Cholecystectomy-induced gut dysbiosis and its consequences: bridging animal models and clinical outcomes in narrative review

Introduction

The gallbladder plays a crucial role in storing, concentrating, and releasing bile acids into the intestine. These bile acids are synthesized from cholesterol in the liver and are known as primary bile acids (1). Approximately 85% of primary bile acids are stored in the gallbladder. Within the gallbladder, the primary bile acids are concentrated through the absorption of water and phospholipid-cholesterol vesicles. Under physiological conditions, these concentrated bile acids are released into the small intestine during the postprandial phase for fat digestion and absorption. Approximately 95% of these primary bile acids are reabsorbed in the distal ileum into enterohepatic circulation, while the remaining 5% of these bile acids are transformed to secondary bile acids by gut microbiota in the colon.

Cholecystectomy is a common surgical procedure for gallstones or cholecystitis (2). This procedure leads to the absence of concentrated primary bile acids entering the intestine and alters their regular secretion pattern. The pulsatile release in response to meals is lost, resulting in continuous low-volume primary bile acid flow. This change is mainly driven by a cholesterol concentration gradient between the bile duct and intestinal lumen, called “gallbladder-independent biliary cholesterol output” (1). In the terminal ileum, the primary site of bile acids reabsorption, continuous primary bile acid flow disrupts normal enterohepatic circulation. To compensate for this disruption, the intestine increases bile acid degradation and attempts to reabsorb primary bile acids back into the enterohepatic circulation (3). Despite these compensatory mechanisms, significant amounts of bile acids remain in the colon, disrupting the gut microbial ecology.

Gut microbiota comprises microorganisms colonizing the intestine, predominantly bacteria, with smaller populations of fungi and bacteriophages (4). The major bacterial phyla include Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Acting like a virtual organ, the gut microbiota supports host health by facilitating digestion, producing short-chain fatty acids (SCFAs), which serve as an energy source for colonocytes and contribute to the metabolism of the host (5). In addition, the gut microbiota regulates the host’s immune system to prevent infections and modulate metabolic function. Disruption of the composition of the microbiota, known as gut dysbiosis, has been associated with intestinal inflammation, metabolic disorders, and increased risk of tumorigenesis, such as colorectal cancer (CRC) (6,7).

Previous studies have suggested that cholecystectomy may disrupt gut microbiota balance (8-10). Therefore, this review aims to summarize and discuss the impact of cholecystectomy on the gut microbiota and its potential consequences for host health, drawing on evidence from in vivo to clinical studies. Contradictory findings are also included and discussed. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0007/rc).

Methods

The search criteria included original research articles in English published in MEDLINE, Scopus, and Web of Science from March 2015 to March 2026. The following search terms were used: “post-cholecystectomy”, “gut microbiota”, and “gut microbiome”. The detailed search strategy is summarized in Table 1.

Impact of cholecystectomy on gut microbiota profiles and metabolomic pathways: evidence from clinical studies (compared to healthy controls)

After gallbladder removal, continuous secretion of bile acids has been shown to increase the amount of primary bile acids in the colon (1,11,12). This change may affect the gut microbiota. To study these effects, several studies had analyzed fecal samples and colonic tissue, using 16S rRNA gene sequencing. The results from a range of studies showed differences in the overall composition of the gut microbiota (beta diversity) between post-cholecystectomy patients and healthy controls (9,10,12-17). Notably, these differences were detectable as early as three months after cholecystectomy and persisted for more than five years (11,12,18,19). These alterations were attributed to the continuous flow of primary bile acids into the colon, leading to rapid shifts and persistent changes in beta diversity. Focusing within the post-cholecystectomy group, alpha diversity was assessed to evaluate the number and balance of the microbiota in each patient. Alpha diversity remained relatively stable during the first year but declined thereafter, indicating a progressive loss of microbial richness over time. The initial stability likely reflected functional redundancy among gut microbes. Over the long term, prolonged exposure to altered primary bile acids in the colon might gradually reduce alpha diversity (8,10,15,20).

At the taxonomic level, the persistently primary bile acid-rich environment favored the enrichment of bile acid-metabolizing genera (Bacteroides, Parabacteroides, Clostridium), along with bile-resistant pathobionts (Escherichia/Shigella). In contrast, bacteria sensitive to elevated primary bile acids, including SCFA-producing genera (Faecalibacterium, Roseburia) and Bifidobacterium, were consistently reduced. Prevotella, however, showed inconsistent changes across studies (10-15,21).

After cholecystectomy, bile acid-metabolizing taxa such as Bacteroides, Parabacteroides, and Clostridium were enriched (10-13). These bacteria produced bile salt hydrolase (BSH), which deconjugated primary bile acids, a key step in secondary bile acid formation. This bile acid utilization supported the growth of these bile acid-metabolizing bacteria (4,19). In this process, BSH-modified primary bile acids became more water-soluble and exerted a reduced detergent effect on the colonic microbiota. These changes promoted bacterial outgrowth in this group, increasing their abundance in post-cholecystectomy patients (12,13,21). Additionally, Clostridium and Bacteroides exhibited high 7α-dehydroxylase activity, enabling conversion of primary bile acids to secondary bile acids (19). Consequently, secondary bile acid levels, particularly deoxycholic acid (DCA) and lithocholic acid (LCA), were increased in post-cholecystectomy patients. These secondary bile acids were hydrophobic and cytotoxic in nature (22,23). They could promote inflammation in the gut epithelium and disrupt farnesoid X receptor (FXR) signaling in the distal ileum and colon. These inflammatory and signaling changes might contribute to long-term systemic metabolic effects in the host, potentially mediated by persistent bile acid dysregulation following cholecystectomy (11,24).

In addition to bile acid-metabolizing genera, other bile acid–resistant bacteria, including pathobionts such as Escherichia/Shigella, particularly the polyketide synthase-positive (pks+) E. coli strain, also grew more extensively in the bile-rich environment (10,11). This strain could upregulate the genes involved in the biosynthesis of primary and secondary bile acids (11). In addition, they released lipopolysaccharides (LPS) from their Gram-negative outer membranes (10,21). LPS-activated immune cells, particularly monocytes and macrophages, via clustering of differentiation 14 (CD14) receptor and toll-like receptor 4 (TLR4). This activation triggered the production of reactive oxygen species (ROS) and exacerbated any intestinal inflammation (11).

In contrast, the SCFA-producing genera, including Faecalibacterium and Roseburia, were reduced in a bile acid-rich environment (25,26). This reduction decreased the production of SCFAs, particularly butyrate. Butyrate was found to act as an anti-inflammatory metabolite and maintained gut barrier integrity (10,12). Low levels of butyrate impaired the energy supply of colonocytes, causing cellular stress and reducing the expression of tight junction proteins and mucus secretion. These changes compromised the integrity of the gut barrier, permitting translocation of endotoxins, including LPS and secondary bile acids, into the circulation. This process subsequently triggered systemic inflammation, a phenomenon commonly referred to as gut leakiness (7,12,27). In addition, reduced butyrate potentially attenuates the secretion of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells in the colon, contributing to metabolic dysfunction in the host (18).

Bifidobacterium, a commensal bacterium in the colon, was reduced in a bile acid-rich environment after cholecystectomy (12). This reduction was associated with lower acetate and lactate production, which serve as substrates for butyrate-producing bacteria (27). Consequently, decreased butyrate synthesis impaired anti-inflammatory functions and compromised gut barrier integrity (28). Over time, some studies reported a partial recovery or even an increased abundance of Bifidobacterium at later post-cholecystectomy time points (14,24). This pattern suggested an initial reduction followed by gradual recovery. However, the functional consequences of these temporal changes remained unclear.

Prevotella showed an inconsistent pattern across the various pieces of research. Several studies in Chinese population compared post-cholecystectomy patients with healthy controls and the authors reported an increase in Prevotella within the first year after surgery, whereas a decline of Prevotella was observed beyond five years (12-15). Given that the included cohorts were geographically similar and applied comparable sampling and sequencing methods, follow-up duration appeared to be the primary factor underlying these divergent findings. The early increase may have reflected the continuous flow of bile acids and a temporary change in intestinal transit, which may have favored its growth. In contrast, the decline beyond five years indicated that bile acid metabolism and gut environment eventually stabilized. This stabilization may have reduced the ecological pressure that initially promoted the expansion of Prevotella. Prevotella is a key genus involved in carbohydrate fermentation and SCFA production, and also contributes to the maintenance of intestinal bile acid homeostasis. Such fluctuations could stimulate the fermentation of carbohydrate into SCFAs and disrupt the balance between primary and secondary bile acids in the intestine, potentially influencing intestinal metabolic stability (8,10). All these findings are summarized in Table 2.

In addition to clinical studies which compared post-cholecystectomy patients with healthy controls, Mendelian randomization studies provided genetic evidence to support a potential causal link between cholecystectomy and alterations in the gut microbiota. These findings suggested that post-cholecystectomy microbial changes were not solely attributable to other confounding clinical factors, indicating a direct effect of gallbladder removal on gut microbial composition (29,30).

Based on these observations, we proposed the concept of the “post-cholecystectomy bile acid-microbiota-host axis” to describe how elevated primary and secondary bile acids reshape the composition of the gut microbiota, reduce beneficial metabolites, and influence systemic inflammation and metabolic function, as shown in Figure 1.

Figure 1 Post-cholecystectomy bile acid-microbiota-host axis and its consequences. This schematic diagram illustrates the “post-cholecystectomy bile acid-microbiota-host axis”. Cholecystectomy disrupts physiological bile acid flow and is associated with gut dysbiosis characterized by enrichment of bile acid-metabolizing and bile acid-resistant bacteria and depletion of short-chain fatty acid-producing taxa. These microbial alterations may reduce butyrate availability, impair gut barrier function, and promote intestinal and systemic inflammation. Increased levels of secondary bile acids activate serotonin (5-HT) signaling via TGR5 and TRPA1, accelerating intestinal motility and secretion and contributing to PCD. Persistent dysbiosis and inflammation further contribute to metabolic disturbances, potentially increasing the risk of NAFLD, metabolic syndrome, and colorectal cancer. High-fat diet consumption may exacerbate dysbiosis-associated intestinal inflammation and metabolic disturbances, whereas bile acid sequestrants may provide partial protective benefits. Solid arrows indicate established mechanisms, whereas dashed arrows represent hypothesized pathways. 2° BAs, secondary bile acids; 5-HT, 5-hydroxytryptamine; Abcb11, ATP-binding cassette subfamily B member 11; BAS, bile acid sequestrant; CRC, colorectal cancer; Cyp7a1, cholesterol 7α-hydroxylase; Cyp7b1, oxysterol 7α-hydroxylase; DNA, deoxyribonucleic acid; FGF15/19, fibroblast growth factor 15/19; FXR, farnesoid X receptor; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; HFD, high-fat diet; LPS, lipopolysaccharide; NAFLD, non-alcoholic fatty liver disease; PCD, post-cholecystectomy diarrhea; ROS, reactive oxygen species; SCFAs, short-chain fatty acids; Srebp1c, sterol regulatory element-binding protein 1c; TGR5, Takeda G-protein-coupled receptor 5; TLR4, Toll-like receptor 4; TRPA1, transient receptor potential ankyrin 1.

Impact of cholecystectomy on gut microbiota profiles and metabolomic pathways: evidence from clinical studies (compared to patients with gallstones)

Gallstones with complications are a common indication for cholecystectomy. Gallstones are associated with metabolic abnormalities and alterations in bile acid metabolism. A reduced bile acid pool, together with an increase in secondary bile acids, contributes to a decrease in cholesterol solubility in patients with gallstones (31). This change facilitates nucleation and promotes the formation of gallstones. Bile stasis in the gallbladder and mucin hypersecretion further support crystal growth. Consequently, patients with gallstones were shown to exhibit altered primary and secondary bile acid profiles in the bile in comparison with healthy controls (16,31,32). These changes might affect the composition of the gut microbiota. Alpha diversity was reduced in gallstone patients compared with healthy controls. This reduction was accompanied by increased abundance of Oscillospira, Bacteroides, Prevotella, and Escherichia/Shigella, and decreased levels of Roseburia and other SCFAs-producing genera (9,10,19,33,34).

Compared with healthy controls, patients with gallstones exhibited some imbalance in their gut microbiota before cholecystectomy. Following the surgery, further alterations in gut microbiota were observed. Beta-diversity shifted rapidly, as early as three months after gallbladder removal. This change likely reflected a response to the continuous flow of primary bile acids (19,35). In contrast, alpha diversity adjusted more gradually, with significant changes after two years. The temporal dynamic changes in gut microbiota in post-cholecystectomy patients compared with gallstone patients were similar to those observed in our previous comparison with healthy controls. Specifically, this similarity reflected rapid shifts in beta-diversity and more gradual changes in alpha-diversity, likely associated with long-term alterations in bile flow dynamics after cholecystectomy. However, the trajectory of alpha diversity changes differed between the two comparator groups. In post-cholecystectomy patients compared with gallstone patients, the decline in alpha diversity was slower. The slower decline likely reflected the reduced resilience of their microbial community (36). In patients with gallstones, pre-existing dysbiosis likely limited the ability of the microbiota to respond promptly to the changes induced by cholecystectomy. This resistance to change might explain the slower decline in alpha diversity observed postoperatively.

Despite the overall slow change, several bile acid-metabolizing bacterial taxa increased rapidly after cholecystectomy. Clostridium genera, in particular, showed a marked rise within one to three days post-surgery (37), whereas Bacteroides and Parabacteroides increased more gradually. In parallel, bile acid-resistant pathobionts such as Escherichia/Shigella also expanded. At the same time, the abundance of SCFA-producing bacteria, including Lachnospira and Roseburia, declined. All these findings are summarized in Table 3.

These microbial shifts were associated with functional consequences similar to those observed in comparison with healthy controls, including alterations in bile acid metabolism, increased production of LPS, and reduced levels of SCFA, as mentioned in section “Impact of cholecystectomy on gut microbiota profiles and metabolomic pathways: evidence from clinical studies (compared to healthy controls)” and shown in Figure 1. Taken together, these findings indicated that the pattern of microbial and functional changes following cholecystectomy occurs similarly across different baseline states of the microbiota. Healthy controls had balanced communities, whereas gallstone patients exhibited pre-existing dysbiosis, which influenced the magnitude and timing of microbial adjustments.

Collectively, evidence from post-cholecystectomy patients highlighted the consistent impact of surgery on gut microbial remodeling. Altered bile flow following gallbladder removal drove the expansion of bile acid-metabolizing and bile acid-resistant taxa while reducing the abundance of SCFA-producing bacteria. These compositional and functional changes disrupted bile acid metabolism and intestinal homeostasis. Notably, this pattern appeared consistent across different baseline microbial states, supporting cholecystectomy as a key factor of the remodelling of the gut microbiota independent of any pre-existing dysbiosis.

Impact of cholecystectomy on gut microbiota profiles and metabolomic pathways: evidence from in vivo studies

Animal models have been widely used to investigate the impact of cholecystectomy on gut microbiota, providing mechanistic insights that complement clinical studies. In these models, continuous exposure to primary bile acids after cholecystectomy significantly altered bacterial beta diversity at six weeks compared with the sham-operated mice (38), as shown in Table 4. In addition, the alpha diversity increased at three months after surgery (24). These findings indicated that cholecystectomy induced gradual remodeling of the gut microbial community over time in animal models, with patterns similar to those observed in clinical studies. At the taxonomic level, the proportions of bile acid-metabolizing bacteria, including Lactobacillus (some species), Clostridium, Ruminococcus, and Enterococcus, were increased. In contrast, Bifidobacterium was decreased.

Following cholecystectomy, animal models showed an increase in bile acid-metabolizing bacteria. This expansion led to elevated levels of secondary bile acids in the colon as early as three weeks post-surgery, which induced that following colonocyte injury (24,28,38). As a consequence, apoptosis occurred and epithelial integrity was compromised, as evidenced by decreased mRNA expression of tight junction proteins, including zonula occludens-1 (ZO-1) and occludin, as early as four weeks after cholecystectomy (28,40). By eight weeks, a concomitant reduction in goblet cell numbers further weakened the colonic mucus layer (39). Together, these changes impaired gut barrier function, permitting translocation of microbial products and LPS into the lamina propria and provoking localized inflammation. This local inflammatory response was associated with an increase in the expression of the interleukin-10 (IL-10) gene in the colonic tissue, reflecting a compensatory anti-inflammatory mechanism (38). Over time, microbial products could also enter the systemic circulation, thereby extending inflammation beyond the gut and contributing to systemic inflammation.

The elevation of secondary bile acids in the colon after cholecystectomy may potentially disrupt the FXR-fibroblast growth factor 15 (FGF15) signaling axis in intestinal epithelial cells in mice. As FGF15 regulates hepatic bile acid metabolism via the gut-liver axis, disruption of the FXR-FGF15 axis resulted in upregulation of hepatic cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 7α-hydroxylase (Cyp7b1) mRNA by six weeks post-cholecystectomy (38,40). Consequently, bile acid synthesis was enhanced through both the classical and alternative pathways to compensate for increases in fecal bile acid loss. In parallel, hepatocytes upregulated the ATP-binding cassette subfamily B member 11 (Abcb11) gene, which encoded the bile salt export pump (BSEP) in the liver, thereby increasing the secretion of bile acids into the bile canaliculi and hence maintaining bile acid homeostasis. Beyond bile acid homeostasis, reduced intestinal FGF15 signaling diminished hepatic FXR activity. This, in turn, increased the expression of sterol regulatory element-binding protein 1c (Srebp1c), a key transcription factor that promoted de novo lipogenesis, which might contribute to the accumulation of hepatic triglycerides and hepatic inflammation (39). Hepatic inflammation was also a consequence of the direct cytotoxic effects of hydrophobic secondary bile acids, which returned to the liver via the enterohepatic circulation and modulated inflammatory signaling through FXR and Takeda G-protein-coupled receptor 5 (TGR5) in hepatocytes (18,41,42). This hepatic inflammation was confirmed by elevated expression of tumor necrosis factor-alpha (TNF-α) mRNA and increased lipid peroxidation in the liver (39,40,42). It also resulted in higher serum levels of alanine aminotransferase (ALT), a marker of liver injury consistent with clinical observations. Together, altered bile acid metabolism, elevated triglyceride levels, and hepatic inflammation promoted early non-alcoholic fatty liver disease (NAFLD) in mice (38-40,42). These changes progressed to liver fibrosis, which was detectable as early as eight weeks after cholecystectomy, as shown in Figure 1.

In parallel, animal models showed that a reduction in Bifidobacterium led to a decrease in energy supply to colonocytes, particularly affecting butyrate synthesis (27,28,39). This caused colonocyte injury and downregulation of the expression of the tight-junction gene as early as four weeks after cholecystectomy (28). It consequently impaired gut barrier function. In addition, reduced butyrate also raised colonic pH and lowered oxygen consumption of the colonocytes (4,27). These changes favored facultative anaerobic pathobionts and further aggravated dysbiosis in the colon.

Comparative timelines across studies also suggest that functional and metabolic shifts in the gut microbiota occur rapidly after cholecystectomy. Secondary bile acids, for example, increased within three weeks after surgery, preceding the typical decline in microbial diversity that appeared after three months (24,42). This sequence is biologically plausible, as small increases in specific bacteria or enzyme activities could alter metabolite levels and host signaling before measurable losses in microbial richness or evenness (28). In contrast, alpha diversity tended to decrease later, likely reflecting sustained selective pressures or the loss of bacterial taxa. Therefore, early functional and metabolic alterations may be more sensitive indicators of post-cholecystectomy dysbiosis than community-level diversity measures.

In summary, animal and clinical studies indicate that the gut microbiota gradually remodels over time after cholecystectomy. In mice, this dysbiosis increased secondary bile acids, disrupted FXR-FGF15 signaling, increased hepatic triglycerides, and hepatic inflammation. These findings help to explain clinical observations in both healthy controls and gallstone patients, including impairment of gut barrier function, elevated serum ALT, and early NAFLD progression, as shown in Figure 1. The temporal sequence of functional and compositional changes highlights their potential to contribute to systemic inflammation, metabolic disorders, and other clinically relevant outcomes, as discussed in the following section.

Impact of dietary fat following cholecystectomy on gut microbiota profiles and metabolomic pathways: evidence from in vivo studies

High-fat diet (HFD) consumption

Dietary patterns profoundly influence long-term metabolic health, partly through alterations of bile acid metabolism and gut microbiota composition (22,23). In particular, a HFD alters bile acid profiles, providing excess nutrients for gut microbes and promoting intestinal inflammation. Following cholecystectomy, these dietary effects may be amplified, accelerating gut microbial communities and metabolic shifts. In animal models, post-cholecystectomy mice fed an HFD (43–60% kcal from fat) developed a distinct gut microbial profile compared with those fed a low-fat diet (LFD, 10–20% kcal from fat) (38,39). Beta diversity changed as early as three weeks after surgery, while alpha diversity reduced by six weeks. These shifts occurred earlier than those typically observed in post-cholecystectomy mice fed a standard diet, where beta and alpha diversity changed at six weeks and three months, respectively, as shown in Table 4. These findings indicate that dietary fat intake could significantly modulate the dynamics of the gut microbiota after cholecystectomy (38,39).

At the taxonomic level, bile acid-metabolizing bacteria, including Bacteroides, Parabacteroides, and Clostridium, were increased in post-cholecystectomy mice fed an HFD compared with those mice an LFD. This expansion contributed to elevated secondary bile acids, which promoted epithelial inflammation by triggering the production of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and TNF-α in the colon (38). Furthermore, elevated levels of secondary bile acids promoted the expansion of bile-resistant pathobionts, including Escherichia/Shigella, which produced LPS. Consumption of an HFD further compromised the intestinal barrier. A mucin-degrading bacterium, Akkermansia, increased in the colon, utilizing the epithelial mucus as an energy source, leading to thinning of the protective mucosal layer (39). Concurrently, Desulfovibrio also increased, producing hydrogen sulfide which disrupted epithelial tight junctions (38). Together, these alterations in post-cholecystectomy mice fed an HFD compromised the integrity of the gut barrier and promoted a pro-inflammatory colonic environment.

Conversely, SCFA-producing genera, including Lachnoclostridium, Ruminiclostridium, and Anaerotruncus, decreased in post-cholecystectomy mice fed an HFD (38). This reduction led to lower levels of butyric acid in the gut. The loss of these beneficial metabolites contributed to local inflammation in the colon and promoted systemic inflammatory responses. These intestinal inflammatory signals impact the liver via the gut-liver axis, reinforcing a cycle of gut dysbiosis and metabolic disturbances.

In post-cholecystectomy mice fed an HFD, liver inflammation developed earlier, and metabolic disturbances were more severe. Signs of hepatic inflammation consistently appeared by six weeks post-surgery, compared with eight weeks in mice on a standard diet (39,40). Early inflammation in the HFD group was potentially driven by hepatic lipid accumulation, as indicated by increased expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ) mRNA, consistent with its role in lipid metabolism and NAFLD development (39,43). Mice fed an HFD exhibited increased body weight, visceral fat accumulation, and a higher risk of insulin resistance, as evidenced by elevated levels of serum insulin and increased homeostatic model assessment for insulin resistance (HOMA-IR) scores, suggesting greater susceptibility to the development of metabolic syndrome (38,39). All these findings are summarized in Table 5.

In summary, in post-cholecystectomy mice, consumption of an HFD accelerated and exacerbated gut dysbiosis compared with an LFD group. Gut dysbiosis and its downstream effects on intestinal inflammation, barrier dysfunction, and liver metabolism were more pronounced in HFD-fed mice than in those on an LFD. These findings also highlighted that an HFD exacerbated metabolic disturbances, as shown in Figure 1.

Bile acid sequestrants (BAS) and pharmacological modulation

Bile acids play a key role in the remodeling of the gut microbiota and host metabolism after cholecystectomy. BAS, such as cholestyramine, have therefore been explored with the aim of potentially modulating bile acid-driven microbial alterations (39). By binding intestinal bile acids and reducing their reabsorption, BAS alter the gut microbial environment and reduce circulating low-density lipoprotein (LDL) cholesterol levels. Preliminary evidence from a single study in post-cholecystectomy mice fed an HFD showed that the BAS treatment altered the composition of the gut microbiota in comparison with mice not receiving BAS (39). The BAS-treated group exhibited distinct beta diversity profiles and an increase in alpha diversity. These changes indicated that BAS reduced bile acid-induced stress on the gut microbiota, promoting the growth of suppressed commensals and partially restoring microbial richness and community structure (39).

At the taxa-specific level, some changes continued to exhibit changes in abundance. For example, Clostridium remained elevated, and Lactobacillus reduced, scenarios which may contribute to increased intestinal inflammation (39). On the other hand, Blautia abundance increased, a scenario potentially linked to higher colonic goblet cell numbers, suggesting localized protective effects on the intestinal barrier (44).

Despite partial improvements in the gut microbiota, the BAS-treated group still exhibited persistent disturbances in lipid metabolism and signs of liver inflammation (39). These changes indicated ongoing progression toward NAFLD. Overall, BAS had limited systemic metabolic impact, and serum LDL levels remained unchanged. Although gut microbial richness improved, these metabolic changes did not translate into significant recovery.

Interestingly, in comparison with the LFD group without BAS treatment, the alpha diversity of BAS-treated HFD mice appeared closer to that of LFD-fed mice (39). This finding suggested partial restoration of the microbiota after BAS treatment. However, metabolic impairments persisted, indicating that dietary composition remained a stronger determinant of host-microbiome homeostasis than pharmacological modulation of bile acids.

However, several limitations must be considered. The eight weeks of BAS treatment may have been too short to induce significant intestinal and hepatic effects (39). The study by Park et al. did not specify the BAS dose, which limits conclusions about its therapeutic potential (39). Finally, as this evidence is derived from a single animal study, caution is needed when translating these findings to clinical settings.

In post-cholecystectomy mice fed an HFD, BAS altered the composition of the gut microbiota, reducing intestinal inflammation, and improving barrier integrity in comparison with untreated controls. However, the BAS treatment only partially restored microbial diversity and metabolic balance. These findings suggest that pharmacological intervention with BAS alone cannot fully reverse HFD-induced dysbiosis.

All these findings are summarized in Table 5. In summary, findings from animal models indicated that consumption of an HFD accelerated gut dysbiosis and inflammation following cholecystectomy, whereas BAS partially restored microbial diversity and gut barrier function. However, systemic metabolic disturbances were not fully reversed. These findings highlight the importance of optimizing dietary composition to maintain gut and metabolic health in post-cholecystectomy patients.

Impact of cholecystectomy on gut microbiota profiles associated with CRC: evidence from clinical and in vivo studies

Following cholecystectomy, altered bile flow may disrupt bacterial metabolism in the gut. Consequently, these bacteria produce pro-inflammatory compounds. Chronic exposure to these metabolites can induce oxidative stress and DNA damage in the colon (45). Over time, these pathological changes may promote epithelial dysplasia and increase the risk of malignancy. Epidemiological studies support this link. Data from the Korean National Health Insurance Service reported an overall cancer incidence of 9.56 per 1,000 person-years among post-cholecystectomy patients (45), whereas the UK General Practice Research Database reported rates up to 119 per 1,000 person-years (46). Among reported malignancies, CRC has received particular attention. The colon, a site of secondary bile acid accumulation and high microbial metabolic activity, may be especially susceptible to tumor development. Epidemiological studies reported a CRC relative risk of 1.11 to 2.27, with right-sided colon cancer carrying the highest risk of up to 3.5 (45-47).

Although epidemiological studies reported an elevated CRC risk after cholecystectomy, genetic studies indicated that the surgery itself was not a direct cause (48). Instead, current evidence suggests that the increased risk of CRC after cholecystectomy might be associated with alterations in the gut microbiota rather than the surgery itself. In support of this idea, clinical studies showed that the gut microbiota profiles of post-cholecystectomy patients closely resembled those observed in CRC patients, particularly five years after surgery, as shown in Table 6. These findings pointed to a potential association between cholecystectomy-induced dysbiosis and CRC-related microbial patterns (12,13). Specific bacterial taxa were altered in post-cholecystectomy patients with CRC. Notably, E. coli, particularly pks⁺ strains, were more abundant in post-cholecystectomy patients with CRC than those without CRC. These strains were associated with alterations in bile acid metabolism and may have contributed to increased production of secondary bile acids. In addition, they also secreted the genotoxin colibactin. Colibactin induced chromosomal instability and DNA damage in the colonic epithelial cells, which could promote cell proliferation and tumor invasion (11,49). In addition, Megamonas funiformis was shown to be associated with CRC development and progression in post-cholecystectomy patients (12). Although a direct causal role of Megamonas funiformis in CRC has yet to be established, several studies have suggested that it might serve as a potential biomarker for detection of CRC.

Similarly, studies in animal models have further confirmed that cholecystectomy-induced gut dysbiosis, rather than the surgery itself, might contribute to CRC tumorigenesis. In antibiotic-treated mice lacking gut microbiota, cholecystectomy did not induce CRC (28). In contrast, mice with intact gut microbiota developed dysbiosis after cholecystectomy, which was associated with tumor formation. These results suggested that dysbiosis might contribute to tumor development. To further investigate the bacterial changes associated with CRC, the conventional mice that developed CRC after cholecystectomy were examined (28). These mice exhibited gut dysbiosis, with increased bile acid-metabolizing bacteria, such as Ruminococcus gnavus, and decreased Bifidobacterium breve, in comparison with mice that underwent cholecystectomy but did not develop CRC (28). This dysbiosis was associated with an elevation of fecal secondary bile acids, particularly tauroursodeoxycholic acid (TUDCA). Notably, the elevation of TUDCA was observed in both inflammation-induced CRC models [azoxymethane/dextran sulfate sodium (AOM/DSS)] and adenoma-carcinoma models [adenomatous polyposis coli mutant, (APC^min/+)], suggesting that elevated secondary bile acids might contribute to colorectal tumorigenesis and progression through metabolite-induced pathological mechanisms (28,50). Mechanistically, TUDCA inhibited FXR signaling and disrupted the interaction of FXR/β-catenin. FXR normally acts as a tumor suppressor in the colon by regulating cell proliferation and apoptosis. Inhibition of FXR by TUDCA might relieve this tumor-suppressive effect, thereby potentially contributing to colorectal tumorigenesis and progression through multiple pathways (28,41,50). All these findings are summarized in Table S1.

Findings from both clinical and animal studies indicated that cholecystectomy-induced alterations in bile acid metabolism reshaped the gut microbiota. This remodeling might promote a pro-inflammatory and pro-tumorigenic environment, as shown in Figure 1. However, current evidence remains limited and does not establish a definitive causal relationship between post-cholecystectomy microbiota changes and CRC development. The current understanding of this process remains largely speculative. Therefore, well-designed, long-term prospective studies are needed to clarify this association and determine its clinical significance.

Impact of cholecystectomy on gut microbiota profiles associated with post-cholecystectomy syndrome (PCS) or post-cholecystectomy diarrhea (PCD): evidence from clinical and in vivo studies

Cholecystectomy is an effective treatment for gallstone disease, but it is often associated with post-operative gastrointestinal complications. PCS encompasses gastrointestinal symptoms following gallbladder removal. One of the most common symptoms of PCS is PCD, which occurs in approximately 28.1% to 57.8% of patients (16,20). In some individuals, diarrhea persists for months or years. Mendelian randomized analysis indicated that cholecystectomy increased the risk of irritable bowel syndrome (IBS), likely representing bile acid-related diarrhea with clinical features overlapping those of PCD (30,48). Two independent cohorts reported odds ratios of 7.537 and 4.077, highlighting a markedly elevated risk (29,48). These findings suggested that post-cholecystectomy IBS/PCD might be mediated by gut microbiota alterations and bile acid malabsorption. However, the direct causal contribution of serum bile acids or microbiota changes remains incompletely defined.

To explore these mechanistic pathways, clinical and in vivo studies have compared microbial and metabolic profiles between symptomatic and asymptomatic patients after cholecystectomy. In clinical cohorts, patients with PCS exhibited distinct gut microbiota compositions in comparison with those without symptoms (51). The Firmicutes/Bacteroidetes ratio was decreased in the PCS group, with a relative reduction in SCFA-producing Firmicutes (51,52). These compositional changes show a correlation with dyspeptic and abdominal pain symptoms, suggesting that mild dysbiosis contributed to impaired mucosal and metabolic homeostasis. Gut dysbiosis has been reported in PCD patients, characterized by altered beta diversity and reduced alpha diversity in comparison with post-cholecystectomy individuals without diarrhea. These patients exhibited an increased abundance of Clostridium and Prevotella, as well as unidentified Lachnospiraceae taxa (15,17,32). In contrast, Lactobacillus and Lactococcus were markedly reduced. These microbial changes not only characterized PCD but might also influence bile acid metabolism, providing a potential mechanistic link to persistent gastrointestinal symptoms.

Consistent with these findings, increased abundance of the genera Clostridium and Prevotella, along with unidentified Lachnospiraceae taxa in PCD patients, was associated with elevated levels of secondary bile acids, particularly DCA, LCA, TUDCA, and hyodeoxycholic acid (HDCA). These bile acids were linked to enhanced tryptophan-serotonin metabolic activity. Together, these microbial and metabolic shifts potentially accelerated intestinal transit and secretion, providing a likely mechanism for chronic diarrhea after cholecystectomy (16,17,32). Faster colonic transit might further reduce populations of slow-growing commensal bacteria, thereby exacerbating gut dysbiosis. In parallel, the reduction of Lactococcus, a beneficial genus within the Lactobacillaceae family, was associated with a decrease in lactic acid production through carbohydrate fermentation. This lactic acid normally helps to maintain gut pH and inhibit pathogen growth. Consequently, the reduction of Lactococcus might weaken colonization resistance and increase the risk of PCD (15). Collectively, these findings from clinical studies indicate that a combination of microbial dysbiosis, elevated secondary bile acids, altered tryptophan-serotonin metabolism, and loss of Lactococcus might contribute to PCD. All these findings are summarized in Table 7.

Similarly, studies in animal models provided mechanistic insights supporting these clinical observations. Microbial composition differed between PCD and non-PCD mice, reflected by changes in beta diversity, as shown in Table S2. Additionally, alpha diversity was also reduced in PCD mice, indicating a loss of microbial richness and evenness (17). Correspondingly, enrichment of the genus Clostridium and unidentified Lachnospiraceae taxa was observed in these mice. These taxa have been shown to produce hydrophobic secondary bile acids, including DCA, LCA, and HDCA. These bile acids affected the intestinal epithelium and activated TGR5 and transient receptor potential ankyrin 1 (TRPA1) (53). TGR5 activation stimulated the cyclic adenosine monophosphate (cAMP) signaling pathway, which promoted serotonin synthesis and release from enterochromaffin cells in the gut (17). In addition, TRPA1, an ion channel in gut cells, might directly stimulate enteric neurons (17,53,54). This effect further promoted intestinal motility and stimulated serotonin release. Consistent with this mechanism, PCD mice exhibited elevated fecal serotonin levels and increased expression of genes involved in serotonin biosynthesis (32). The released serotonin stimulated intestinal contraction and fluid secretion, contributing to accelerated gastrointestinal transit and diarrhea in PCD mice (17). Furthermore, gallbladder removal resulted in loss of surfactant protein D, which normally modulates the gut microbiota and suppresses intestinal inflammation. Reduced surfactant protein D might contribute to dysbiosis and further promote diarrhea (55). Together, these microbial and metabolic changes contributed to diarrhea following cholecystectomy, as shown in Figure 1.

These findings highlighted a consistent pattern across genetic, clinical, and animal studies. Mendelian analyses indicated a causal effect of cholecystectomy on IBS or PCD. In patients with PCS, mild alterations in gut microbial communities were observed, which might precede the more pronounced changes seen in PCD. PCD was associated with microbial alterations that increased the levels of hydrophobic secondary bile acids. These bile acids activated TGR5 and TRPA1, enhancing serotonin-mediated intestinal motility and secretion. Restoration of microbial balance may improve outcomes and quality of life after cholecystectomy.

Limitations and future perspective

Current evidence has several limitations. Most clinical studies are heterogeneous in sample size and follow-up duration, with limited direct comparisons. In addition, many studies have adopted case-control designs, which are susceptible to confounding factors such as dietary intake, antibiotic exposure, metabolic status, and other host-related factors, limiting the ability to establish temporal relationships. Prospective longitudinal cohort studies are further required.

Cultural differences, particularly dietary patterns, strongly influence gut microbiota composition and may introduce bias. Inconsistent control of diet and medication use further confounds results and obscures conclusions.

Most previous studies of post-cholecystectomy microbiome rely on 16S rRNA sequencing, which provides limited taxonomic resolution and functional insight. Although cost-effective, this method may overlook species- or strain-level variation. Shotgun metagenomic and metabolomic profiling offers improved functional characterization of the microbiome but remains underutilized. Integrated multi-omics approaches may therefore provide deeper mechanistic insight in future studies. Notably, concurrent metabolomic assessment is crucial in this setting; however, the metabolomics data are still lacking. Therefore, future studies on metabolomic alterations in the post-cholecystectomy are still required.

Regarding disease implications, particularly the potential link between post-cholecystectomy dysbiosis and CRC, existing evidence remains largely theoretical. Proposed mechanisms, including chronic inflammation and microbial metabolites, have yet to be confirmed in humans due to limited clinical and mechanistic data, therefore, causality cannot be established.

Future research should clarify the timing and trajectory of microbial changes after cholecystectomy, which may offer opportunities for early intervention. Longitudinal studies and controlled trials are needed to establish causality and guide targeted interventions.

Conclusions

Clinical and animal studies support the gallbladder’s role in maintaining microbial and metabolic balance. Cholecystectomy disrupts physiological bile acid flow, inducing gut dysbiosis characterized by enrichment of bile acid-metabolizing and bile-resistant bacteria and depletion of SCFAs-producing taxa. These alterations are associated with intestinal inflammation and metabolic disturbances. Short-term consequences, such as PCD, may occur, whereas long-term microbial and metabolic shifts may increase the risk of CRC or metabolic syndrome.

Together, these findings support the concept of the “post-cholecystectomy bile acid-microbiota-host axis”, as shown in Figure 1. This axis integrates microbial, metabolic, and host signaling alterations, thereby providing a unifying explanation for post-cholecystectomy consequences. These mechanistic insights are suggestive, but further studies are needed to translate them into effective clinical interventions.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0007/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0007/prf

Funding: This study was supported by the Distinguished Research Professor Grant from the National Research Council of Thailand (No. N42A690147. to N.C.) and a Chiang Mai University Center of Excellence Award (to N.C.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0007/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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