Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice

Frederic A. Carvalho; Omry Koren; Julia K. Goodrich; Malin E.V. Johansson; Ilke Nalbantoglu; Jesse D. Aitken; Yueju Su; Benoit Chassaing; William A. Walters; Antonio González; Jose C. Clemente; Tyler C. Cullender; Nicolas Barnich; Arlette Darfeuille-Michaud; Matam Vijay-Kumar; Rob Knight; Ruth E. Ley; Andrew T. Gewirtz

doi:10.1016/j.chom.2012.07.004

Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice

Frederic A. Carvalho, Omry Koren, Julia K. Goodrich, Malin E.V. Johansson, Ilke Nalbantoglu, Jesse D. Aitken, Yueju Su, Benoit Chassaing, William A. Walters, Antonio González, Jose C. Clemente, Tyler C. Cullender, Nicolas Barnich, Arlette Darfeuille-Michaud, Matam Vijay-Kumar, Rob Knight, Ruth E. Ley, Andrew T. Gewirtz

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

416 Scopus citations

Abstract

Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal proinflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and noncolitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO, while their noncolitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of proteobacteria, especially enterobacteria species including E. coli, observed in close proximity to the gut epithelium were a striking feature of colitic microbiota. A Crohn's disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation, and harboring proteobacteria can drive and/or instigate chronic colitis.

Original language	English
Pages (from-to)	139-152
Number of pages	14
Journal	Cell Host and Microbe
Volume	12
Issue number	2
DOIs	https://doi.org/10.1016/j.chom.2012.07.004
State	Published - 16 Aug 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank Catherine Paul for technical support and Gunnar Hannson for helpful discussions. We also gratefully acknowledge Maureen Bower, Dr. Balfour Sartor, and the National Gnotobiotic Rodent Resource Center (NGRRC) at UNC. This work was supported by NIH grants DK061417 and DK083890 (to A.T.G.). F.A.C. is a recipient of the Research Fellowship award from the Crohn’s and Colitis Foundation of America (CCFA). NGRRC is supported by grants from the NIH (P40RR018603 and P30 DK 34987) and CCFA. R.K. is supported in part by the NIH, CCFA, and the Howard Hughes Medical Institute.

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10.1016/j.chom.2012.07.004

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Carvalho, F. A., Koren, O., Goodrich, J. K., Johansson, M. E. V., Nalbantoglu, I., Aitken, J. D., Su, Y., Chassaing, B., Walters, W. A., González, A., Clemente, J. C., Cullender, T. C., Barnich, N., Darfeuille-Michaud, A., Vijay-Kumar, M., Knight, R., Ley, R. E., & Gewirtz, A. T. (2012). Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host and Microbe, 12(2), 139-152. https://doi.org/10.1016/j.chom.2012.07.004

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title = "Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice",

abstract = "Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal proinflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and noncolitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO, while their noncolitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of proteobacteria, especially enterobacteria species including E. coli, observed in close proximity to the gut epithelium were a striking feature of colitic microbiota. A Crohn's disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation, and harboring proteobacteria can drive and/or instigate chronic colitis.",

author = "Carvalho, {Frederic A.} and Omry Koren and Goodrich, {Julia K.} and Johansson, {Malin E.V.} and Ilke Nalbantoglu and Aitken, {Jesse D.} and Yueju Su and Benoit Chassaing and Walters, {William A.} and Antonio Gonz{\'a}lez and Clemente, {Jose C.} and Cullender, {Tyler C.} and Nicolas Barnich and Arlette Darfeuille-Michaud and Matam Vijay-Kumar and Rob Knight and Ley, {Ruth E.} and Gewirtz, {Andrew T.}",

note = "Funding Information: We thank Catherine Paul for technical support and Gunnar Hannson for helpful discussions. We also gratefully acknowledge Maureen Bower, Dr. Balfour Sartor, and the National Gnotobiotic Rodent Resource Center (NGRRC) at UNC. This work was supported by NIH grants DK061417 and DK083890 (to A.T.G.). F.A.C. is a recipient of the Research Fellowship award from the Crohn{\textquoteright}s and Colitis Foundation of America (CCFA). NGRRC is supported by grants from the NIH (P40RR018603 and P30 DK 34987) and CCFA. R.K. is supported in part by the NIH, CCFA, and the Howard Hughes Medical Institute. ",

year = "2012",

month = aug,

day = "16",

doi = "10.1016/j.chom.2012.07.004",

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Carvalho, FA, Koren, O, Goodrich, JK, Johansson, MEV, Nalbantoglu, I, Aitken, JD, Su, Y, Chassaing, B, Walters, WA, González, A, Clemente, JC, Cullender, TC, Barnich, N, Darfeuille-Michaud, A, Vijay-Kumar, M, Knight, R, Ley, RE & Gewirtz, AT 2012, 'Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice', Cell Host and Microbe, vol. 12, no. 2, pp. 139-152. https://doi.org/10.1016/j.chom.2012.07.004

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T1 - Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice

AU - Carvalho, Frederic A.

AU - Koren, Omry

AU - Goodrich, Julia K.

AU - Johansson, Malin E.V.

AU - Nalbantoglu, Ilke

AU - Aitken, Jesse D.

AU - Su, Yueju

AU - Chassaing, Benoit

AU - Walters, William A.

AU - González, Antonio

AU - Clemente, Jose C.

AU - Cullender, Tyler C.

AU - Barnich, Nicolas

AU - Darfeuille-Michaud, Arlette

AU - Vijay-Kumar, Matam

AU - Knight, Rob

AU - Ley, Ruth E.

AU - Gewirtz, Andrew T.

N1 - Funding Information: We thank Catherine Paul for technical support and Gunnar Hannson for helpful discussions. We also gratefully acknowledge Maureen Bower, Dr. Balfour Sartor, and the National Gnotobiotic Rodent Resource Center (NGRRC) at UNC. This work was supported by NIH grants DK061417 and DK083890 (to A.T.G.). F.A.C. is a recipient of the Research Fellowship award from the Crohn’s and Colitis Foundation of America (CCFA). NGRRC is supported by grants from the NIH (P40RR018603 and P30 DK 34987) and CCFA. R.K. is supported in part by the NIH, CCFA, and the Howard Hughes Medical Institute.

PY - 2012/8/16

Y1 - 2012/8/16

N2 - Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal proinflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and noncolitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO, while their noncolitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of proteobacteria, especially enterobacteria species including E. coli, observed in close proximity to the gut epithelium were a striking feature of colitic microbiota. A Crohn's disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation, and harboring proteobacteria can drive and/or instigate chronic colitis.

AB - Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal proinflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and noncolitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO, while their noncolitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of proteobacteria, especially enterobacteria species including E. coli, observed in close proximity to the gut epithelium were a striking feature of colitic microbiota. A Crohn's disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation, and harboring proteobacteria can drive and/or instigate chronic colitis.

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Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice

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