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. 2025 Feb 5;25:56. doi: 10.1186/s12876-025-03653-0

Optimization of the cholesterol gallstone model in C57BL/6 mice and evaluation of Lactobacillus intervention effects

Cong Wang 1,#, Ting Jiang 1,#, Lvwang Ye 1, Mengyan Du 1, Fang Liu 1,✉
PMCID: PMC11800605  PMID: 39910449

Abstract

Gallstone disease is a common and complex condition, strongly associated with abnormal cholesterol metabolism, changes in bile composition, and impaired gallbladder motility. Recent studies have suggested that the gut microbiota, particularly probiotics like lactic acid bacteria, may play a significant role in the prevention and treatment of cholesterol gallstones. This study aims to optimize the cholesterol gallstone model in C57BL/6 mice and evaluate the effects of Lactobacillus intervention on gallstone formation induced by a high-fat diet. In this study, 8-week-old male C57BL/6 mice were randomly divided into four groups: a high-fat diet + saline group (HF-S), a high-fat diet + probiotic group (HF-P), a normal diet + saline group (ND-S), and a normal diet + probiotic group (ND-P), to assess the effect of probiotics on gallstone formation. The results showed significant differences among the four groups in body weight gain, liver weight, gallstone formation, and histopathology. Based on these preliminary findings, we added two more experimental groups: a 2-week probiotic pretreatment + high-fat diet group (Pre2w-HF) and a 4-week probiotic pretreatment + high-fat diet group (Pre4w-HF), to further investigate the dose-dependence and efficacy of probiotic pretreatment. The results indicated that probiotic intervention significantly reduced the incidence and severity of gallstones induced by a high-fat diet, with the pretreatment groups showing more pronounced effects. Histological analysis also revealed that probiotic intervention reduced inflammation and pathological changes in the liver and gallbladder. This study suggests that probiotics have potential therapeutic value in the prevention and treatment of cholesterol gallstones. Future research should explore the effects of different strains and doses, as well as the underlying mechanisms involved.

Keywords: Cholesterol gallstones, Probiotics, Lactobacillus, High-fat diet, C57BL/6 mice, Gut microbiota

Introduction

Gallstone disease is a multifactorial disorder of the biliary system, with its pathogenesis involving abnormal cholesterol metabolism, alterations in bile composition, and gallbladder motility dysfunction [1, 2]. In recent years, increasing evidence has highlighted the critical role of the gut microbiota in various diseases [3–6]. Probiotics, especially Lactobacillus species, are thought to play a key role in preventing and treating cholesterol gallstones by modulating the gut microbiota [7–8]. C57BL/6 mice, due to their high sensitivity to gallstone formation induced by a high-fat diet, have become a standard animal model for studying cholesterol gallstones [9]. Typically, a high-fat diet intervention for 6 to 8 weeks is used to induce gallstone formation in these models [10–11]. However, the optimal induction time for gallstone formation and the specific experimental conditions have not been fully explored or established. Given the potential of probiotics to regulate the gut microbiota, this study evaluates the effect of Lactobacillus intervention on gallstone formation induced by a high-fat diet, optimizing the animal model for future research on gallstone prevention and treatment.

Materials and methods

Animals

Eight-week-old male C57BL/6 mice were purchased from the Laboratory Animal Center of Shihezi University. They were housed in a specific pathogen-free environment at a constant temperature of 22 °C, with a 12-hour light-dark cycle. Before the start of the experiment, the mice were acclimated for one week. This study involved 240 C57BL/6 mice, and all procedures were conducted in accordance with the guidelines for the care and use of laboratory animals. The study was approved by the Ethics Committee of the Medical School of Shihezi University (approval number: A2023-217-01).

Experimental design

The experimental design of this study was divided into two phases. The first phase aimed to preliminarily evaluate the effect of probiotics on cholesterol gallstone formation in mice. Eight-week-old male C57BL/6 mice were randomly assigned to four groups (n = 40 per group):

  1. High-fat diet + saline group (HF-S): Mice were fed a high-fat diet (including 1.25% cholesterol, 15% fat, and 0.5% bile acids) and administered 0.2 mL of saline daily via gavage.

  2. High-fat diet + probiotic group (HF-P): Mice were fed a high-fat diet and administered Lactobacillus (1 × 10^9 CFU/mL, 0.2 mL) daily via gavage.

  3. Normal diet + saline group (ND-S): Mice were fed a normal diet and administered saline daily via gavage.

  4. Normal diet + probiotic group (ND-P): Mice were fed a normal diet and administered Lactobacillus probiotic (1 × 10^9 CFU/mL, 0.2 mL) daily via gavage.

At the end of the first phase, based on observations of body weight, gallstone formation (scoring), liver-to-body weight ratio, and histopathological differences in the liver and gallbladder, Lactobacillus was found to have a protective effect against cholesterol gallstone formation. To further explore the dose-dependence of probiotics and their effect in pretreatment, a second phase was conducted, adding the following two probiotic pretreatment groups(n = 40 per group):

  • 5.

    Probiotic pretreatment (2 weeks) + high-fat diet group (Pre2w-HF): Mice received a 2-week gavage of Lactobacillus (1 × 10^9 CFU/mL, 0.2 mL) before transitioning to a high-fat diet, followed by continued Lactobacillus gavage.

  • 6.

    Probiotic pretreatment (4 weeks) + high-fat diet group (Pre4w-HF): Mice received a 4-week gavage of Lactobacillus before transitioning to a high-fat diet, followed by continued Lactobacillus gavage.

This design allowed us to evaluate the direct effects of probiotics and their efficacy under different pretreatment durations, providing more detailed evidence for the potential application of probiotics in gallstone prevention.

Diet and gavage protocol

The high-fat diet consisted of 1.25% cholesterol, 15% fat, and 0.5% bile acids, while the normal diet contained 10% fat. Both diets were provided by the Laboratory Animal Center of Shihezi University. Lactobacillus was freshly prepared daily and administered via gavage at 0.2 mL per mouse.

Sample collection

During the 8-week experiment, 5 mice from each group were euthanized weekly by cardiac puncture under deep anesthesia. Anesthesia was induced using 1% pentobarbital sodium solution (10 mg/mL) administered via intraperitoneal injection at a dose of 0.1 mL/10 g body weight, which corresponds to 100 mg/kg. This dosage ensures that the mice are in a deep anesthetic state, eliminating pain and consciousness. Cardiac puncture was performed after confirming the absence of reflexes and complete immobility, and the procedure was carried out using sterile syringes to ensure humane euthanasia.

Following euthanasia, the body weight and liver weight of each mouse were recorded. The gallbladder was carefully removed and examined to assess the presence and severity of cholesterol gallstones, which were subsequently scored. (Grade 0:The gallbladder is filled with clear bile, with no stones observed; Grade 1:A few fine crystals are found; Grade 2:Around ten fine crystals are found; Grade 3:Fine crystals occupy about half of the gallbladder; Grade 4:Leaflet or stratified crystals occupy more than half of the gallbladder; Grade 5:Round gallstones are found). Liver and gallbladder tissues were collected for histological analysis.

Histological analysis

Tissues were fixed in 10% formalin, embedded in paraffin, and sectioned at a thickness of 4 μm. Sections were stained with hematoxylin and eosin (H&E) and Oil Red O for histopathological examination. Inflammation severity and hepatic lipid accumulation were assessed using light microscopy.

Statistical analysis

Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test for multiple comparisons. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using GraphPad Prism software (version 8.0).

Results

Gallstone composition analysis

In both the high-fat diet group (HF-S) and the high-fat diet + probiotic group (HF-P), gallstones were observed in the experimental mice. To further determine the composition of these gallstones, infrared spectroscopy analysis was conducted, and the results were compared with the standard cholesterol infrared spectrum (Fig. 1). The results showed that the gallstones were primarily composed of cholesterol. In contrast, no gallstones were found in the mice in the normal diet groups (ND-S and ND-P), further confirming that dietary fat and cholesterol intake play a critical role in gallstone formation.

Fig. 1.

Fig. 1

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Infrared spectrum of gallstones

Liver index of mice

The liver index of the high-fat diet group (HF-S) was generally higher than that of the normal diet group (ND-S), as shown in Fig. 2. Throughout the experiment, the liver-to-body weight ratio in the HF-S group was significantly higher than that in the ND-S group (p < 0.05), indicating that the high-fat diet not only led to weight gain but also significantly increased liver weight. This further confirms the substantial impact of a high-fat diet on liver metabolism. The liver-to-body weight ratio in the high-fat diet group began to rise significantly in weeks 3–4 and then stabilized, while changes in the normal diet group were minimal.

Fig. 2.

Fig. 2

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Liver index of mice

Optimal stone formation time

We used the scoring criteria established by Takashi Akiyoshi [12] to assess gallstones in mice. The gallstone formation score in the high-fat diet group (HF-S) gradually increased over time (Fig. 3). Through one-way analysis of variance (ANOVA), we found significant differences in the rate of gallstone formation across different time points (p < 0.05). This indicates that the probability of gallstone formation significantly increases over time, especially in the latter half of the experiment. Tukey test results show that from week 5 onward, the rate of gallstone formation significantly increases (p < 0.05). Between weeks 6 and 7, the rate of gallstone formation rises significantly (p < 0.05) and reaches a peak at week 7. Optimal Time for Gallstone Formation: Based on the statistical analysis results, weeks 5 to 7 were identified as the optimal period for gallstone formation. Week 5 marks the point where the rate of gallstone formation starts to accelerate significantly, and between weeks 6 and 7, the rate reaches its peak.

Fig. 3.

Fig. 3

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Time-dependent changes in mean gallstone scores

Body weight changes in mice

Repeated measures ANOVA showed that body weight differed significantly between the experimental groups from week 1 to week 8, particularly in weeks 7 (p < 0.05) and 8 (p < 0.05), indicating that different treatments had significant effects on body weight. These results suggest that the cumulative effect of the interventions became more apparent in the later stages of the experiment. As shown in Fig. 4A and B, the body weight of mice in the high-fat diet group (HF-S) increased significantly, with greater weight gain compared to the normal diet groups (ND-S and ND-P). Mice in the probiotic intervention group (HF-P) showed slower weight gain compared to the HF-S group, suggesting that probiotic intervention had a suppressive effect on weight gain. Additionally, in the second phase of the experiment, the body weight of mice in the probiotic pretreatment groups (Pre2w-HF and Pre4w-HF) showed a more moderate increase than in the HF-S group, particularly in the Pre4w-HF group, where weight gain was minimal. These findings suggest that probiotics may play a role in mitigating weight gain induced by a high-fat diet, further supporting the potential protective effects of probiotic pretreatment in controlling weight gain.

Fig. 4.

Fig. 4

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Trend of average body weight changes in mice

Gallstone formation in mice

The gallstone score in the high-fat diet group (HF-S) was significantly higher than in the other groups (p < 0.05), indicating that a high-fat diet significantly induced gallstone formation. The gallstone score in the probiotic intervention group (HF-P) was significantly lower than in the HF-S group (p < 0.05), suggesting that probiotics have a mitigating effect on gallstone formation. The gallstone scores in the probiotic pre-treatment groups (Pre2w-HF and Pre4w-HF) were significantly lower than in the HF-S group (p < 0.05), particularly in the group with 4 weeks of pre-treatment, indicating that a longer period of probiotic pre-treatment provides stronger protection. The normal diet groups (ND-S and ND-P) had overall low gallstone scores, suggesting that a regular diet does not induce gallstone formation (Fig. 5).

Fig. 5.

Fig. 5

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Gallstone scores in mice

Liver pathology in mice

In this study, Oil Red O staining was used to assess the effects of different diets and probiotic interventions on hepatic lipid accumulation in mice (Fig. 6A-F). The normal diet group (Fig. 6A) and the probiotic intervention group (Fig. 6B) exhibited mild lipid accumulation, while the high-fat diet group (Fig. 6F) showed the most severe steatosis. The high-fat diet plus probiotic intervention group (Fig. 6E) showed a certain degree of lipid accumulation, although less pronounced than the high-fat diet group (Fig. 6F), suggesting that probiotic intervention can partially alleviate liver lipid deposition induced by a high-fat diet. The probiotic pretreatment groups (Pre2w-HF and Pre4w-HF; Fig. 6C and D) significantly reduced lipid accumulation induced by the high-fat diet, especially in the 4-week pretreatment group (Fig. 6D), where hepatic lipid deposition was notably reduced. These results indicate that probiotics effectively mitigate the damage caused by a high-fat diet, with more pronounced effects in the pretreatment groups.

Fig. 6.

Fig. 6

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Liver pathology in mice

Discussion

The effect of probiotics on cholesterol gallstone formation

This study found that probiotic intervention has a significant protective effect against cholesterol gallstone formation induced by a high-fat diet. The HF-P group showed significantly reduced weight gain, incidence, and severity of gallstone formation compared to the HF-S group. This finding is consistent with previous research, which suggests that Lactobacillus can modulate the gut microbiota environment and inhibit cholesterol gallstone formation induced by a high-fat diet [7, 13]. Probiotics play a multifaceted role in gallstone formation. Most studies suggest that gut probiotics help prevent gallstone formation [13], but some also indicate that probiotics may promote stone formation under certain pathways or conditions.

First, the bile salt hydrolase (BSH) activity of probiotics may have indirect negative effects on the host. Specifically, BSH activity deconjugates bile salts to generate free bile acids, which can further be converted into secondary bile acids and metabolites such as hydrogen sulfide. These have been linked to the development of colorectal cancer, gallstones, and other gastrointestinal diseases [14]. Secondary bile acids reduce the reabsorption of bile acids in the intestine. This process lowers the solubility of cholesterol in bile, leading to cholesterol precipitation and crystallization, ultimately resulting in gallstone formation. Hydrogen sulfide, a highly toxic compound, has been shown to promote the formation of gallstones [15].Second, probiotics can activate the Farnesoid X receptor (FXR) pathway [16], regulating bile acid metabolism, promoting cholesterol excretion, and reducing cholesterol accumulation in the gallbladder [17–18]. FXR activation not only reduces cholesterol precipitation in the gallbladder but also regulates liver enzymes involved in cholesterol synthesis, further decreasing cholesterol production.Additionally, probiotics ferment dietary fiber to produce short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. These SCFAs activate the PPAR-α receptor, regulate lipid metabolism, reduce fat accumulation in the liver, and decrease cholesterol deposition in the gallbladder. SCFAs also improve gut microbiota balance and reduce inflammatory responses, preventing excessive cholesterol accumulation in the gallbladder and further inhibiting stone formation. Probiotics also enhance intestinal barrier function, reduce the production of inflammatory factors such as TNF-α and IL-6, and lower systemic inflammation, which is crucial for preventing gallstone formation [20].Probiotics demonstrate potential in inhibiting gallstone formation by reducing cholesterol absorption, promoting its metabolic excretion, and decreasing lipid deposition in the liver. However, the specific effects of these mechanisms may vary depending on individual conditions and dietary habits, and further research is needed to clarify their precise role in different environments and conditions. Notably, in our study, probiotics had no significant impact on body weight and liver weight in mice on a normal diet, suggesting that their primary function lies in mitigating metabolic disturbances related to a high-fat diet [19].This indicates that probiotics may reduce gallstone formation by improving lipid metabolism and bile composition, which was further verified in subsequent probiotic pretreatment experiments.

The protective effect of probiotic pretreatment and mechanistic exploration

In the second phase of the experiment, probiotic pretreatment groups were added to explore the dose-dependence and effect of pretreatment. Both the Pre2w-HF and Pre4w-HF groups showed significantly better protective effects against gallstone formation, liver lipid accumulation, and severity compared to the HF-P group, especially in the Pre4w-HF group. This result suggests that the duration of probiotic pretreatment plays a crucial role in its protective efficacy.Pretreatment may allow more stable colonization of probiotics in the gut and optimize the microbial environment, making it more effective in resisting metabolic disturbances induced by a high-fat diet. This finding implies that probiotics’ effect is not only in short-term metabolic regulation but may also involve long-term remodeling of the gut microbiota structure. Given the rising prevalence of gallstone disease and related conditions such as fatty liver, probiotics, as a safe and readily available intervention, hold great promise. By modulating the gut microbiota, probiotics could become a potential preventive or therapeutic method, helping reduce long-term damage to organs such as the liver caused by a high-fat diet. Future research could further explore how probiotics alter gut microbiota composition and function during pretreatment, particularly their role in cholesterol metabolism and bile acid synthesis pathways.

Dose-dependence of probiotics and future applications

This study revealed a possible dose-dependence of probiotics. Although only a fixed dose was used in this study, the differences in effects under different pretreatment times suggest that the dose and timing of probiotic administration may be critical factors affecting its protective efficacy [20]. Future studies should systematically evaluate the effects of different probiotic strains, doses, and administration times on cholesterol gallstone formation to optimize clinical applications.

Study limitations and future research directions

1.Limitation of a Single Probiotic Strain This study only utilized one strain of Lactobacillus for the experiments, which limits the ability to comprehensively compare the effects of different probiotic strains on cholesterol gallstone formation. Future research should extend to multiple probiotic strains to identify the most effective strain or strain combinations. 2. Short Study Duration The study primarily focused on the short-term effects of probiotic intervention, without evaluating the long-term safety and sustained efficacy of probiotics. Future studies should include long-term interventions to assess the prolonged effects of probiotics in preventing gallstone formation. 3. Lack of In-depth Mechanistic Exploration Although this study explored the potential mechanisms of probiotics, it did not delve into the specific molecular pathways involved in regulating cholesterol metabolism and bile acid synthesis. Future research could utilize metabolomics and transcriptomics to uncover the key molecular pathways by which probiotics exert their effects. 4. Differences Between Animal Models and Humans This study was conducted using a mouse model, which, although useful for investigating gallstone formation, may not fully replicate the physiological conditions in humans. Further clinical trials in humans are necessary to validate the efficacy of probiotics. 5. Fixed Dose and Duration The study used a fixed dose of probiotics (1 × 10⁹ CFU/mL) and did not explore the effects of varying doses or intervention durations on gallstone formation. Future studies should evaluate different dosages and intervention timelines to optimize clinical application strategies. 6. Limited Dietary Factors The experiment induced gallstone formation using a high-fat diet but did not consider the potential effects of other dietary patterns, such as high-sugar or high-salt diets. Future research should explore the efficacy of probiotics under various dietary conditions.

Conclusion

This study evaluated the role of probiotics in preventing cholesterol gallstone formation, particularly the effects of probiotic pretreatment on gallstone formation induced by a high-fat diet. It provides new perspectives for the clinical application of probiotics in cholesterol gallstone prevention. The potential role and mechanisms of probiotics in gallstone formation warrant further investigation, which will provide a foundation for developing more effective strategies for cholesterol gallstone prevention and treatment.

Acknowledgements

Not applicable.

Abbreviations

HF-S

High-fat diet + Saline group

HF-P

High-fat diet + Probiotic group

ND-S

Normal diet + Saline group

ND-P

Normal diet + Probiotic group

Pre2w-HF

2-week Probiotic Pretreatment + High-fat diet group

Pre4w-HF

4-week Probiotic Pretreatment + High-fat diet group

CFU

Colony-Forming Units

H&E

Hematoxylin and Eosin

SCFAs

Short-Chain Fatty Acids

BSH

Bile Salt Hydrolase

FXR

Farnesoid X Receptor

TNF-α

Tumor Necrosis Factor Alpha

IL-6

Interleukin 6

ANOVA

Analysis of Variance

Author contributions

CW: Conceptualization, Research design, Data analysis, Writing– original draft, Writing– review & editing; TJ: Research design, Experimental process, Data analysis, Writing– original draft, Writing– review & editing; LWY and MYD: Research design, Data analysis, Experimental process; FL: Research design, Writing– review & editing, Technical guidance during the experimental process; All authors revised the manuscript and approved the final version.

Funding

Xinjiang Production and Construction Corps Guiding Science and Technology Program (2022ZD086, 2023ZD006).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethical approval

This study has been approved by the Ethics Review Committee of the School of Medicine, Shihezi University.

Consent for publication

This item is not applicable to this study.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cong Wang and Ting Jiang share co-first authorship.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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