Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota

Abstract

The incidence and mortality of colorectal cancer (CRC) have been markedly increasing worldwide, causing a tremendous burden to the healthcare system. Therefore, it is crucial to investigate the risk factors and pathogenesis of CRC. Cholecystectomy is a gold standard procedure for treating symptomatic cholelithiasis and gallstone diseases. The rhythm of bile acids entering the intestine is altered after cholecystectomy, which leads to metabolic disorders. Nonetheless, emerging evidence suggests that cholecystectomy might be associated with the development of CRC. It has been reported that alterations in bile acid metabolism and gut microbiota are the two main reasons. However, the potential mechanisms still need to be elucidated. In this review, we mainly discussed how bile acid metabolism, gut microbiota, and the interaction between the two factors influence the development of CRC. Subsequently, we summarized the underlying mechanisms of the alterations in bile acid metabolism after cholecystectomy including cellular level, molecular level, and signaling pathways. The potential mechanisms of the alterations on gut microbiota contain an imbalance of bile acid metabolism, cellular immune abnormality, acid-base imbalance, activation of cancer-related pathways, and induction of toxin, inflammation, and oxidative stress.

Keywords: bile acid metabolism; cholecystectomy; colorectal cancer; development; gut microbiota.

FIGURE 1

Cholecystectomy promotes the development of CRC by the alternation of bile acid metabolism and the gut microbiota. The green arrow indicates the levels are upregulated or the pathway is activated, while the red arrow indicates the levels are downregulated or the pathway is inactivated. CRC, colorectal cancer; CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; CYP27A1, mitochondrial sterol 27-hydroxylase; CA, cholic acid; CDCA, chenodeoxycholic acid; COX-2, cyclooxygenase 2; EGFR, epidermal growth factor receptor; uPAR, urokinase-type plasminogen activator receptor; MR, muscarinic receptor; MMPs, matrix metalloproteinases; miR, microRNA; MUC2, mucin 2, oligomeric mucus/gel-forming; TR, thioredoxin reductase; IL, interleukin; EPHA2, EPH receptor A2; ABCB1, ATP binding cassette subfamily B member 1; ABCG2, ATP binding cassette subfamily G member 2; HLA, human leukocyte antigen; sIgA, secretory antibodies of the type IgA; XIAP, X-linked inhibitor of apoptosis protein; ROS, reactive oxygen species; PGE2, prostaglandin E2; ERK, extracellular signal regulated kinases; CREB, cAMP response element binding protein; PI3K, phosphoInositide-3 kinase; IKKB, Ikappa B; NF-κB, nuclear factor kappa-B; MAPK, mitogen activated protein kinase; STAT, signal transduction and transcriptional activator; PKC, protein kinase C; MSK1, mitogen and stress-activated protein kinase 1; AP-1, activated protein-1; JNK, c-jun N-terminal kinase.