assembly in intestinal epithelium and to attenuate experimental colitis by metformin. Front. Pharmacol. 9, 761.
  18. Chey, W. D., Leontiadis, G. I., Howden, C. W. and Moss, S. F. (2017) ACG clinical guideline: treatment of Helicobacter pylori infection. Am. J. Gastroenterol. 112, 212-239.
  19. Choy, M. C., Visvanathan, K. and De Cruz, P. (2017) An overview of the innate and adaptive immune system in inflammatory bowel disease. Inflamm. Bowel Dis. 23, 2-13.
  20. Ciechomska, I. A., Gabrusiewicz, K., Szczepankiewicz, A. A. and Kaminska, B. (2013) Endoplasmic reticulum stress triggers autophagy in malignant glioma cells undergoing cyclosporine A-induced cell death. Oncogene 32, 1518-1529.
  21. Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D. and Simmons, A. (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16, 90-97.
  22. Correa, P. (1988) Chronic gastritis: a clinico-pathological classification. Am. J. Gastroenterol. 83, 504-509.
  23. D'Elios, M. M., Bergman, M. P., Azzurri, A., Amedei, A., Benagiano, M., De Pont, J. J., Cianchi, F., Vandenbroucke-Grauls, C. M., Romagnani, S., Appelmelk, B. J. and Del Prete, G. (2001) H(+),K(+)-atpase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology 120, 377-386.
  24. De Block, C. E., Van Campenhout, C. M., De Leeuw, I. H., Keenoy, B. M., Martin, M., Van Hoof, V. and Van Gaal, L. F. (2000) Soluble transferrin receptor level: a new marker of iron deficiency anemia, a common manifestation of gastric autoimmunity in type 1 diabetes. Diabetes Care 23, 1384-1388.
  25. Delgado, M. A. and Deretic, V. (2009) Toll-like receptors in control of immunological autophagy. Cell Death Differ. 16, 976-983.
  26. Du, H., Xie, S., Guo, W., Che, J., Zhu, L., Hang, J. and Li, H. (2021) Development and validation of an autophagy-related prognostic signature in esophageal cancer. Ann. Transl. Med. 9, 317.
  27. Faller, G., Winter, M., Steininger, H., Lehn, N., Meining, A., Bayerdorffer, E. and Kirchner, T. (1999) Decrease of antigastric autoantibodies in Helicobacter pylori gastritis after cure of infection. Pathol. Res. Pract. 195, 243-246.
  28. Farrugia, G. (2008) Interstitial cells of Cajal in health and disease. Neurogastroenterol. Motil. 20 Suppl 1, 54-63.
  29. Feng, Y., Liu, J., Guo, W., Guan, Y., Xu, H., Guo, Q., Song, X., Yi, F., Liu, T., Zhang, W., Dong, X., Cao, L. L., O'Rourke, B. P. and Cao, L. (2018) Atg7 inhibits Warburg effect by suppressing PKM2 phosphorylation resulting reduced epithelial-mesenchymal transition. Int. J. Biol. Sci. 14, 775-783.
  30. Folkerts, H., Hilgendorf, S., Vellenga, E., Bremer, E. and Wiersma, V. R. (2019) The multifaceted role of autophagy in cancer and the microenvironment. Med. Res. Rev. 39, 517-560.
  31. Fritz, T., Niederreiter, L., Adolph, T., Blumberg, R. S. and Kaser, A. (2011) Crohn's disease: NOD2, autophagy and ER stress converge. Gut 60, 1580-1588.
  32. Fu, Y., Hong, L., Xu, J., Zhong, G., Gu, Q., Gu, Q., Guan, Y., Zheng, X., Dai, Q., Luo, X., Liu, C., Huang, Z., Yin, X. M., Liu, P. and Li, M. (2019) Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo. Autophagy 15, 295-311.
  33. Ghislat, G., Patron, M., Rizzuto, R. and Knecht, E. (2012) Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-beta (CaMKK-beta). J. Biol. Chem. 287, 38625-38636.
  34. Gomes, L. R., Menck, C. F. M. and Cuervo, A. M. (2017) Chaperonemediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation. Autophagy 13, 928-940.
  35. Greenfield, L. K. and Jones, N. L. (2013) Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis. Trends Microbiol. 21, 602-612.
  36. Hardbower, D. M., Peek, R. M., Jr. and Wilson, K. T. (2014) At the Bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J. Leukoc. Biol. 96, 201-212.
  37. He, C. L., Bian, Y. Y., Xue, Y., Liu, Z. X., Zhou, K. Q., Yao, C. F., Lin, Y., Zou, H. F., Luo, F. X., Qu, Y. Y., Zhao, J. Y., Ye, M. L., Zhao, S. M. and Xu, W. (2016) Pyruvate kinase M2 activates mTORC1 by phosphorylating AKT1S1. Sci. Rep. 6, 21524.
  38. Henderson, P. and Stevens, C. (2012) The role of autophagy in Crohn's disease. Cells 1, 492-519.
  39. Hooper, K. M., Casanova, V., Kemp, S., Staines, K. A., Satsangi, J., Barlow, P. G., Henderson, P. and Stevens, C. (2019) The inflammatory bowel disease drug azathioprine induces autophagy via mTORC1 and the unfolded protein response sensor PERK. Inflamm. Bowel Dis. 25, 1481-1496.
  40. Hu, C. A. A., Hou, Y., Yi, D., Qiu, Y., Wu, G., Kong, X. and Yin, Y. (2015) Autophagy and tight junction proteins in the intestine and intestinal diseases. Anim. Nutr. 1, 123-127.
  41. Huizinga, J. D., Thuneberg, L., Kluppel, M., Malysz, J., Mikkelsen, H. B. and Bernstein, A. (1995) W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373, 347-349.
  42. Hussein, G., Sankawa, U., Goto, H., Matsumoto, K. and Watanabe, H. (2006) Astaxanthin, a carotenoid with potential in human health and nutrition. J. Nat. Prod. 69, 443-449.
  43. Ihara, E. and MacDonald, J. A. (2007) The regulation of smooth muscle contractility by zipper-interacting protein kinase. Can. J. Physiol. Pharmacol. 85, 79-87.
  44. Iino, S., Horiguchi, K., Nojyo, Y., Ward, S. M. and Sanders, K. M. (2009) Interstitial cells of Cajal contain signalling molecules for transduction of nitrergic stimulation in guinea pig caecum. Neurogastroenterol. Motil. 21, 542-550, e12-e13.
  45. International Agency for Research on Cancer (1994) Schistosomes, Liver Flukes and Helicobacter pylori. World Health Organization.
  46. Jairath, V. and Feagan, B. G. (2020) Global burden of inflammatory bowel disease. Lancet Gastroenterol. Hepatol. 5, 2-3.
  47. Jiao, L., Zhang, H. L., Li, D. D., Yang, K. L., Tang, J., Li, X., Ji, J., Yu, Y., Wu, R. Y., Ravichandran, S., Liu, J. J., Feng, G. K., Chen, M. S., Zeng, Y. X., Deng, R. and Zhu, X. F. (2018) Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy 14, 671-684.
  48. Jing, Y., Liang, W., Liu, J., Zhang, L., Wei, J., Yang, J., Zhang, Y. and Huang, Z. (2020) Autophagy-mediating microRNAs in cancer chemoresistance. Cell Biol. Toxicol. 36, 517-536.
  49. Jung, S., Jeong, H. and Yu, S. W. (2020) Autophagy as a decisive process for cell death. Exp. Mol. Med. 52, 921-930.
  50. Karasic, T. B., O'Hara, M. H., Loaiza-Bonilla, A., Reiss, K. A., Teitelbaum, U. R., Borazanci, E., De Jesus-Acosta, A., Redlinger, C., Burrell, J. A., Laheru, D. A., Von Hoff, D. D., Amaravadi, R. K., Drebin, J. A. and O'Dwyer, P. J. (2019) Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol. 5, 993-998.
  51. Khamri, W., Walker, M. M., Clark, P., Atherton, J. C., Thursz, M. R., Bamford, K. B., Lechler, R. I. and Lombardi, G. (2010) Helicobacter pylori stimulates dendritic cells to induce interleukin-17 expression from CD4+ T lymphocytes. Infect. Immun. 78, 845-853.
  52. Kim, H. S., Choi, S. I., Jeung, E. B. and Yoo, Y. M. (2014) Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells. PLoS ONE 9, e108981.
  53. Klionsky, D. J. (2005) The molecular machinery of autophagy: unanswered questions. J. Cell Sci. 118, 7-18.
  54. Klionsky, D. J. (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931-937.
  55. Kokten, T., Gibot, S., Lepage, P., D'Alessio, S., Hablot, J., Ndiaye, N. C., Busby-Venner, H., Monot, C., Garnier, B., Moulin, D., Jouzeau, J. Y., Hansmannel, F., Danese, S., Gueant, J. L., Muller, S. and Peyrin-Biroulet, L. (2018) TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice. J. Crohns Colitis 12, 230-244.
  56. Lapaquette, P., Glasser, A. L., Huett, A., Xavier, R. J. and Darfeuille-Michaud, A. (2010) Crohn's disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell. Microbiol. 12, 99-113.
  57. Lauzier, A., Normandeau-Guimond, J., Vaillancourt-Lavigueur, V., Boivin, V., Charbonneau, M., Rivard, N., Scott, M. S., Dubois, C. M. and Jean, S. (2019) Colorectal cancer cells respond differentially to autophagy inhibition in vivo. Sci. Rep. 9, 11316.
  58. Lee, H., Lim, J. W. and Kim, H. (2020) Effect of astaxanthin on activation of autophagy and inhibition of apoptosis in Helicobacter pyloriinfected gastric epithelial cell line AGS. Nutrients 12, 1750.
  59. Lee, H. J., Venkatarame Gowda Saralamma, V., Kim, S. M., Ha, S. E., Raha, S., Lee, W. S., Kim, E. H., Lee, S. J., Heo, J. D. and Kim, G. S. (2018) Pectolinarigenin induced cell cycle arrest, autophagy, and apoptosis in gastric cancer cell via PI3K/AKT/mTOR signaling pathway. Nutrients 10, 1043.
  60. Lee, Y. C., Chiang, T. H., Chou, C. K., Tu, Y. K., Liao, W. C., Wu, M. S. and Graham, D. Y. (2016) Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology 150, 1113-1124.e5.
  61. Lenti, M. V., Rugge, M., Lahner, E., Miceli, E., Toh, B. H., Genta, R. M., De Block, C., Hershko, C. and Di Sabatino, A. (2020) Autoimmune gastritis. Nat. Rev. Dis. Primers 6, 56.
  62. Leung, K. M., Hui, P. K., Chan, W. Y. and Thomas, T. M. (1992) Helicobacter pylori-related gastritis and gastric ulcer. A continuum of progressive epithelial degeneration. Am. J. Clin. Pathol. 98, 569-574.
  63. Li, G. M., Li, L., Li, M. Q., Chen, X., Su, Q., Deng, Z. J., Liu, H. B., Li, B., Zhang, W. H., Jia, Y. X., Wang, W. J., Ma, J. Y., Zhang, H. L., Xie, D., Zhu, X. F., He, Y. L., Guan, X. Y. and Bi, J. (2021) DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy. Cell Death Differ. 28, 952-967.
  64. Li, L. Q., Pan, D., Zhang, S. W., D., Y. X., Zheng, X. L. and Chen, H. (2018) Autophagy regulates chemoresistance of gastric cancer stem cells via the Notch signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 22, 3402-3407.
  65. Li, N., Tang, B., Jia, Y. P., Zhu, P., Zhuang, Y., Fang, Y., Li, Q., Wang, K., Zhang, W. J., Guo, G., Wang, T. J., Feng, Y. J., Qiao, B., Mao, X. H. and Zou, Q. M. (2017) Helicobacter pylori CagA protein negatively regulates autophagy and promotes inflammatory response via c-Met-PI3K/Akt-mTOR signaling pathway. Front. Cell. Infect. Microbiol. 7, 417.
  66. Lin, Y. M., Chen, C. I., Hsiang, Y. P., Hsu, Y. C., Cheng, K. C., Chien, P. H., Pan, H. L., Lu, C. C. and Chen, Y. J. (2018) Chrysin attenuates cell viability of human colorectal cancer cells through autophagy induction unlike 5-fluorouracil/oxaliplatin. Int. J. Mol. Sci. 19, 1763.
  67. Liu, B., Gulati, A. S., Cantillana, V., Henry, S. C., Schmidt, E. A., Daniell, X., Grossniklaus, E., Schoenborn, A. A., Sartor, R. B. and Taylor, G. A. (2013) Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G573-G584.
  68. Liu, H., Song, J., Zhou, Y., Cao, L., Gong, Y., Wei, Y., Yang, H. and Tang, L. (2019) Methylxanthine derivatives promote autophagy in gastric cancer cells targeting PTEN. Anticancer Drugs 30, 347-355.
  69. Lueschow, S. R. and McElroy, S. J. (2020) The Paneth cell: the curator and defender of the immature small intestine. Front. Immunol. 11, 587.
  70. Luettig, J., Rosenthal, R., Barmeyer, C. and Schulzke, J. D. (2015) Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers 3, e977176.
  71. Lv, L., Li, D., Zhao, D., Lin, R., Chu, Y., Zhang, H., Zha, Z., Liu, Y., Li, Z., Xu, Y., Wang, G., Huang, Y., Xiong, Y., Guan, K. L. and Lei, Q. Y. (2011) Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719-730.
  72. Mabe, K., Yamada, M., Oguni, I. and Takahashi, T. (1999) In vitro and in vivo activities of tea catechins against Helicobacter pylori. Antimicrob. Agents Chemother. 43, 1788-1791.
  73. Macias-Ceja, D. C., Cosin-Roger, J., Ortiz-Masia, D., Salvador, P., Hernandez, C., Esplugues, J. V., Calatayud, S. and Barrachina, M. D. (2017) Stimulation of autophagy prevents intestinal mucosal inflammation and ameliorates murine colitis. Br. J. Pharmacol. 174, 2501-2511.
  74. Maes, H., Rubio, N., Garg, A. D. and Agostinis, P. (2013) Autophagy: shaping the tumor microenvironment and therapeutic response. Trends Mol. Med. 19, 428-446.
  75. Malfertheiner, P., Megraud, F., O'Morain, C. A., Gisbert, J. P., Kuipers, E. J., Axon, A. T., Bazzoli, F., Gasbarrini, A., Atherton, J., Graham, D. Y., Hunt, R., Moayyedi, P., Rokkas, T., Rugge, M., Selgrad, M., Suerbaum, S., Sugano, K. and El-Omar, E. M.; European Helicobacter and Microbiota Study Group and Consensus panel (2017) Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 66, 6-30.
  76. Marshall, B. J. and Warren, J. R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311-1315.
  77. Massey, D. C., Bredin, F. and Parkes, M. (2008) Use of sirolimus (rapamycin) to treat refractory Crohn's disease. Gut 57, 1294-1296.
  78. Massey, D. C. and Parkes, M. (2007) Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease. Autophagy 3, 649-651.
  79. Mehto, S., Jena, K. K., Nath, P., Chauhan, S., Kolapalli, S. P., Das, S. K., Sahoo, P. K., Jain, A., Taylor, G. A. and Chauhan, S. (2019) The Crohn's disease risk factor IRGM limits NLRP3 inflammasome activation by impeding its assembly and by mediating its selective autophagy. Mol. Cell 73, 429-445.e7.
  80. Milenkovic, N., Frahm, C., Gassmann, M., Griffel, C., Erdmann, B., Birchmeier, C., Lewin, G. R. and Garratt, A. N. (2007) Nociceptive tuning by stem cell factor/c-Kit signaling. Neuron 56, 893-906.
  81. Mizushima, N. (2018) A brief history of autophagy from cell biology to physiology and disease. Nat. Cell Biol. 20, 521-527.
  82. Mo, S., Dai, W., Xiang, W., Li, Y., Feng, Y., Zhang, L., Li, Q. and Cai, G. (2019) Prognostic and predictive value of an autophagy-related signature for early relapse in stages I-III colon cancer. Carcinogenesis 40, 861-870.
  83. Mutalib, M., Borrelli, O., Blackstock, S., Kiparissi, F., Elawad, M., Shah, N. and Lindley, K. (2014) The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children. J. Crohns Colitis 8, 1730-1734.
  84. Naser, S. A., Arce, M., Khaja, A., Fernandez, M., Naser, N., Elwasila, S. and Thanigachalam, S. (2012) Role of ATG16L, NOD2 and IL23R in Crohn's disease pathogenesis. World J. Gastroenterol. 18, 412-424.
  85. Nazim, U. M., Moon, J. H., Lee, J. H., Lee, Y. J., Seol, J. W., Eo, S. K., Lee, J. H. and Park, S. Y. (2016) Activation of autophagy flux by metformin downregulates cellular FLICE-like inhibitory protein and enhances TRAIL- induced apoptosis. Oncotarget 7, 23468-23481.
  86. Nazio, F., Bordi, M., Cianfanelli, V., Locatelli, F. and Cecconi, F. (2019) Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ. 26, 690-702.
  87. Neumann, W. L., Coss, E., Rugge, M. and Genta, R. M. (2013) Autoimmune atrophic gastritis--pathogenesis, pathology and management. Nat. Rev. Gastroenterol. Hepatol. 10, 529-541.
  88. Nighot, P. K., Hu, C. A. and Ma, T. Y. (2015) Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation. J. Biol. Chem. 290, 7234-7246.
  89. Oh, J. E. and Lee, H. K. (2014) Pattern recognition receptors and autophagy. Front. Immunol. 5, 300.
  90. Osaki, L. H., Bockerstett, K. A., Wong, C. F., Ford, E. L., Madison, B. B., DiPaolo, R. J. and Mills, J. C. (2019) Interferon-gamma directly induces gastric epithelial cell death and is required for progression to metaplasia. J. Pathol. 247, 513-523.
  91. Pan, H. H., Zhou, X. X., Ma, Y. Y., Pan, W. S., Zhao, F., Yu, M. S. and Liu, J. Q. (2020) Resveratrol alleviates intestinal mucosal barrier dysfunction in dextran sulfate sodium-induced colitis mice by enhancing autophagy. World J. Gastroenterol. 26, 4945-4959.
  92. Parkes, M., Barrett, J. C., Prescott, N. J., Tremelling, M., Anderson, C. A., Fisher, S. A., Roberts, R. G., Nimmo, E. R., Cummings, F. R., Soars, D., Drummond, H., Lees, C. W., Khawaja, S. A., Bagnall, R., Burke, D. A., Todhunter, C. E., Ahmad, T., Onnie, C. M., McArdle, W., Strachan, D., Bethel, G., Bryan, C., Lewis, C. M., Deloukas, P., Forbes, A., Sanderson, J., Jewell, D. P., Satsangi, J., Mansfield, J. C., Cardon, L. and Mathew, C. G. (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830-832.
  93. Philpott, D. J., Sorbara, M. T., Robertson, S. J., Croitoru, K. and Girardin, S. E. (2014) NOD proteins: regulators of inflammation in health and disease. Nat. Rev. Immunol. 14, 9-23.
  94. Pisani, A., Riccio, E., Sabbatini, M., Andreucci, M., Del Rio, A. and Visciano, B. (2015) Effect of oral liposomal iron versus intravenous iron for treatment of iron deficiency anaemia in CKD patients: a randomized trial. Nephrol. Dial. Transplant. 30, 645-652.
  95. Qian, H. R. and Yang, Y. (2016) Functional role of autophagy in gastric cancer. Oncotarget 7, 17641-17651.
  96. Quach, C., Song, Y., Guo, H., Li, S., Maazi, H., Fung, M., Sands, N., O'Connell, D., Restrepo-Vassalli, S., Chai, B., Nemecio, D., Punj, V., Akbari, O., Idos, G. E., Mumenthaler, S. M., Wu, N., Martin, S. E., Hagiya, A., Hicks, J., Cui, H. and Liang, C. (2019) A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat. Commun. 10, 5681.
  97. Raju, D., Hussey, S., Ang, M., Terebiznik, M. R., Sibony, M., Galindo-Mata, E., Gupta, V., Blanke, S. R., Delgado, A., Romero-Gallo, J., Ramjeet, M. S., Mascarenhas, H., Peek, R. M., Correa, P., Streutker, C., Hold, G., Kunstmann, E., Yoshimori, T., Silverberg, M. S., Girardin, S. E., Philpott, D. J., El Omar, E. and Jones, N. L. (2012) Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology 142, 1160-1171.
  98. Retnakumar, S. V. and Muller, S. (2019) Pharmacological autophagy regulators as therapeutic agents for inflammatory bowel diseases. Trends Mol. Med. 25, 516-537.
  99. Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., Shugart, Y. Y., Griffiths, A. M., Targan, S. R., Ippoliti, A. F., Bernard, E. J., Mei, L., Nicolae, D. L., Regueiro, M., Schumm, L. P., Steinhart, A. H., Rotter, J. I., Duerr, R. H., Cho, J. H., Daly, M. J. and Brant, S. R. (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596-604.
  100. Rugge, M., Correa, P., Dixon, M. F., Fiocca, R., Hattori, T., Lechago, J., Leandro, G., Price, A. B., Sipponen, P., Solcia, E., Watanabe, H. and Genta, R. M. (2002) Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. Aliment. Pharmacol. Ther. 16, 1249-1259.
  101. Saber, S., Abd El-Kader, E. M., Sharaf, H., El-Shamy, R., El-Saeed, B., Mostafa, A., Ezzat, D. and Shata, A. (2020) Celastrol augments sensitivity of NLRP3 to CP-456773 by modulating HSP-90 and inducing autophagy in dextran sodium sulphate-induced colitis in rats. Toxicol. Appl. Pharmacol. 400, 115075.
  102. Sanders, K. M., Koh, S. D., Ro, S. and Ward, S. M. (2012) Regulation of gastrointestinal motility--insights from smooth muscle biology. Nat. Rev. Gastroenterol. Hepatol. 9, 633-645.
  103. Simon, P. M., Goode, P. L., Mobasseri, A. and Zopf, D. (1997) Inhibition of Helicobacter pylori binding to gastrointestinal epithelial cells by sialic acid-containing oligosaccharides. Infect. Immun. 65, 750-757.
  104. Somlyo, A. P. and Somlyo, A. V. (2003) Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev. 83, 1325-1358.
  105. Stolte, M., Meier, E. and Meining, A. (1998) Cure of autoimmune gastritis by Helicobacter pylori eradication in a 21-year-old male. Z. Gastroenterol. 36, 641-643.
  106. Su, H., Hu, N., Yang, H. H., Wang, C., Takikita, M., Wang, Q. H., Giffen, C., Clifford, R., Hewitt, S. M., Shou, J. Z., Goldstein, A. M., Lee, M. P. and Taylor, P. R. (2011) Global gene expression profiling and validation in esophageal squamous cell carcinoma and its association with clinical phenotypes. Clin. Cancer Res. 17, 2955-2966.
  107. Sugano, K., Tack, J., Kuipers, E. J., Graham, D. Y., El-Omar, E. M., Miura, S., Haruma, K., Asaka, M., Uemura, N. and Malfertheiner, P.; faculty members of Kyoto Global Consensus Conference (2015) Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64, 1353-1367.
  108. Sui, X., Liang, X., Chen, L., Guo, C., Han, W., Pan, H. and Li, X. (2017) Bacterial xenophagy and its possible role in cancer: a potential antimicrobial strategy for cancer prevention and treatment. Autophagy 13, 237-247.
  109. Sun, D., Tao, W., Zhang, F., Shen, W., Tan, J., Li, L., Meng, Q., Chen, Y., Yang, Y. and Cheng, H. (2020) Trifolirhizin induces autophagy-dependent apoptosis in colon cancer via AMPK/mTOR signaling. Signal Transduct. Target. Ther. 5, 174.
  110. Tanaka, S., Nagashima, H., Uotani, T., Graham, D. Y. and Yamaoka, Y. (2017) Autophagy-related genes in Helicobacter pylori infection. Helicobacter 22, e12376.
  111. Tang, B., Li, N., Gu, J., Zhuang, Y., Li, Q., Wang, H. G., Fang, Y., Yu, B., Zhang, J. Y., Xie, Q. H., Chen, L., Jiang, X. J., Xiao, B., Zou, Q. M. and Mao, X. H. (2012) Compromised autophagy by MIR30B benefits the intracellular survival of Helicobacter pylori. Autophagy 8, 1045-1057.
  112. Tang, L., Zeng, Y., Li, L., Wang, J., Peng, D., Zhang, T., Zhang, H. and An, X. (2020) Electroacupuncture upregulated ghrelin in rats with functional dyspepsia via AMPK/TSC2/Rheb-mediated mTOR inhibition. Dig. Dis. Sci. 65, 1689-1699.
  113. Terebiznik, M. R., Raju, D., Vazquez, C. L., Torbricki, K., Kulkarni, R., Blanke, S. R., Yoshimori, T., Colombo, M. I. and Jones, N. L. (2009) Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy 5, 370-379.
  114. Tian, S., Guo, X., Yu, C., Sun, C. and Jiang, J. (2017) miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1. Oncotarget 8, 11071-11082.
  115. Troilo, A., Grassi, A., Petrone, L., Cianchi, F., Benagiano, M., Bella, C. D., Capitani, N., Bitetti, J., D'Elios, S., Tapinassi, S., Azzurri, A., Alnwaisri, H., Romagnoli, J., Bizzaro, N., Bergman, M., Baldari, C. T. and D'Elios, M. M. (2019) Intrinsic factor recognition promotes T helper 17/T helper 1 autoimmune gastric inflammation in patients with pernicious anemia. Oncotarget 10, 2921-2929.
  116. Tu, S. P., Quante, M., Bhagat, G., Takaishi, S., Cui, G., Yang, X. D., Muthuplani, S., Shibata, W., Fox, J. G., Pritchard, D. M. and Wang, T. C. (2011) IFN-gamma inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis. Cancer Res. 71, 4247-4259.
  117. Wang, C., Jiang, J., Ji, J., Cai, Q., Chen, X., Yu, Y., Zhu, Z. and Zhang, J. (2017) PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. Sci. Rep. 7, 2886.
  118. Wang, C. W. and Klionsky, D. J. (2003) The molecular mechanism of autophagy. Mol. Med. 9, 65-76.
  119. Wang, J., Miao, Y., Ran, J., Yang, Y., Guan, Q. and Mi, D. (2020a) Construction prognosis model based on autophagy-related gene signatures in hepatocellular carcinoma. Biomark. Med. 14, 1229-1242.
  120. Wang, S. L., Shao, B. Z., Zhao, S. B., Fang, J., Gu, L., Miao, C. Y., Li, Z. S. and Bai, Y. (2018a) Impact of paneth cell autophagy on inflammatory bowel disease. Front. Immunol. 9, 693.
  121. Wang, T., Liu, K., Wen, L., Yang, Y., Yin, X., Liu, K., Chen, Y., He, Y., Yang, M., Wei, Y., Wang, B. and Chen, D. (2020b) Autophagy and gastrointestinal diseases. Adv. Exp. Med. Biol. 1207, 529-556.
  122. Wang, Y., Xu, W., Yan, Z., Zhao, W., Mi, J., Li, J. and Yan, H. (2018b) Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J. Exp. Clin. Cancer Res. 37, 63.
  123. Wang, Y. H., Wu, J. J. and Lei, H. Y. (2009) The autophagic induction in Helicobacter pylori-infected macrophage. Exp. Biol. Med. (Maywood) 234, 171-180.
  124. Wang, Z., Shi, L., Hua, S., Qi, C. and Fang, M. (2019) IL-33 ameliorates experimental colitis involving regulation of autophagy of mac- rophages in mice. Cell Biosci. 9, 10.
  125. Wehkamp, J. and Stange, E. F. (2020) An update review on the paneth cell as key to ileal Crohn's disease. Front. Immunol. 11, 646.
  126. Wolpin, B. M., Rubinson, D. A., Wang, X., Chan, J. A., Cleary, J. M., Enzinger, P. C., Fuchs, C. S., McCleary, N. J., Meyerhardt, J. A., Ng, K., Schrag, D., Sikora, A. L., Spicer, B. A., Killion, L., Mamon, H. and Kimmelman, A. C. (2014) Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19, 637-638.
  127. Wu, J., Hu, L., Chen, M., Cao, W., Chen, H. and He, T. (2016) Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies. OncoTargets Ther. 9, 4277-4288.
  128. Xavier, R. J. and Podolsky, D. K. (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427-434.
  129. Xia, M., Chen, H. and Liu, S. (2020) The synergy of resveratrol and alcohol against Helicobacter pylori and underlying anti-Helicobacter pylori mechanism of resveratrol. J. Appl. Microbiol. 128, 1179-1190.
  130. Xiang, Z., Censini, S., Bayeli, P. F., Telford, J. L., Figura, N., Rappuoli, R. and Covacci, A. (1995) Analysis of expression of CagA and VacA virulence factors in 43 strains of Helicobacter pylori reveals that clinical isolates can be divided into two major types and that CagA is not necessary for expression of the vacuolating cytotoxin. Infect. Immun. 63, 94-98.
  131. Xiao, B., Liu, Z., Li, B. S., Tang, B., Li, W., Guo, G., Shi, Y., Wang, F., Wu, Y., Tong, W. D., Guo, H., Mao, X. H. and Zou, Q. M. (2009) Induction of microRNA-155 during Helicobacter pylori infection and its negative regulatory role in the inflammatory response. J. Infect. Dis. 200, 916-925.
  132. Xiao, M., Lin, C., Yang, Z., Tian, S., Huang, Y. and Fu, J. (2021) Compound TDB (Tricyclic decyl benzoxazole) induces autophagydependent apoptosis in the gastric cancer cell line MGC-803 by regulating PI3K/AKT/mTOR. Am. J. Transl. Res. 13, 73-87.
  133. Xie, J., Li, L., Deng, S., Chen, J., Gu, Q., Su, H., Wen, L., Wang, S., Lin, C., Qi, C., Zhang, Q., Li, J., He, X., Li, W., Wang, L. and Zheng, L. (2020) Slit2/Robo1 mitigates DSS-induced ulcerative colitis by activating autophagy in intestinal stem cell. Int. J. Biol. Sci. 16, 1876-1887.
  134. Xu, J. L., Yuan, L., Tang, Y. C., Xu, Z. Y., Xu, H. D., Cheng, X. D. and Qin, J. J. (2020a) The role of autophagy in gastric cancer chemoresistance: friend or foe? Front. Cell Dev. Biol. 8, 621428.
  135. Xu, J., Dai, S., Yuan, Y., Xiao, Q. and Ding, K. (2020b) A prognostic model for colon cancer patients based on eight signature autophagy genes. Front. Cell Dev. Biol. 8, 602174.
  136. Xu, R., Ji, Z., Xu, C. and Zhu, J. (2018) The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: a systematic review and meta-analysis. Medicine (Baltimore) 97, e12912.
  137. Yan, S., Zhou, N., Zhang, D., Zhang, K., Zheng, W., Bao, Y. and Yang, W. (2019) PFKFB3 inhibition attenuates oxaliplatin-induced autophagy and enhances its cytotoxicity in colon cancer cells. Int. J. Mol. Sci. 20, 5415.
  138. Yang, J. C., Yang, H. C., Shun, C. T., Wang, T. H., Chien, C. T. and Kao, J. Y. (2013) Catechins and sialic acid attenuate Helicobacter pylori-triggered epithelial caspase-1 activity and eradicate Helicobacter pylori infection. Evid. Based Complement. Alternat. Med. 2013, 248585.
  139. Yang, J. S., Wang, C. M., Su, C. H., Ho, H. C., Chang, C. H., Chou, C. H. and Hsu, Y. M. (2018) Eudesmin attenuates Helicobacter pyloriinduced epithelial autophagy and apoptosis and leads to eradication of H. pylori infection. Exp. Ther. Med. 15, 2388-2396.
  140. Yue, P., Zhu, C., Gao, Y., Li, Y., Wang, Q., Zhang, K., Gao, S., Shi, Y., Wu, Y., Wang, B., Xie, J. and Meng, X. (2020) Development of an autophagy-related signature in pancreatic adenocarcinoma. Biomed. Pharmacother. 126, 110080.
  141. Yue, W., Liu, Y., Li, X., Lv, L., Huang, J. and Liu, J. (2019) Curcumin ameliorates dextran sulfate sodium-induced colitis in mice via regulation of autophagy and intestinal immunity. Turk. J. Gastroenterol. 30, 290-298.
  142. Zeh, H. J., Bahary, N., Boone, B. A., Singhi, A. D., Miller-Ocuin, J. L., Normolle, D. P., Zureikat, A. H., Hogg, M. E., Bartlett, D. L., Lee, K. K., Tsung, A., Marsh, J. W., Murthy, P., Tang, D., Seiser, N., Amaravadi, R. K., Espina, V., Liotta, L. and Lotze, M. T. (2020) A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/nab-paclitaxel in pancreatic cancer patients. Clin. Cancer Res. 26, 3126-3134.
  143. Zhang, Q., Wang, X., Cao, S., Sun, Y., He, X., Jiang, B., Yu, Y., Duan, J., Qiu, F. and Kang, N. (2020) Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed. Pharmacother. 128, 110245.
  144. Zhang, X., Jiang, A., Qi, B., Ma, Z., Xiong, Y., Dou, J. and Wang, J. (2015) Resveratrol protects against Helicobacter pylori-associated gastritis by combating oxidative stress. Int. J. Mol. Sci. 16, 27757-27769.
  145. Zhang, X., Li, Z., Xuan, Z., Xu, P., Wang, W., Chen, Z., Wang, S., Sun, G., Xu, J. and Xu, Z. (2018) Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis. J. Exp. Clin. Cancer Res. 37, 320.
  146. Zhao, J. M., Liu, Y. N., Zheng, H. D., Huang, Y., Qi, Q., Liu, H. R., Shi, Y., Ma, X. P., Lu, Y. and Wu, L. Y. (2019) Effect of herb-partitioned moxibustion on autophagy and immune-associated gene expression profiles in a rat model of Crohn's disease. Evid. Based Complement. Alternat. Med. 2019, 3405146.
  147. Zhou, X., Qian, H., Zhang, D. and Zeng, L. (2020) Inhibition of autophagy of Cajal mesenchymal cells by gavage of tong bian decoction based on the rat model of chronic transit constipation. Saudi J. Biol. Sci. 27, 623-628.