Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains

Rachel K. Zwick; Petr Kasparek; Brisa Palikuqi; Sara Viragova; Laura Weichselbaum; Christopher S. McGinnis; Kara L. McKinley; Asoka Rathnayake; Dedeepya Vaka; Vinh Nguyen; Coralie Trentesaux; Efren Reyes; Alexander R. Gupta; Zev J. Gartner; Richard M. Locksley; James M. Gardner; Shalev Itzkovitz; Dario Boffelli; Ophir D. Klein

doi:10.1038/s41556-023-01337-z

Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains

Rachel K. Zwick, Petr Kasparek, Brisa Palikuqi, Sara Viragova, Laura Weichselbaum, Christopher S. McGinnis, Kara L. McKinley, Asoka Rathnayake, Dedeepya Vaka, Vinh Nguyen, Coralie Trentesaux, Efren Reyes, Alexander R. Gupta, Zev J. Gartner, Richard M. Locksley, James M. Gardner, Shalev Itzkovitz, Dario Boffelli, Ophir D. Klein^*

^*Corresponding author for this work

Department of Molecular Cell Biology

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

2 Citations (Scopus)

Abstract

A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.

Original language	English
Pages (from-to)	250-262
Number of pages	13
Journal	Nature Cell Biology
Volume	26
Issue number	2
DOIs	https://doi.org/10.1038/s41556-023-01337-z
Publication status	Published Online - 6 Feb 2024

Bibliographical note

We are grateful to H. Miyazaki, D. Castillo-Azofeifa and other members of the Klein laboratory for valuable discussions, experimental assistance and protocol development. We thank M. Helmrath, N. Shroyer, Y.-H. Lo and members of the Intestinal Stem Cell Consortium for critical scientific input throughout this project. We also thank B. Ohlstein, I. Chen, K. Bahar Halpern, Z. Sullivan, D. Conrad, J. Sheu-Gruttadauria, J. Bush, and E. Chow for sharing data, resources and expertise. This study benefited from the following cores and facilities at UCSF: the Center for Advanced Technology, the Institute for Human Genetics, Parnassus Flow Cytometry Core, ViraCore, VIable Tissue Acquisition Lab, the Biological Imaging Development CoLab, and the Laboratory Animal Resource Center. Portions of schematic figure panels were created with BioRender.com. This work was funded by NIH R35-DE026602 and U01DK103147 from the Intestinal Stem Cell Consortium, a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases (to O.D.K.). R.K.Z. was supported by NIH F32 DK125089 and an American Cancer Society—South Florida Research Council Postdoctoral Fellowship (PF-20-037-01-DDC). Finally, our most sincere gratitude goes to Donor Network West, and to the organ donors and their families for their generosity in supporting basic science research.
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.

All Science Journal Classification (ASJC) codes

Cell Biology

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10.1038/s41556-023-01337-z

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Zwick, R. K., Kasparek, P., Palikuqi, B., Viragova, S., Weichselbaum, L., McGinnis, C. S., McKinley, K. L., Rathnayake, A., Vaka, D., Nguyen, V., Trentesaux, C., Reyes, E., Gupta, A. R., Gartner, Z. J., Locksley, R. M., Gardner, J. M., Itzkovitz, S., Boffelli, D., & Klein, O. D. (2024). Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. Nature Cell Biology, 26(2), 250-262. Advance online publication. https://doi.org/10.1038/s41556-023-01337-z

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abstract = "A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.",

author = "Zwick, {Rachel K.} and Petr Kasparek and Brisa Palikuqi and Sara Viragova and Laura Weichselbaum and McGinnis, {Christopher S.} and McKinley, {Kara L.} and Asoka Rathnayake and Dedeepya Vaka and Vinh Nguyen and Coralie Trentesaux and Efren Reyes and Gupta, {Alexander R.} and Gartner, {Zev J.} and Locksley, {Richard M.} and Gardner, {James M.} and Shalev Itzkovitz and Dario Boffelli and Klein, {Ophir D.}",

note = "We are grateful to H. Miyazaki, D. Castillo-Azofeifa and other members of the Klein laboratory for valuable discussions, experimental assistance and protocol development. We thank M. Helmrath, N. Shroyer, Y.-H. Lo and members of the Intestinal Stem Cell Consortium for critical scientific input throughout this project. We also thank B. Ohlstein, I. Chen, K. Bahar Halpern, Z. Sullivan, D. Conrad, J. Sheu-Gruttadauria, J. Bush, and E. Chow for sharing data, resources and expertise. This study benefited from the following cores and facilities at UCSF: the Center for Advanced Technology, the Institute for Human Genetics, Parnassus Flow Cytometry Core, ViraCore, VIable Tissue Acquisition Lab, the Biological Imaging Development CoLab, and the Laboratory Animal Resource Center. Portions of schematic figure panels were created with BioRender.com. This work was funded by NIH R35-DE026602 and U01DK103147 from the Intestinal Stem Cell Consortium, a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases (to O.D.K.). R.K.Z. was supported by NIH F32 DK125089 and an American Cancer Society—South Florida Research Council Postdoctoral Fellowship (PF-20-037-01-DDC). Finally, our most sincere gratitude goes to Donor Network West, and to the organ donors and their families for their generosity in supporting basic science research. Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

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Zwick, RK, Kasparek, P, Palikuqi, B, Viragova, S, Weichselbaum, L, McGinnis, CS, McKinley, KL, Rathnayake, A, Vaka, D, Nguyen, V, Trentesaux, C, Reyes, E, Gupta, AR, Gartner, ZJ, Locksley, RM, Gardner, JM, Itzkovitz, S, Boffelli, D & Klein, OD 2024, 'Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains', Nature Cell Biology, vol. 26, no. 2, pp. 250-262. https://doi.org/10.1038/s41556-023-01337-z

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T1 - Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains

AU - Zwick, Rachel K.

AU - Kasparek, Petr

AU - Palikuqi, Brisa

AU - Viragova, Sara

AU - Weichselbaum, Laura

AU - McGinnis, Christopher S.

AU - McKinley, Kara L.

AU - Rathnayake, Asoka

AU - Vaka, Dedeepya

AU - Nguyen, Vinh

AU - Trentesaux, Coralie

AU - Reyes, Efren

AU - Gupta, Alexander R.

AU - Gartner, Zev J.

AU - Locksley, Richard M.

AU - Gardner, James M.

AU - Itzkovitz, Shalev

AU - Boffelli, Dario

AU - Klein, Ophir D.

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N2 - A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.

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DO - 10.1038/s41556-023-01337-z

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ER -

Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains

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