Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4

doi:10.1016/j.immuni.2014.06.014

. 2014 Aug 21;41(2):296-310.

doi: 10.1016/j.immuni.2014.06.014. Epub 2014 Jul 24.

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4

Madhukumar Venkatesh¹, Subhajit Mukherjee¹, Hongwei Wang¹, Hao Li¹, Katherine Sun², Alexandre P Benechet³, Zhijuan Qiu³, Leigh Maher³, Matthew R Redinbo⁴, Robert S Phillips⁵, James C Fleet⁶, Sandhya Kortagere⁷, Paromita Mukherjee¹, Alessio Fasano⁸, Jessica Le Ven⁹, Jeremy K Nicholson⁹, Marc E Dumas⁹, Kamal M Khanna¹⁰, Sridhar Mani¹¹

Affiliations

¹ Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
² Department of Pathology, Montefiore Medical Center, Bronx, NY 10467, USA.
³ Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
⁴ Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
⁶ Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
⁷ Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
⁸ Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
⁹ Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK.
¹⁰ Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA. Electronic address: kkhanna@uchc.edu.
¹¹ Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: sridhar.mani@einstein.yu.edu.

PMID: 25065623
PMCID: PMC4142105
DOI: 10.1016/j.immuni.2014.06.014

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4

Madhukumar Venkatesh et al. Immunity. 2014.

. 2014 Aug 21;41(2):296-310.

doi: 10.1016/j.immuni.2014.06.014. Epub 2014 Jul 24.

Authors

Affiliations

¹ Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
² Department of Pathology, Montefiore Medical Center, Bronx, NY 10467, USA.
³ Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
⁴ Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
⁶ Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
⁷ Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
⁸ Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
⁹ Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK.
¹⁰ Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA. Electronic address: kkhanna@uchc.edu.
¹¹ Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: sridhar.mani@einstein.yu.edu.

PMID: 25065623
PMCID: PMC4142105
DOI: 10.1016/j.immuni.2014.06.014

Abstract

Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.

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Figures

**Figure 1. Commensal derived indole metabolite, IPA, regulates PXR activation**
(A) Transcriptional activity of a PXR reporter gene (multi-drug resistance-associated protein 2 or MRP2 luciferase) co-transfected with mPXR (black) and hPXR (red) expression plasmids in 293T cells following treatment with IPA (n=3). RLU, relative light unit. (B) Transcriptional activity of a PXR reporter gene (MRP2 luciferase) co-transfected with hPXR expression plasmid in 293T cells following treatment with fixed concentration of indole (1 mM) and increasing concentrations of IPA (n=3). RLU, relative light unit. Data expressed as fold change in RLU compared to vehicle (DMSO) controls. (C) Real-time qPCR analysis of *Mdr-1* expression in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum villi enterocytes following oral treatment with IPA (20 mg/kg/day) (n=5 per group). *P ≤ 0.0001; **P ≤ 0.001;n.s. not significant (Two-way ANOVA with Tukey’s multiple comparison test). (D) Schematic of germ free mouse treatment schedule. Six treatment groups are shown by color code: Swiss Webster Germ Free mice (SWGF) group, administered 100 μl LB and 100 μl sterilized water by oral gavage; SWGF + tryptophan (Trp) group, administered 100 μl LB + L-tryptophan; SWGF + Heat-killed *C. sporogenes* (*C.s*) group, administered *C.s* by oral gavage; SWGF + (*C.s*) group, administered *C.s* by oral gavage; SWGF + Heat-killed (*C.s*) + Trp group; and SWGF + *C.s* + Trp group, administered *C.s* and Trp by oral gavage (see Experimental Procedures). All the treatments were scheduled for six sequential days. (E) Plasma IPA peak area intensity values plotted by treatment group as illustrated in the schema (D) Color coded histograms show mean ± s.e.m. values pertaining to each treatment group. IPA concentrations in micromoles (μM) are listed by color code. (F) erum FITC-dextran recovery in treatment groups illustrated in schema (D). *P ≤ 0.0001; (Two-way ANOVA with Tukey’s multiple comparison test ); (n=6 per group). (G) Real-time qPCR analysis of *Mdr1, Cyp3a11 and Ugt1a1* mRNA expression in small intestinal mucosa from schema (D). All graphs show mean values ± s.e.m. Also see Figure S1,Table S1 and supplemental movies S1 and S2.

**Figure 2. Commensal *C. sporogenes* reconstitution decreases intestinal permeability and inflammation in a PXR-dependent manner in mice**
(A) Schematic of commensal depletion and *C. sporogenes* reconstitution experiment in *Nr1i2^+/+* and *Nr1i2^−/−* mice (see Experimental Procedures). (B) Plasma IPA peak area intensity values plotted by treatment groups as illustrated in the schema (A). The IPA concentrations in micromoles (μM) pertaining to each group is illustrated above each histogram. (C) Hematoxylin and eosin staining of *C. sporogenes* + L-tryptophan and Heat killed *C. sporogenes* + L-tryptophan exposed *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum cross-sections in accordance with schema (A). Scale bars, 50 μm. (D) Jejunal MPO activity (unit/g of total protein) in treatment groups from schema (A) as illustrated. (E) Real-time qPCR analysis of *Ugt1a1* mRNA expression in small intestinal mucosa from schema (A). (F and G) Serum FITC-dextran recovery following oral gavage of IPA (20 mg/kg/day) and indomethacin (see schematic) in (F) *Nr1i2^+/+* (n = 9) and (G) *Nr1i2^−/−* (n = 9) mice. All graphs show mean values ± s.e.m. *P ≤ 0.01 (Two-way ANOVA with Sidak’s multiple comparison test); (n=6 per group). **P ≤ 0.01 (Student’s t-test); n.s. not significant. Also see Figure S2 and Table S2

**Figure 3**
*Nr1i2^−/−* mice are more susceptible to toxic injuries to the small intestine (A) Hematoxylin and eosin staining of indomethacin (Indo) treated *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum cross-sections. (B) Jejunal MPO activity (unit/g of total protein) in *Nr1i2^+/+* and *Nr1i2^−/−* mice treated with indomethacin (n=6 per group). (C) Histological score measuring severity of tissue damage in jejunum from *Nr1i2^+/+* and *Nr1i2^−/−* mice in indomethacin treated and untreated groups (n=6 per group). (D) Weight to length ratio of the jejunum (enteropooling) in *Nr1i2^+/+* and *Nr1i2^−/−* mice treated with anti-CD3 antibody. The change in weight-to-length ratio in *Nr1i2^+/+* and *Nr1i2^−/−* mice exposed to anti-CD3 was 27.6% and 22.9%, respectively. Values represent mean ± s.e.m. (n=5 per group). (E) Hematoxylin and eosin staining of anti-CD3 antibody treated *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum cross-sections. (F) Serum FITC-dextran recovery following gastrointestinal ischemia-reperfusion (I/R) injury in *Nr1i2+/+* and *Nr1i2^−/−* mice (n=5 per group). The change in permeability as assessed by a change in recovery of mean levels of FITC - dextran in the serum of *Nr1i2^+/+* and *Nr1i2^−/−* mice was 193% and 488.9%, respectively. (G) Kaplan-Meier survival curves of *Nr1i2^+/+* and *Nr1i2^−/−* mice treated with LPS (n=6 per group). All graphs show mean values ± s.e.m. *P ≤ 0.02; **P ≤ 0.0001 (Two-way ANOVA with Tukey’s multiple comparison test ). Scale bars, 50 μm. Also see Figure S3.

**Figure 4. Ultra-structural and functional defects in *Nr1i2^−/−* mice small intestine**
(A and B) Representative TEM images of *Nr1i2^+/+* (A) and *Nr1i2^−/−* (B) mice jejunum shows loose packing of microvilli in *Nr1i2^−/−* mice. γ represents packing angle between adjacent microvilli. Packing of microvilli in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum was quantified by assessing the packing angle (γ) between adjacent microvilli. γ in *Nr1i2^−/−* mice cross-sections (81.0 ± 23.6°, n=273) is significantly higher and more variable compared to *Nr1i2^+/+* mice (59.6 ± 7.0°, n=275) (n=5 per group). (C) Sucrase, maltase, lactase and dipeptidyl peptidase (DPPIV) enzyme activities in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum villi enterocytes. Proportionality between amount of enzyme present (jejunal villi enterocyte homogenate containing 20 mg/ml of protein as enzyme, x-axis) and amount of substrate liberated (optical density, y-axis) in 60 minutes was plotted in the graph (n=8-10 per group). (D) Alkaline phosphatase enzyme activity in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum villi enterocyte homogenate (n=8-10 per group). (E) Immunoblot analysis of alkaline phosphatase and β-actin (loading control) in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum villi enterocytes (n=5 per group). (F) Representative TEM images of *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum enterocytes demonstrating cell-cell junctional complexes and perijunctional cytoskeletal condensation. Inset shows magnified views of cell-cell junctional complex. (G) Real-time qPCR analysis of key Tj and Aj regulatory genes in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum villi enterocytes (n=8-10 per group). Data plotted as fold change in *Nr1i2^−/−* mice relative to mRNA levels in *Nr1i2^+/+* mice. (H) Serum FITC-dextran recovery in *Nr1i2^+/+* and *Nr1i2^−/−* mice following treatment with KDO2. (n=8-10 per group). All graphs show mean values ± s.e.m.* , **P ≤ 0.0001; n.s. not significant (Two-way ANOVA with Tukey’s multiple comparison test). Scale bars: A, B and F, 0.5 μm. Also see Figure S4.

**Figure 5. Small intestine epithelial barrier dysfunction in *Nr1i2^−/−* mice requires TLR4 expression and signaling**
(A and B) Real-time qPCR analysis of (A) anti-inflammatory, anti-microbial, pro-inflammatory and (B) *Tlr* gene expression in *Nr1i2^+/+* and *Nr1i2^−/−* mice jejunum villi enterocytes (n=8-10 per group). Data plotted as fold change in *Nr1i2^−/−* mice relative to mRNA levels in *Nr1i2^+/+* mice. (C) Immunoblot shows increased expression of TLR4 in *Nr1i2^−/−* mice (n=6 per group) (left). Immunoblots are representative of three independent experiments. Quantitation of band density was performed with two blots each with three different exposure times (right). (D) Real - time qPCR analysis of key regulatory genes of epithelial barrier function in *Nr1i2^+/+*, *Nr1i2^−/−*, *Tlr4^−/−* and *Nr1i2^−/− /Tlr4^−/−* mice jejunum villi enterocytes (n=8-10 per group). (E) Representative TEM images of *Nr1i2^+/+*, *Nr1i2^−/−*, *Tlr4^−/−* and *Nr1i2^−/− / Tlr4^−/−* mice jejunum showing microvilli (left) and quantitation of average microvillus length (right). (F) Representative TEM images of *Nr1i2^+/+*, *Nr1i2^−/−*, *Tlr4^−/−* and *Nr1i2^−/− / Tlr4^−/−* mice jejunum showing cell-cell junctional complex. (G) Enzyme (as denoted) activity assays performed with jejunal villi enterocyte homogenate from *Nr1i2^+/+*, *Nr1i2^−/−*, *Tlr4^−/−* and *Nr1i2^−/− /Tlr4^−/−* mice. Data are expressed as fold change relative to *Nr1i2^+/+* mice. (H) Serum FITC-dextran levels in *Nr1i2^+/+*, *Nr1i2^−/−*, *Tlr4^−/−* and *Nr1i2^−/− /Tlr4^−/−* mice (n=8-10 per group). All graphs show mean values ± s.e.m. *P ≤ 0.05; **P ≤ 0.01; n.s. not significant (A,B,D,E,G,H) (Two-way ANOVA with Tukey’s multiple comparison test); (C) Student t-test. Scale bars: E and F, 0.5 μm. Also see Figure S5.

Figure 6. TLR4 is critical for indomethacin-induced intestinal injury as well as IPA effects on permeability *in vivo*
(A) Representative Hematoxylin and eosin staining of vehicle (-Indo) and indomethacin (Indo) treated *Nr1i2^−/− /Tlr4^−/−* mice jejunum cross-sections (n=6 per group). (B) Jejunal MPO activity (unit/g of total protein) in *Nr1i2^−/−* and *Nr1i2^−/− /Tlr4^−/−* mice treated with indomethacin (n=6 per group). *P ≤ 0.005 (One-way ANOVA with Sidak’s multiple comparison test). (C) Serum FITC-dextran recovery following oral gavage of IPA (20 mg/kg/day) and indomethacin (see schematic ) in *Tlr^−/−* (n = 9) mice. (D) Serum FITC-dextran recovery following oral gavage of IPA (20 mg/kg/day) and KDO2 200μg/day (see schematic) in conventional mice (*Nr1i2^+/+* ) and commensal depleted (CD) mice (*Nr1i2^+/+* ) (n = 8 per group). All graphs show mean values ± s.e.m. *P ≤ 0.004 ,**P ≤ 0.05; n.s. not significant (Two-way ANOVA with Tukey’s multiple comparison test).

**Figure 7. Epithelial barrier defects in *Nr1i2^−/−* mice small intestine is dependent on non-hematopoietic (epithelium) compartment**
(A and B) Real-time qPCR analysis of pro-inflammatory markers (A) *Tnf-α* and (B) *Il-6* was assessed in *Nr1i2^+/+* (n=10), *Nr1i2^−/−* (n=10), *Nr1i2^+/+* BM→ *Nr1i2^+/+* (n=9), *Nr1i2^+/+* BM→ *Nr1i2^−/−* (n=9), *Nr1i2^−/−* BM→ *Nr1i2^+/+* (n=6) and *Nr1i2^−/−* BM→ *Nr1i2^−/−* (n=5) mice jejunal villi enterocytes. Data are expressed as fold change in all mice groups compared to *Nr1i2^+/+* mice. (C) *In vivo* FITC-dextran permeability assay was performed in *Nr1i2^+/+* (n=10 mice), *Nr1i2^−/−* (n=10), *Nr1i2^+/+* BM→ *Nr1i2^+/+* (n=9), *Nr1i2^+/+* BM→ *Nr1i2^−/−* (n=9), *Nr1i2^−/−* BM→ *Nr1i2^+/+* (n=6) and *Nr1i2^−/−* BM→ *Nr1i2^−/−* (n=5) mice. (D) Real-time PCR analysis of proinflammatory markers (blue) *Tnf-α* and (red) *Il-6* was assessed in genotypes illustrated (n=5) mice jejunal mucosa. Data are expressed as fold change in all mice groups compared to *Nr1i2^−/− /Tlr4^+/+*→ *Nr1i2^+/+ /Tlr4^+/+* mice. (E) *In vivo* FITC-dextran permeability assay was performed in (n=5) mice jejunal mucosa. All graphs show mean values ± s.e.m.; n.s. not significant (Two-way ANOVA with Tukey’s multiple comparison test).

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References

1. Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10:131–144. - PubMed
1. Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. Journal of immunology. 2001;167:1609–1616. - PubMed
1. Asano T, Tanaka K, Yamakawa N, Adachi H, Sobue G, Goto H, Takeuchi K, Mizushima T. HSP70 confers protection against indomethacin-induced lesions of the small intestine. The Journal of pharmacology and experimental therapeutics. 2009;330:458–467. - PubMed
1. Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C. Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol. 2011;8:36–45. - PubMed
1. Asquith M, Powrie F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. The Journal of experimental medicine. 2010;207:1573–1577. - PMC - PubMed

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[1] Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10:131–144. - PubMed

[2] Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10:131–144. - PubMed

[3] Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. Journal of immunology. 2001;167:1609–1616. - PubMed

[4] Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. Journal of immunology. 2001;167:1609–1616. - PubMed

[5] Asano T, Tanaka K, Yamakawa N, Adachi H, Sobue G, Goto H, Takeuchi K, Mizushima T. HSP70 confers protection against indomethacin-induced lesions of the small intestine. The Journal of pharmacology and experimental therapeutics. 2009;330:458–467. - PubMed

[6] Asano T, Tanaka K, Yamakawa N, Adachi H, Sobue G, Goto H, Takeuchi K, Mizushima T. HSP70 confers protection against indomethacin-induced lesions of the small intestine. The Journal of pharmacology and experimental therapeutics. 2009;330:458–467. - PubMed

[7] Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C. Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol. 2011;8:36–45. - PubMed

[8] Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C. Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol. 2011;8:36–45. - PubMed

[9] Asquith M, Powrie F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. The Journal of experimental medicine. 2010;207:1573–1577. - PMC - PubMed

[10] Asquith M, Powrie F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. The Journal of experimental medicine. 2010;207:1573–1577. - PMC - PubMed

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Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4

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Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4

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