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. Author manuscript; available in PMC: 2024 Jun 1.
Published in final edited form as: J Pediatr Surg. 2023 Feb 21;58(6):1074–1078. doi: 10.1016/j.jpedsurg.2023.02.031

Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury

Maria E Tecos 1,^, Allie E Steinberger 2,^, Jun Guo 3, Deborah C Rubin 4, Nicholas O Davidson 4, Brad W Warner 3,*
PMCID: PMC10355217  NIHMSID: NIHMS1914593  PMID: 36914459

Abstract

Background:

Massive small bowel resection (SBR) is associated with liver injury and fibrosis. Efforts to elucidate the driving force behind hepatic injury have identified multiple factors, including the generation of toxic bile acid metabolites.

Methods:

Sham, 50% proximal, and 50% distal SBR were carried out in C57BL/6 mice to determine the effect of jejunal (proximal SBR) versus ileocecal resection (distal SBR) on bile acid metabolism and liver injury. Tissues were harvested at 2 and 10-week postoperative timepoints.

Results:

When compared with 50% proximal SBR, mice that underwent distal SBR exhibited less hepatic oxidative stress as verified by decreased mRNA expression of tumor necrosis factor-α (TNFα, p ≤ 0.0001), nicotinamide adenine dinucleotide phosphate oxidase (NOX, p ≤ 0.0001), and glutathione synthetase (GSS, p ≤ 0.05). Distal SBR mice also exhibited a more hydrophilic bile acid profile with reduced abundance of insoluble bile acids (cholic acid (CA), taurodeoxycholic acid (TCA), and taurolithocholic acid (TLCA)), and increased abundance of soluble bile acids (tauroursodeoxycholic acid (TUDCA)). In contrast with proximal SBR, ileocecal resection alters enterohepatic circulation leading to reduced oxidative stress and promotes physiological bile acid metabolism.

Conclusion:

These findings challenge the notion that preservation of the ileocecal region is beneficial in patients with short bowel syndrome. Administration of selected bile acids may present potential therapy to mitigate resection-associated liver injury.

Keywords: Short bowel syndrome, Small bowel resection, Enterohepatic circulation, Hepatic injury, Bile acids

Introduction

Longstanding total parenteral nutrition (TPN) is a recognized factor in the development of intestinal failure associated liver disease (IFALD) [1–3]. This is of critical concern to the pediatric population, considering the multitude of conditions that require massive small bowel resection (SBR), and ultimate short bowel syndrome (SBS). Liver injury with progression to fibrosis is one of the most significant morbidities encountered in SBS patients. Overall prognosis can be grim, with potential fatalities in up to half of cases, and less than half of survivors ever able to recover beyond requiring auxiliary parenteral support [1–8]. We have discovered hepatic injury in the context of a TPN-independent murine SBR model [9–17]. The finding of hepatic dysfunction after SBR in the absence of TPN has directed our investigation into multiple other factors that may contribute to this injury.

In the evaluation of specific mechanisms for liver injury associated with massive SBR, we have observed increased hepatic expression of inflammatory mediators tumor necrosis factor-alpha (TNFα) and glutathione synthetase (GSS) [13], as well as the activation of a unique unfolded protein response (UPR) within the liver [18]. Along these lines, we found that the hepatic damage and fibrosis induced in our proximal SBR model could be mitigated by the supplementation of tauroursodeoxycholic acid (TUDCA), which exhibits intrinsic antioxidant effects.

In contrast with proximal bowel SBR, removal of the ileum and cecum (distal SBR) appears to prevent liver injury. Resection of the ileum is known to disrupt enterohepatic bile acid recycling [19–21]. These findings therefore provide the rationale to propose a mechanism of liver injury that requires oxidative stress and enterohepatic recycling of bile acids. The purpose of this study was to elucidate the bile acid profile associated with proximal SBR, distal SBR, and TUDCA-supplemented proximal SBR murine models of SBS. We specifically tested the hypothesis that proximal SBR results in the production of hepatotoxic bile acid species and that distal SBR and TUDCA administration is associated with a more normal bile acid profile.

Methods

Mice

Male C57BL/6 mice were sourced from Jackson Laboratory (Bar Harbor, ME, USA), and transported directly to the animal housing facilities Washington University in St. Louis School of Medicine (St. Louis, MO, USA). While in holding, they experienced a 12–12 hour light-dark cycle and had access to water and food at all times. Experimentation followed protocol #20–0197, which was approved by the Washington University Animal Studies Committee, in accordance with the National Institute of Health guidelines for animal care.

Operations

10-week-old male mice were fed solid pellet chow until 24 hours before procedures, at which time they were placed on a liquid diet (LD; PMI Micro-Stabilized Rodent Liquid Diet LD 101; TestDiet, St. Louis, MO, USA). On the day of surgery, preoperative weight was recorded, and a 1 cc normal saline bolus was administered intraperitoneally (IP). Operations were performed under isoflurane anesthesia with the mice positioned supine on a heating pad for the duration of the procedure. Sham operation (division of the bowel and reanastomosis without resection), 50% proximal SBR [15], or 50% distal SBR [21] were carried out as previously described, and additional 1 cc normal saline boluses were administered IP immediately and 24 hours postoperatively [4]. Liquid diet administration was restarted on postoperative day 1, and all animals were housed in an incubator for 1 week after operation. Liquid diet was continued until harvest. Weights were recorded weekly, and mice were harvested at both 2 and 10 week timepoints. Acceptable survival was ≥70%. Structural adaptation was confirmed by measuring villous height and crypt depth, which was previously published for these mice in our prior manuscripts. [18, 21]

TUDCA Administration

A subset of 7 proximal SBR mice were administered 300 mg/kg/d (human equivalent 24.3 mg/kg) of TUDCA (Calbiochem; La Jolla, CA, USA) mixed in food and water for the duration of the postoperative timeframe, dose split for average food and water consumption [22–24]. All mice were monitored for signs of illness and failure to thrive after TUDCA administration; no subject experienced any clinical decline secondary to TUDCA supplementation.

Real Time Polymerase Chain Reaction (RT PCR)

RNA extraction from excised liver tissue was carried out in accordance with the manufacturer’s protocol (RNAqueous Kit, Ambion; Austin, TX, USA). RNA concentration was measured with a NanoDrop Spectophotomer (ND-1000, NanoDrop Technologies; Wilmington, DE, USA). Applied Biosystems amino acid N-acyltransferase (BAT), bile acid-CoA ligase (BAL), TNFα, nicotinamide adenine dinucleotide phosphate oxidase (NOX), GSS, and lipocalin 2 (LCN2) primers were used (Life Technologies; Carlsbad, CA, USA) for RT PCR with the Applied Biosystems 7500 Fast Real Time PCR system (Life Technologies; Carlsbad, CA, USA) against a GAPDH control. All tests were run with at least 5 samples per experimental group. For all experiments sham n = 5–8, proximal SBR n = 6–15, distal SBR n = 9, and proximal SBR supplemented with TUDCA n = 7.

Bile Acid Pool

All mice were fasted for 4 hours prior to sacrifice and bile acid analysis to standardize post-prandial timing. Liver was homogenized and hepatic bile acid pool measurement and speciation was carried out in accordance with the manufacturer’s specifications as published for the Bioquat Kit (Thermo Fisher Scientific; Waltham, MA, USA). The Applied Biosystems Sciex 4000QTRAP tandem mass spectrometer (Life Technologies; Carlsbad, CA, USA) was used as previously described [25]. A Mouse Total Bile Acids Assay Kit (Crystal Chem USA; Elk Grove Village, IL, USA) was used in accordance with the manufacturer’s specifications to assess the total bile acid pool for each subject. For all experiments sham n = 7–12, proximal SBR n = 7–20, distal SBR n = 7–14, and proximal SBR supplemented with TUDCA n = 7.

Statistical Analysis

GraphPad Prism (GraphPad Software Inc.; San Diego, CA, USA) was utilized for all statistical analyses. Each dataset underwent normality assessment and non-parametric tests were used for non-normally distributed data. Student’s t-test or ANOVA was used for normally distributed date. P-value 0.05 was employed as the cutoff for statistical significance, with GraphPad Prism annotations of *, **, ***, and **** representing p ≤ 0.05, ≤ 0.01, ≤ 0.001, and ≤ 0.0001 respectively.

Results

SBR-Associated Oxidative Stress

All resected mice demonstrated normal structural adaptation of the remnant small bowel as quantified by significant increases in villus height and crypt depth (data not shown). TNF-α, NOX, and GSS mRNA expression were found to be elevated in the livers of the proximal SBR cohort consistent with oxidative stress (Figure 1A). In contrast, TNFα and NOX mRNA levels were lowest in the distal SBR arm, and significantly decreased compared to their TUDCA treated counterparts. GSS mRNA levels for distal SBR and TUDCA supplemented mice were similar and equivalent with baseline sham operated animals. Together, these data reveal greater oxidative stress after proximal SBR. Increases in GSS mRNA expression after proximal SBR were not observed in the distal SBR and proximal SBR-TUDCA treated mice.

Figure 1: SBR-Associated Oxidative Stress is Mitigated by Distal SBR and TUDCA Treatment.

Figure 1:

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Oxidative stress in the livers of each group was assessed by comparing mRNA expression of inflammatory mediators. A) mRNA for oxidative stress markers TNFα, NOX, and GSS were increased in proximal SBR compared to all other groups. TNFα and NOX mRNA were decreased in both distal SBR and TUDCA treated proximal SBR subjects, with distal SBR animals having the lowest values. Sham n = 7–8, proximal SBR n = 6–10, distal SBR n = 9, TUDCA n = 7. B) mRNA for hepatic LCN2 was increased in proximal SBR compared to sham and distal SBR. Distal SBR LCN2 was also decreased compared to TUDCA treated mice. Sham n = 8, proximal SBR n = 10, distal SBR n = 9, TUDCA n = 7. For all graphs, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, and **** p < 0.0001.

A compensatory antioxidant response was evaluated by measuring mRNA levels of hepatic LCN2, which has been previously demonstrated to play a role in protective antioxidant activity in the setting of increase oxidative stress [26–28]. LCN2 was indeed found to be increased after proximal SBR compared to all other groups. Again, distal SBR was found to mount the lowest LCN2 response and was significantly decreased compared to TUDCA treated mice (Figure 1B).

Bile Acid Alterations associated with SBR

Considering the known impact of distal SBR and TUDCA supplementation on bile acid physiology, we postulated that bile acids play a key role in the pathogenesis of SBR-associated hepatic injury. We therefore investigated hepatic bile acid concentrations and composition after proximal and distal SBR. In line with disrupted enterohepatic circulation (EHC) of bile acids, distal SBR mice were found to have decreased hepatic bile acid content at postoperative week 10 compared with all other experimental groups (Figure 2A). Conversely, TUDCA-supplemented mice showed no difference in hepatic bile acid pool size in comparison with sham and proximal SBR. When the total bile acid pool was assessed (hepatic including gallbladder plus fecal bile acid) with adjustment for amount of resected bowel, distal SBR was associated with a smaller overall pool size compared to sham and proximal SBR counterparts (Figure 2B). The bile acid pool has been found to have the following distribution: gallbladder 15–20%, liver 1–2%, and intestine 75–80% [29]. Distal SBR was also associated with upward trends in mRNA expression of both BAT and BAL, enzymes involved in the hepatic conjugation of unconjugated bile acid (Figure 2C). This is consistent with increased de novo bile acid production and subsequent conjugation after distal SBR [30]. TUDCA treated mice also exhibited an increase in BAL, consistent with its reported role in fatty acid and bile acid processing [31].

Figure 2: Resection-associated alterations in bile acids.

Figure 2:

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Bile acid pool size and bile acid species were assessed in each group. The expression of mRNA of enzymes involved in hepatic bile acid conjugation were also measured. A) Bile acid content in livers removed from mice at 10 weeks following sham operation (n=7), proximal SBR (n=7), distal SBR (n=11), or proximal SBR and provided oral TUDCA (n=7). B) Total hepatic bile acid content at 10 weeks following sham operation (n=12), proximal SBR (n=20), or distal SBR (n=14). C) mRNA expression of BAT and BAL, enzymes involved in bile acid conjugation in the liver of mice at 10 weeks following sham operation (n=5), proximal SBR (n=15), distal SBR (n=9), or proximal SBR and provided oral TUDCA (n=7). D) Hepatic bile acid species from mice 10 weeks following sham operation (n=7), proximal SBR (n=11), distal SBR (n=7), or proximal SBR and provided oral TUDCA (n=7). Muricholic acid (MCA), taurocholic acid (TCA), cholic acid (CA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA), and TUDCA measurements for each group. For all graphs, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, and **** p ≤ 0.0001.

Differences in bile acid pool size prompted us to further investigate changes in bile acid composition. Relative distribution of the two most abundant bile acids, muricholic acid (MCA) and taurocholic acid (TCA), were either maintained or increased after distal SBR, despite the decreased overall pool. This supports the notion of greater de novo bile acid production in distal SBR mice, which we have further confirmed via measurement of hepatic Cyp7a1 mRNA expression (a surrogate for the generation of new bile acids in the liver). Compared to sham controls, proximal SBR, distal SBR, and TUDCA treated mice had −2.19, +3.22, and −6.63 fold changes respectively in hepatic Cyp7a1 mRNA levels. Remarkably, levels of the most insoluble, toxic, hydrophobic bile acids (cholic acid (CA), taurodeoxycholic acid (TDCA), and taurolithocholic acid (TLCA) were all decreased in the distal SBR mice, where hepatic injury was absent. Conversely, TLCA was highest in the proximal SBR group. Interestingly, there was an increase in endogenous TUDCA in the distal SBR group as well (Figure 2D). Overall, our evidence suggests that distal SBR promotes de novo bile acid synthesis with a propensity for production of a more physiological, less toxic, hydrophilic bile acid profile.

Speciation of the TUDCA treated group revealed a decrease in most bile acids, which is consistent with exogenous bile acid suppression of hepatic bile acid production. Both the most abundant (MCA, TCA) and toxic (CA, TDCA) bile acids were decreased. However, there was an increase in TLCA, which was still attenuated compared to the untreated proximal SBR group. Markedly elevated TUDCA confirmed supplemental TUDCA in this experimental arm (Figure 2D). Overall, the bile acid profile after TUDCA supplementation revealed suppression of overall bile acid production with a shift toward a more physiologic, less toxic, and more hydrophilic bile acids.

Discussion

In this study, we have demonstrated that proximal SBR is associated with oxidative stress in the liver as well as the production of more toxic bile acid species, TLCA. These data sharply contrast with a less toxic bile acid profile when a resection of a similar length of distal bowel was removed. Finally, the injurious bile acid profile associated with proximal SBR was mitigated by the administration of an exogenous bile acid TUDCA. Taken together, these findings highlight the significance of the site of intestinal resection (jejunum versus ileum) as a major contributor to liver injury after massive SBR. Further, the protective effects of TUDCA administration in our murine model suggest the potential therapeutic benefit of supplemental bile acid therapy to prevent liver injury in patients with SBS. While our murine studies show a locus-based hepatoprotective effect of SBR, we acknowledge that preservation of intestinal length and the ileocolic valve has been a critical surgical paradigm in human patients. The clinical application of our findings may support the inhibition of the specific function of bile acid recycling in the ileum of SBS patients, a theory that warrants further investigation.

Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The relationship between bile acid metabolism and the gut microbiota is therefore critical. We have previously demonstrated significant alterations in the gut microbiome in our proximal SBR model [10,32]. While we have not previously explored changes after distal SBR, we posit that the microbial community would likely be different. This consideration is supported by the disparate bile acid profiles associated with proximal versus distal SBR. What is not known at the present time is whether the differences in bile acids between site of resection is due to removal of the major site of bile acid recycling, or secondary to alterations in the gut microbial community. This is the subject of our future laboratory investigations.

Contrary to the findings of the present study, we had previously reported that distal SBR was more injurious to the liver compared with proximal SBR [33]. In the prior report, the ileum was resected, but the cecum and ileocecal valve were preserved. In the current study, the distal ileum and cecum were both removed. It is possible, therefore that the cecum may function to slow intestinal transit and/or allow for alterations in the microbiota. It is certainly a large reservoir of bacteria within the gut. Direct comparison of changes in gut microbiota between ileal resections with or without the cecum will be needed to answer this question more directly.

Our previous work has provided evidence for the association of an increased inflammatory and oxidative stress response in the liver, which triggers an unfolded protein response after proximal SBR [9–13,17,18]. Here, we have shown preliminary support that it is possible to mitigate the oxidative stress resultant from SBR via both TUDCA administration and physical disengagement of the EHC via removal of the ileum. This results in a subsequent decrease in TNFα, NOX, and GSS in both TUDCA-supplemented proximal SBR and distal SBR compared to proximal SBR mice.

Distal SBR was associated with a more physiological bile acid profile, with a comparative increase in hydrophilic bile acids and decrease in insoluble, hydrophobic and potentially injurious bile acids. Moreover, the hepatic bile acid pool of the distal SBR mice was smaller, yet production of the most common bile acid (MCA) was unchanged compared to control and associated with increased mRNA expression of bile acid conjugation enzymes. Together, these data support the notion that distal SBR may stimulate increased hepatic bile acid production via the interruption of bile acid recycling. It also stands to reason that de novo bile acid production, paired with mRNA expression profiles suggesting enhanced conjugation, results in a healthier overall profile compared to intact EHC bile acid metabolism where toxic bile acids may be recycled. Further investigation regarding the activity of bile acid metabolism at different points along EHC is necessary to continuing characterizing this mechanism contributing to the hepatoprotection observed in distal SBR mice.

It is likely that the mechanism driving the hepatoprotection obtained from TUDCA differs from that conferred by distal SBR. Notably, MCA levels were reduced to a greater extent in the TUDCA supplemented group, consistent with an overall decrease in hepatic bile acid production, likely secondary to the negative feedback that may be present after exogenous bile acid supplementation. This difference in bile acid profile compared to distal SBR mice, paired with the intrinsic nature of TUDCA as a cellular chaperone and antioxidant bolsters the theory that its hepatoprotective mechanism is distinct from that which shields the liver from damage after distal SBR [22–24]. Exploration of this mechanism necessitates further study.

Beyond investigation into the mechanism driving this protective phenotype, the limitations of this study designate additional directions for future work. While the microbiome was not investigated within this body of work, it is likely to play a significant role, particularly when considering presence and absence of the cecum. As previously mentioned, this study does seem to challenge the dogma of preserving the terminal ileum and ileocecal valve. Rather than advocate for resection of this region in human subjects, it would be reasonable to explore pharmacologic inhibition of bile acid recycling in patients with retained distal small bowel.

Highlights.

  • Distal SBR and TUDCA supplementation after proximal SBR decrease oxidative stress that contributes to SBR-associated hepatic injury compared to proximal SBR

  • Distal SBR and TUDCA supplementation have healthier bile acid profiles compared to proximal SBR

  • Enterohepatic circulation has critical involvement in liver injury prevention, but distal SBR and TUDCA supplementation likely differ in the mechanism utilized to confer hepatoprotection

Financial support:

NIH RO1 R01DK128169 (Warner, Rubin, Davidson), NIH T32 DK007120 (Tecos), NIH T32 DK077653 (Steinberger), The Children’s Surgical Sciences Research Institute of the St. Louis Children’s Hospital Foundation (Warner) and NIH P30DK52574 Digestive Diseases Research Core Center of the Washington University School of Medicine (Rubin, Davidson)

Abbreviations:

SBS

Short bowel syndrome

SBR

small bowel resection

EHC

enterohepatic circulation

TPN

total parenteral nutrition

TNFα

tumor necrosis factor-α

GSS

glutathione synthetase

TUDCA

tauroursodeoxycholic acid

LCN2

lipocalin 2

NOX

nicotinamide adenine dinucleotide phosphate oxidase

BAT

bile acid-CoA: amino acid N-acyltransferase

BAL

bile acid-CoA ligase

MCA

muricholic acid

TCA

taurocholic acid

CA

cholic acid

TDCA

taurodeoxycholic acid

TLCA

taurolithocholic acid

UPR

unfolded protein response

Footnotes

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Previous Communication: American Academy of Pediatrics National Conference

Competing Interests: No authors have any competing interests to disclose

Level of Evidence: III—Case-Control Study

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