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

Madhukumar Venkatesh; Subhajit Mukherjee; Hongwei Wang; Hao Li; Katherine Sun; Alexandre P. Benechet; Zhijuan Qiu; Leigh Maher; Matthew R. Redinbo; Robert S. Phillips; James C. Fleet; Sandhya Kortagere; Paromita Mukherjee; Alessio Fasano; Jessica Le Ven; Jeremy K. Nicholson; Marc E. Dumas; Kamal M. Khanna; Sridhar Mani

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, Subhajit Mukherjee, Hongwei Wang, Hao Li, Katherine Sun, Alexandre P. Benechet, Zhijuan Qiu, Leigh Maher, Matthew R. Redinbo, Robert S. Phillips, James C. Fleet, Sandhya Kortagere, Paromita Mukherjee, Alessio Fasano, Jessica Le Ven, Jeremy K. Nicholson, Marc E. Dumas, Kamal M. Khanna, Sridhar Mani

Oncology

Research output: Contribution to journal › Article › peer-review

647 Scopus citations

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 invivo, 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.

Original language	English (US)
Pages (from-to)	296-310
Number of pages	15
Journal	Immunity
Volume	41
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2014.06.014
State	Published - Aug 21 2014

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2014.06.014

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Venkatesh, M., Mukherjee, S., Wang, H., Li, H., Sun, K., Benechet, A. P., Qiu, Z., Maher, L., Redinbo, M. R., Phillips, R. S., Fleet, J. C., Kortagere, S., Mukherjee, P., Fasano, A., Le Ven, J., Nicholson, J. K., Dumas, M. E., Khanna, K. M., & Mani, S. (2014). Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4. Immunity, 41(2), 296-310. https://doi.org/10.1016/j.immuni.2014.06.014

Venkatesh, M, Mukherjee, S, Wang, H, Li, H, Sun, K, Benechet, AP, Qiu, Z, Maher, L, Redinbo, MR, Phillips, RS, Fleet, JC, Kortagere, S, Mukherjee, P, Fasano, A, Le Ven, J, Nicholson, JK, Dumas, ME, Khanna, KM & Mani, S 2014, 'Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4', Immunity, vol. 41, no. 2, pp. 296-310. https://doi.org/10.1016/j.immuni.2014.06.014

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title = "Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4",

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 invivo, 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.",

author = "Madhukumar Venkatesh and Subhajit Mukherjee and Hongwei Wang and Hao Li and Katherine Sun and Benechet, {Alexandre P.} and Zhijuan Qiu and Leigh Maher and Redinbo, {Matthew R.} and Phillips, {Robert S.} and Fleet, {James C.} and Sandhya Kortagere and Paromita Mukherjee and Alessio Fasano and {Le Ven}, Jessica and Nicholson, {Jeremy K.} and Dumas, {Marc E.} and Khanna, {Kamal M.} and Sridhar Mani",

note = "Funding Information: We thank the Analytical Imaging and Histotechnology and comparative pathology facilities of the Albert Einstein College of Medicine. We thank J. Staudinger (University of Kansas, Lawrence, KS) and W. Xie (University of Pittsburgh, Pittsburgh, PA) for providing Nr1i2 −/− and humanized PXR transgenic mice ( hNr1i2 ), respectively. This work was supported by NIH grants CA127231 (S. Mani), CA161879 (S. Mani), and AI097375 (K.M.K.), by Damon Runyon Foundation Clinical Investigator Award (CI 1502) P30CA013330 (S. Mani), by institutional support funds from the University of Connecticut Health Center (K.M.K.), and by European Commission FP7 grant METACARDIS (FP7- HEALTH-2012-INNOVATION-I-305312 to J.L.V., J.K.N., and M.E.D.). ",

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T1 - Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4

AU - Venkatesh, Madhukumar

AU - Mukherjee, Subhajit

AU - Wang, Hongwei

AU - Li, Hao

AU - Sun, Katherine

AU - Benechet, Alexandre P.

AU - Qiu, Zhijuan

AU - Maher, Leigh

AU - Redinbo, Matthew R.

AU - Phillips, Robert S.

AU - Fleet, James C.

AU - Kortagere, Sandhya

AU - Mukherjee, Paromita

AU - Fasano, Alessio

AU - Le Ven, Jessica

AU - Nicholson, Jeremy K.

AU - Dumas, Marc E.

AU - Khanna, Kamal M.

AU - Mani, Sridhar

N1 - Funding Information: We thank the Analytical Imaging and Histotechnology and comparative pathology facilities of the Albert Einstein College of Medicine. We thank J. Staudinger (University of Kansas, Lawrence, KS) and W. Xie (University of Pittsburgh, Pittsburgh, PA) for providing Nr1i2 −/− and humanized PXR transgenic mice ( hNr1i2 ), respectively. This work was supported by NIH grants CA127231 (S. Mani), CA161879 (S. Mani), and AI097375 (K.M.K.), by Damon Runyon Foundation Clinical Investigator Award (CI 1502) P30CA013330 (S. Mani), by institutional support funds from the University of Connecticut Health Center (K.M.K.), and by European Commission FP7 grant METACARDIS (FP7- HEALTH-2012-INNOVATION-I-305312 to J.L.V., J.K.N., and M.E.D.).

PY - 2014/8/21

Y1 - 2014/8/21

N2 - 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 invivo, 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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ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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