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. 2010 Jun;45(6):1256-65.
doi: 10.1016/j.jpedsurg.2010.02.094.

Dietary bile acid supplementation improves intestinal integrity and survival in a murine model

Erin E Perrone  1 , Chen Chen, Shannon W Longshore, Oneybuchi Okezie, Brad W Warner, Chen-Chih Sun, Samuel M Alaish, Eric D Strauch
Affiliations

Dietary bile acid supplementation improves intestinal integrity and survival in a murine model

Erin E Perrone et al. J Pediatr Surg. 2010 Jun.

Abstract

Purpose: In vitro supplementation of the bile salt, taurodeoxycholic acid (TDCA), has been shown to stimulate proliferation and prevent intestinal apoptosis in IEC-6 cells. We hypothesize that addition of TDCA to a rodent liquid diet will be protective against induced intestinal injury.

Methods: C57Bl6 mice were fed a liquid diet with or without 50-mg/(kg d) TDCA supplementation. After 6 days, the mice were injected with lipopolysaccharide (LPS) (10 mg/kg) to induce intestinal injury. Specimens were obtained 24 hours later and evaluated for intestinal apoptosis, crypt proliferation, and villus length. A separate cohort of animals was injected with LPS (25 mg/kg) and followed 7 days for survival.

Results: Mice whose diet was supplemented with TDCA had significantly increased survival. After LPS-induced injury, mice supplemented with TDCA showed decreased intestinal apoptosis by both H&E and caspase-3. They also had increased intestinal proliferation by 5-bromo-2'deoxyuridine staining and increased villus length.

Conclusions: Dietary TDCA supplementation alleviates mucosal damage and improves survival after LPS-induced intestinal injury. Taurodeoxycholic acid is protective of the intestinal mucosa by increasing resistance to injury-induced apoptosis, stimulating enterocyte proliferation, and increasing villus length. Taurodeoxycholic acid supplementation also results in an increased survival benefit. Therefore, bile acid supplementation may potentially protect the intestine from injury or infection.

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Figures

FIG 1
FIG 1. TDCA Supplementation Improves Survival After LPS-Induced Injury
Mice were given a diet with or without TDCA supplementation for 7 days prior to injury. They were then given an intraperitoneal injection of LPS at 25mg/kg. Mice were followed for 7 days after the injury, given the same diet as before the injury, and survival was monitored. Animals that received the TDCA supplemented diet had significantly increased survival when compared to those that had control diets.
FIG 2
FIG 2. TDCA Supplementation Reverses LPS-Induced Intestinal Apoptosis
Apoptosis was quantified in 100 crypts using both H&E (arrows, A-C) and active caspase-3 staining (brown stained cells, D-F). Animals that received LPS (10mg/kg IP) had significantly increased levels of crypt apoptosis by both staining methods. With the addition of TDCA to the diet, mice that received LPS had levels of apoptosis comparable to non-injured mice (G-H).
FIG 2
FIG 2. TDCA Supplementation Reverses LPS-Induced Intestinal Apoptosis
Apoptosis was quantified in 100 crypts using both H&E (arrows, A-C) and active caspase-3 staining (brown stained cells, D-F). Animals that received LPS (10mg/kg IP) had significantly increased levels of crypt apoptosis by both staining methods. With the addition of TDCA to the diet, mice that received LPS had levels of apoptosis comparable to non-injured mice (G-H).
FIG 2
FIG 2. TDCA Supplementation Reverses LPS-Induced Intestinal Apoptosis
Apoptosis was quantified in 100 crypts using both H&E (arrows, A-C) and active caspase-3 staining (brown stained cells, D-F). Animals that received LPS (10mg/kg IP) had significantly increased levels of crypt apoptosis by both staining methods. With the addition of TDCA to the diet, mice that received LPS had levels of apoptosis comparable to non-injured mice (G-H).
FIG 3
FIG 3. TDCA Supplementation Partially Ameliorates LPS-Induced Reduction of Intestinal Proliferation
S-phase cells stain brown after BrdU injection and were quantified in 100 crypts (A-C). Animals that received LPS had significantly fewer proliferative cells than non-injured mice. The addition of TDCA to the diet was able to ameliorate this decrease but it did not reach baseline levels of non-injury proliferation (D).
FIG 3
FIG 3. TDCA Supplementation Partially Ameliorates LPS-Induced Reduction of Intestinal Proliferation
S-phase cells stain brown after BrdU injection and were quantified in 100 crypts (A-C). Animals that received LPS had significantly fewer proliferative cells than non-injured mice. The addition of TDCA to the diet was able to ameliorate this decrease but it did not reach baseline levels of non-injury proliferation (D).
FIG 4
FIG 4. TDCA Supplementation Restores LPS-Induced Reduction in Villus Length
Villus length was measured in 12 healthy jejunal villi per mouse. Representative pictures are shown at 10x magnification. The black bars each measure 50μm (A-C). Mice that underwent LPS-induced injury had significantly shorter villi. This effect reversed with the addition of TDCA to the diet (D).
FIG 4
FIG 4. TDCA Supplementation Restores LPS-Induced Reduction in Villus Length
Villus length was measured in 12 healthy jejunal villi per mouse. Representative pictures are shown at 10x magnification. The black bars each measure 50μm (A-C). Mice that underwent LPS-induced injury had significantly shorter villi. This effect reversed with the addition of TDCA to the diet (D).
FIG 5
FIG 5. TDCA Supplementation is Not Protective in LPS-Induced Liver Injry
Liver injury was measured by the number of PMN infiltration. Representative pictures are shown at 40x magnification. Mice that received NS showed little inflammation (A) while mice that received LPS showed marked inflammation (arrow, B). The addition of TDCA to the diet did not result in improvement of this liver injury (C).
FIG 5
FIG 5. TDCA Supplementation is Not Protective in LPS-Induced Liver Injry
Liver injury was measured by the number of PMN infiltration. Representative pictures are shown at 40x magnification. Mice that received NS showed little inflammation (A) while mice that received LPS showed marked inflammation (arrow, B). The addition of TDCA to the diet did not result in improvement of this liver injury (C).
FIG 6
FIG 6. TDCA Supplementation Has No Effect on LPS-Induced Lung Injury
Lung injury was scored from 1 to 4 based upon the amount of neutrophil infiltration into the alveolar septa. Mice that did not receive LPS had very little inflammation whereas mice that received systemic LPS had marked inflammation (A-D). The addition of TDCA to the diet did not result in significant improvement of this lung injury (E).
FIG 6
FIG 6. TDCA Supplementation Has No Effect on LPS-Induced Lung Injury
Lung injury was scored from 1 to 4 based upon the amount of neutrophil infiltration into the alveolar septa. Mice that did not receive LPS had very little inflammation whereas mice that received systemic LPS had marked inflammation (A-D). The addition of TDCA to the diet did not result in significant improvement of this lung injury (E).
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