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Factors Influencing Gallstone Formation
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This entry is adapted from the peer-reviewed paper 10.3390/biom12040550

Dysfunction of the gallbladder or other parts of the bile-secretion pathway can result in gallstone formation. Given that the bile-secretion pathway is a complex process, there are many reasons for the formation of gallstones. Evidence suggests that gallstones are related to age, gender, female physiological status, obesity, cardiovascular disease, microbiome, sugar metabolism, and various environmental exposures. Based on a large number of mouse and human studies, the interaction of five main factors were proposed. The pathogenesis of cholesterol gallstone disease is precipitated by: genetic factors; excessive cholesterol secretion by the liver (leading to supersaturation of cholesterol in gallbladder bile); rapid phase change by accelerating the growth of cholesterol crystals and solid cholesterol crystals; impairment of gallbladder motility; and intestinal factors. Intestinal factors can be further broken down into two categories: increased cholesterol absorption from the small intestine to the liver, eventually resulting in increased bile secretion, and microbiota that inhabit the intestinal tract. These factors will increase the production or growth of cholesterol crystals, eventually leading to the formation of stones.

gallstone disease bile acids obesity

1. Genetic Mechanism of Gallstone Formation

Gallstone-susceptible mice (C57L/J) and gallstone-resistant mice (AKR/J) have been used to better elucidate the genetic components of gallstone formation. Using these mice, it has been described that lithogenic genes 1 and 2 (Lith1 and Lith2) may play a role in gallstone formation. Lith1, located on mouse chromosome 2, plays a major role in the determination of liver cholesterol hypersecretion. Lith2, located on mouse chromosome 19, regulates the bile salt-dependent flow of bile [1]. The functional counterparts of Mouse Lith1 and Lith 2 are ABCG5 and ABCG8 in the human equivalents. ABCG5 and ABCG8 are ATP-binding cassette (ABC) transporters with significant expression in hepatocytes and intestinal cells [2]. These two proteins form heterodimers in the endoplasmic reticulum and are subsequently transported to the apical membrane. In hepatocytes, they transport neutral sterols to bile or they promote active efflux of cholesterol from the enterocyte back into the intestinal lumen for fecal excretion [3]. Inactivation of ABCG5/G8 will result in significantly reduced cholesterol secretion in bile, making the level of cholesterol in liver and plasma very sensitive to changes in dietary cholesterol content. Because of this, hypercholesterolemia, phytosterolemia, and premature coronary heart disease may result [4][5]. However, the overexpression of ABCG5/G8 protein increases cholesterol content in the gallbladder, thus increasing the likelihood of cholesterol crystal precipitation [6]. Subsequently, ABCG5/G8 was found to be associated with cholesterol gallstone disease in patients, and two gallstone associated variants in ABCG5/G8 (ABCG5-R50C and ABCG8-D19H) were identified in Germans, Chileans, Chinese, and Indians. Taking this information into account, these may be the primary promoter genes of gallstones.

2. Gallbladder Contraction

After ingesting a large amount of food containing fat and protein, the neuroenteropeptide hormone cholecystokinin (CCK), released by endocrine cells of the duodenum, reaches the gallbladder and directly binds with the CCK1 receptor (CCK-1R) on the smooth muscle cells of the gallbladder wall. This triggers contraction of the gallbladder and discharges the concentrated bile into the intestine. CCK-1R is also located in the sphincter of Oddi, pancreas, small intestine, gastric mucosa, and pyloric sphincter. It is responsible for CCK regulation of pancreatic secretion, small intestine transport, gastric emptying, and other digestive processes. Observing CCK or CCK-1R gene knockout mice shows that gallbladder emptying and bile cholesterol metabolism are inhibited, intestinal absorption of cholesterol is increased, and cholesterol stone formation is significantly increased [7]. This suggests that CCK can regulate gallbladder and small intestine motility through the CCK-1R signal cascade, promote small intestine transport, and regulate intestinal cholesterol absorption. This also explains why the abnormal gallbladder motility caused by exogenous cholecystokinin is mainly found in patients with cholesterol stones [8][9].
Clinical studies have found that glucagon-like peptide 1 (GLP-1) receptor agonists have achieved good results in the treatment of type II diabetes, obesity, and other diseases. However, such drugs have a negative impact on the gallbladder and seem to increase the risk of gallbladder-related diseases [10]. In one study after acute injection of the glp-1r agonist exendin-4, there was no significant change in gallbladder volume in mice. When combined with CCK injection, exendin-4 reduced the emptying ability of the gallbladder. The effect of the glp-1r agonist for 12 weeks on patients with type 2 diabetes mellitus was not significant. In addition, the mRNA transcription level of GLP-1R in the gallbladder of mice was low, suggesting that GLP-1 has a more indirect effect on the gallbladder. This further suggests that GLP-1 may be related to slowing down of upper gastrointestinal motility. However, the molecular mechanism is still unclear [11].

3. Microbiome

The various flora in the body are in a dynamic balance and, when disturbed, many tissues and organs are affected. This complex system of microorganisms also exists in bile, and the occurrence of gallstones is closely related to abnormalities with flora. In almost all stages of bile formation, the microbiota of the gastrointestinal and biliary tracts are involved, including the regulation of lipid metabolism, cholesterol metabolism, biotransformation, and enterohepatic circulation of bile acids [12].
Microbiome in the biliary tract. Studies have shown the presence of living bacteria in gallstones. The flora in the biliary tract and duodenum are highly homologous and closely related to the formation of gallstones. Microorganisms can enter the biliary system from the duodenum by migrating through the sphincter of Oddi. They can also spread hematogenously to the liver and from there into bile [13][14]. When in bile, microorganisms play an important role as nucleating factors, leading to the formation of pigment and cholesterol gallstones [15].
The properties of bacteria that reside in the gallbladder can control the formation of gallstones. Bacteria that produce beta-glucuronidase and phospholipase in the bile yield a higher percentage of pigment in the stones, while bacteria that cause mucus abnormalities are more likely to lead to the formation of cholesterol stones [16][17]. Biofilm-forming bacteria in the gallbladder, bile, and gallstones are closely associated with gallstone formation [18]. For example, biofilms are formed during the formation of pigment stones, and the aggregating factor in this case is the glycocalyx (anionic glycoprotein) [19]. Differences in the functional metagenomes of microbial communities have been found by comparing pigment gallstones and cholesterol gallstones. Gram-positive bacteria were predominant in most of the cholesterol gallstones examined, whereas they were not found in the pigment stones. A high proportion of genes involved in carbohydrate metabolism were found in the pigment stones, whereas genes dominating protein metabolism were more active in the cholesterol stones. Helicobacter pylori is a Gram-negative, spiral-shaped, motile microorganism [20]. The presence of H. pylori in patients with symptomatic gallstone disease (GSD) has been shown to promote the formation of gallstones. However, this finding is still controversial and more data are required for adequate discussion of this topic [21].
Oral flora. Microflora of the oral cavity affects the secretion of cholecystokinin [22], the main factor involved in the emptying and filling of the gallbladder [23]. A microbiome changes the expression of mucin genes (MUC1, MUC3, and MUC4 genes) through immunomodulation, thereby changing the accumulation of mucin gel, which is the nucleation matrix for the formation of cholesterol gallstones in the gallbladder [23]. Studies have shown that H. pylori and enterohepatic strains of Helicobacter contribute to the formation of cholesterol gallstones [24][25][26].
The composition of the gut and biliary tract microbiome varies significantly in patients with GSD and in healthy subjects [27]. In patients with GSD, microbial diversity is reduced, beneficial bacteria such as Roseburia are reduced, and an overgrowth of bacteria of the Proteobacteria type—including a wide range of pathogenic microorganisms such as Escherichia, Salmonella, Vibrio and Helicobacter—more easily occurs [28]. Disorders of bile acid metabolism are the leading factors in the pathogenesis of cholesterol GSD [1].
Gut microbes. Gut microbiota-mediated biotransformation of the bile acid pool regulates bile acid signaling by influencing the activation of host bile acid receptors, such as the nuclear receptor farnesoid X receptor (FXR). The role of FXR in liver cells and intestinal cells is recognized as a regulator of bile acid, lipid, and glucose balance [29][30]. In the intestine, bile acids directly bind to and activate the bile acid receptors FXR and fibroblast growth factor 15/19 (FGF15/19) gene expression. FGF15/19 inhibits the synthesis of bile acids by reducing the expression of CYP7A1, which plays a negative feedback role in bile acid synthesis [31]. In fact, disturbances in the intestinal microbiota and changes in the composition of bile can adversely affect the metabolism of bile acids and the balance of glucose and cholesterol, leading to the development of gallstones [32][33].
Gut microbes lower cholesterol in bile. Bifidobacteria have been proven to lower cholesterol in bile by assimilation or precipitation [16][34]. A meta-analysis showed that probiotics (L. acidophilus, B. lactis, VSL#3, and the L. plantarum group) can significantly reduce total serum cholesterol [35]. The consumption of a BSH-positive strain of Lactobacillus significantly reduced cholesterol in patients with hypercholesterolemia [36].

4. Effect of Estrogen in Gallstone Formation

According to grouping analysis of cholelithiasis, the number of female patients of all ages with gallstones is significantly higher than that of men. The incidence rate of gallbladder diseases in women is further increased during pregnancy, which has become the second most common indication of non-obstetric intervention during pregnancy [37][38][39]. Furthermore, the incidence rate of gallbladder disease in women who have had multiple pregnancies is higher than that of those who have been pregnant once [40]. The importance of estrogen in terms of cholelithiasis is well documented. Estrogen, such as 17β-estradiol (E2), is a major female steroid hormone which plays an important role in health and disease [6]. As a steroid, estrogen has liposoluble properties which allows it to passively diffuse into cells and play the role of a transcription factor. After entering cells, it directly binds to ESR1 and ESR2 receptors and initiates changes in receptor tertiary and quaternary structures. As a result, active complexes that regulate transcription are formed [41]. When E2 reaches the liver, it also passively diffuses into cells and increases liver secretion of cholesterol into bile, thus increasing the cholesterol saturation in bile and the risk of cholelithiasis. It has been confirmed that ESR1, rather than ESR2, plays a more major role in the formation of cholesterol gallstones in mice induced by high dose E2. E2 has also been shown to play important roles in health and disease [42][43]. It regulates a wide range of biological processes, including reproduction, cardiovascular function, hepatobiliary secretion, metabolic processes, nerve function, and inflammation. There is a large amount of clinical evidence suggesting that oral contraceptive steroids and conjugated estrogen play a significant part in promoting cholesterol stone formation in premenopausal women [44][45][46][47]. The classical estrogen regulatory pathway involves E2 promotion of cholesterol biosynthesis and liver secretion of bile cholesterol through the “e2-esr1-srebp-2” pathway. During estrogen treatment or in times of increased blood estrogen concentration, synthesis of cholesterol increases mainly by estrogen-induced stimulation of sterol regulatory element binding protein-2 (SREBP-2) [48]. These changes lead to excessive secretion of newly synthesized cholesterol, supersaturation of bile, and easily lead to cholesterol precipitation and gallstone formation. Estrogen-activated ESR1 also stimulates the activity of ABCG5 and ABCG8, which are only expressed in hepatocytes and intestinal cells. These two proteins form heterodimers in the endoplasmic reticulum and are then transported to the apical membrane. There, they transport neutral sterols to bile or the intestinal lumen which promotes the secretion of bile cholesterol, eventually leading to the supersaturation of cholesterol in bile [5].
G protein-coupled receptor 30 (GPR30), a newly discovered estrogen receptor in humans, is produced by the gallstone gene lith18 [49][50][51]. It was found that E2 can effectively bind and activate GPR30 and ER-α [52]. In order to distinguish the role of Er-α and GPR30 in stone formation, a mouse model of ovariectomized female wild type, GPR30 gene knockout, ER-α gene knockout, and GPR30/ER-α double gene knockout was constructed. It was found that E2 activated GPR30 and ER-α produced liquid crystal and amorphous metastable intermediates. These evolved into cholesterol monohydrate crystals from supersaturated bile. In addition, the cholesterol crystal of GPR30/ER-α double knockout mice decreased significantly. This suggests that GPR30 and ER-α have a synergistic effect on the formation of gallstones induced by E2 [51][53]. Because GPR30 is mainly located in the endoplasmic reticulum rather than the nucleus of hepatocytes, E2 may activate GPR30 through the signal cascade of epidermal growth factor receptor, thus inhibiting the classical pathway of hepatic cholesterol 7α-hydroxylase and bile acid synthesis. This results in excessive cholesterol production, leading to increased cholesterol secretion by the liver and increased likelihood of bile stone formation [53].

5. Obesity and Gallstone

Nonalcoholic fatty liver disease (NAFLD) is an important risk factor for gallstone formation. The abnormally low expression of aquaporin 8 (AQP8) mediated by hypoxia inducible factor-1α (HIF-1α) in NAFLD seems to explain this situation [54]. HIF-1α is an important transcription factor regulating gene expression of oxygen transfer, cell growth, and redox homeostasis that promotes an adaptive response to hypoxic conditions resulting in greater cell survival [54][55]. Given this, it makes sense that in the liver HIF-1α mainly exists in the area around the hepatic vein. During the development of hepatic steatosis, lipid accumulation significantly increases the size of hepatocytes, thereby reducing hepatic sinusoidal perfusion and microcirculation, and ultimately leading to liver hypoxia [56]. In one study examining the upregulated expression of AQP8, a water channel protein responsible for the secretion of liver water into the bile duct [57][58][59], researchers found a significant 35% increase in bile flow, diluted bile lipid concentration in gallbladder and hepatobiliary juice by 36%, and alleviation of gallbladder inflammation. As a result, cholesterol crystal formation was inhibited in the liver-specific HIF-1α knockout mice. On the contrary, activation of the HIF-1α pathway in diet-induced fatty liver has been shown to accelerate the formation of gallstones in wild-type mice. In addition, the increased expression of HIF-1α and its downstream targets in the liver suggests that HIF-1α may play an important role in the formation of cholesterol gallstones in patients with NAFLD [60].

6. Carbohydrate Metabolism

The classic role of bile in the digestion and absorption of fat is well documented. In addition, the gallbladder also plays a physiological role in glucose, fat, and energy homeostasis. Both GSD and cholecystectomy can reduce insulin sensitivity [61], which suggests that obesity is not a correlate between gallstone and insulin resistance (IR) but is a common risk factor for both. GSD and cholecystectomy increase triglyceride content in the liver, and possibly increase IR in the liver as well. On the other hand, the gallbladder not only regulates the secretion and transport of bile acids, but also affects the homeostasis of lipids and glucose, which may affect whole body energy consumption [62][63]. In addition, experimental evidence suggests that liver IR may promote GSD by increasing the diagenesis of bile.

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Wei han
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,
Jonathan Warren
,
James Yip
,
Yuchuan Ding
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Update Date: 16 May 2022
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