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October 28, 2023, 15:15

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Biliary dyskinesia is one of the more common gastrointestinal diseases, with the continuous improvement of people's living standards, its incidence is showing an increasing trend year by year. Moreover, the pathogenesis of biliary dyskinesia is still unclear, which directly hinders the progress of drug development. Fortunately, Xu et al demonstrated that cholecystokinin (CCK) regulates the contractile function of the common bile duct by acting on cholecystokinin-A receptor (CCK-A receptor) in interstitial Cajal-like cells of the common bile duct. We agree with the authors' findings that cholecystokinin-A receptors (CCK-A receptors) is highly expressed on common bile duct (CBD) interstitial Cajal-like cells (ICLC) and that cholecystokinin (CCK) acts on ICLC CCK-A receptors to regulate CBD smooth muscle contraction in a dose-dependent manner. We are grateful to the authors for their commitment to the study of CCK and CCK-A receptors in biliary dyskinesia, which will help to further elucidate the key cells and their receptors affecting biliary dyskinesia and provide promising directions for emerging therapies in the clinic. CCK is an important gastrointestinal and neuronal peptide hormone that regulates the functions of the digestive, cardiovascular, and neurological systems upon binding to the CCKR of target cells. In the digestive system, CCK regulates cholecystic contraction, pancreatic enzyme secretion and gastrointestinal peristalsis. CCK binds to CCKR to contract the gallbladder and promote cholecystic emptying and bile release. CCK mediates rhythmic gallbladder contraction and sphincter of Oddi diastole, allowing the release of bile from the gallbladder into the duodenum to participate in food digestion. Therefore, a animal study has found that increasing CCK levels were conducive to the enhancement of cholecystic contractile function, on the contrary, decreasing CCK levels cause cholecystic contractile dysfunction and ultimately lead to gallstone formation. Importantly, Xu et al found that CCK acted on ICLC CCK-A receptors to regulate guinea pig CBD smooth muscle contractility in a dose-dependent manner, suggesting that CCK and CCK-A receptors play a key role in regulating CBD smooth muscle contraction. CCK-A receptor is a major mediator of gallbladder smooth muscle contraction and is highly expressed on guinea pig CBD ICLC. Reduced CCK-A receptor in mouse gallbladder is an important cause of cholelithiasis. The above animal studies suggest that CCK and CCK-A receptors may be attractive targets for combating biliary dyskinesia. However, little research has been reported on the safety and efficacy of CCK and CCK-A receptors in humans. A clinical study exploring whether a CCK-A agonist (GI181771X) was beneficial in reducing body weight in obese patients. GI181771X was found to have no significant effect on body weight, waist circumference, hepatobiliary, pancreatic and other cardiometabolic markers, but had side effects on the gastrointestinal tract, suggests that increasing CCK-A receptor levels has no effect on the gallbladder system in obese patients, but affects gastrointestinal function. In contrast, another clinical study analyzed the role of CCK-A receptors in patients with functional dyspepsia and found that CCK-A antagonist (dexloxiglumide) attenuated gastric volume and dyspepsia during duodenal lipid infusion, and also reduced gastric compliance during gastric distension, implies that CCK-A receptors is an important cause of gastric distension and duodenal lipid-induced dyspeptic symptoms. Similar clinical studies have used the CCK-A antagonist (loxiglumide) to assess the role of CCK-A receptors in duodenal lipids and postprandial satiety and nausea, and found that loxiglumide reduced postprandial satiety and nausea, revealing that CCK-A receptors induced symptoms such as duodenal lipids and postprandial satiety and nausea. Thus, the above studies suggest that there are limitations to the safety of CCK-A receptors and their associated roles in humans, and that there are a number of core issues that remain to be resolved. As an important hormone that affects the contraction of gallbladder tissue, CCK plays an irreplaceable role in the physiological homeostasis of the body. However, current animal and clinical studies cannot fully prove its biological effects, and its safety and effectiveness are worth of further discussion. A study has found that CCK promotes gastric motility in guinea pigs, while it has opposite effects on gastric motility for humans and dogs, indicating that the effect of CCK on gastric motility is species different. Whether there are species differences in the impact of CCK on biliary motility needs to be fully designed and studied. In addition, the biological mechanisms underlying the interaction between CCK and CCK-A receptors, which mediate the cholecystic contractile function, remains to be further elucidated. After clarifying the safety and effectiveness between CCK and CCK-A receptors in animal experiments, it is necessary to conduct large-scale clinical trials in order to promote the clinical transformation of basic research results and better serve patients. After the safety and efficacy of CCK and CCK-A receptors have been clarified in animal experiments, it is necessary to carry out large-scale clinical trials to promote the clinical translation of basic research results, and then better serve patients. In conclusion, the traditional treatment of biliary dyskinesia mainly cholecystectomy, but cholecystectomy may cause side effects such as diarrhea, dyspepsia, and duodenal gastrointestinal reflux, as well as damage to the patient's immune system, and in recent years, gallbladder conservation therapy is mostly adopted for biliary dyskinesia-related disorders, which makes the search for potential targets for the prevention and treatment of biliary dyskinesia particularly important. Biliary tract dynamics is a hotspot direction in the research of extra-biliary science. With the continuous deepening of basic and clinical research on biliary tract dynamics, it is expected to clarify its key cells and receptors and their functions and regulatory mechanisms, to search for therapeutic targets for biliary dyskinesia, and to design drugs against unique targets, which in turn will provide theoretical basis for the standardized treatment of biliary dyskinesia.

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