Sleeve gastrectomy reveals the plasticity of the human gastric epithelium

Amit Elad; Botros Moalem; Dana Sender; Aya Bardugo; Ki Suk Kim; Yhara Arad; Haya Benhayon; Ayelet Gal Etzyoni; Nehemia Greenstein; Aviv Halfon; Sarah Knapp; Michelle Malis; Bailey Peck; Itia Samuel; Amram Kupietzky; Saleh Daher; Esther Forkosh; David Hakimian; Tiberiu Hershcovici; Nadav Ilani; Lior Katz; Moshe Rottenstreich; Elez Vainer; Yuval Ishay; Eitan Zlotnick; Abed Nasereddin; Idid Shiff; Ariel Benson; Ronit Grinbaum; Siddhartha Mishra; Shlomi Kotler; Linda C. Samuelson; Darleen A. Sandoval; Rachel Ben-Haroush Schyr; Danny Ben-Zvi

doi:10.1038/s41467-025-56135-y

Sleeve gastrectomy reveals the plasticity of the human gastric epithelium

Amit Elad, Botros Moalem, Dana Sender, Aya Bardugo, Ki Suk Kim, Yhara Arad, Haya Benhayon, Ayelet Gal Etzyoni, Nehemia Greenstein, Aviv Halfon, Sarah Knapp, Michelle Malis, Bailey Peck, Itia Samuel, Amram Kupietzky, Saleh Daher, Esther Forkosh, David Hakimian, Tiberiu Hershcovici, Nadav IlaniLior Katz, Moshe Rottenstreich, Elez Vainer, Yuval Ishay, Eitan Zlotnick, Abed Nasereddin, Idid Shiff, Ariel Benson, Ronit Grinbaum, Siddhartha Mishra, Shlomi Kotler, Linda C. Samuelson, Darleen A. Sandoval, Rachel Ben-Haroush Schyr, Danny Ben-Zvi^*

^*Corresponding author for this work

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

Abstract

Gastrin is secreted following a rise in gastric pH, leading to gastric acid secretion. Sleeve gastrectomy (SG), a bariatric surgery where 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. Using histology, and single-cell RNA sequencing of the gastric epithelium in 12 women, we observed that SG is associated with an increase in a sub-population of acid-secreting parietal cells that overexpress respiratory enzymes and an increase in histamine-secreting enterochromaffin-like cells (ECLs). ECLs of SG-operated patients overexpressed genes coding for biosynthesis of neuropeptides and serotonin. Mathematical modeling showed that pH homeostasis by gastrin is analogous to non-linear proportional and integral control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative model predictions were validated in patients. The results demonstrate human gastric epithelium remodeling following SG at the molecular and cellular levels, and more generally how trophic hormones enable robust adaptation of tissue function to meet physiological demand.

Original language	English
Article number	869
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-56135-y
State	Published - Dec 2025

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Elad, A., Moalem, B., Sender, D., Bardugo, A., Kim, K. S., Arad, Y., Benhayon, H., Gal Etzyoni, A., Greenstein, N., Halfon, A., Knapp, S., Malis, M., Peck, B., Samuel, I., Kupietzky, A., Daher, S., Forkosh, E., Hakimian, D., Hershcovici, T., ... Ben-Zvi, D. (2025). Sleeve gastrectomy reveals the plasticity of the human gastric epithelium. Nature Communications, 16(1), Article 869. https://doi.org/10.1038/s41467-025-56135-y

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abstract = "Gastrin is secreted following a rise in gastric pH, leading to gastric acid secretion. Sleeve gastrectomy (SG), a bariatric surgery where 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. Using histology, and single-cell RNA sequencing of the gastric epithelium in 12 women, we observed that SG is associated with an increase in a sub-population of acid-secreting parietal cells that overexpress respiratory enzymes and an increase in histamine-secreting enterochromaffin-like cells (ECLs). ECLs of SG-operated patients overexpressed genes coding for biosynthesis of neuropeptides and serotonin. Mathematical modeling showed that pH homeostasis by gastrin is analogous to non-linear proportional and integral control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative model predictions were validated in patients. The results demonstrate human gastric epithelium remodeling following SG at the molecular and cellular levels, and more generally how trophic hormones enable robust adaptation of tissue function to meet physiological demand.",

author = "Amit Elad and Botros Moalem and Dana Sender and Aya Bardugo and Kim, {Ki Suk} and Yhara Arad and Haya Benhayon and {Gal Etzyoni}, Ayelet and Nehemia Greenstein and Aviv Halfon and Sarah Knapp and Michelle Malis and Bailey Peck and Itia Samuel and Amram Kupietzky and Saleh Daher and Esther Forkosh and David Hakimian and Tiberiu Hershcovici and Nadav Ilani and Lior Katz and Moshe Rottenstreich and Elez Vainer and Yuval Ishay and Eitan Zlotnick and Abed Nasereddin and Idid Shiff and Ariel Benson and Ronit Grinbaum and Siddhartha Mishra and Shlomi Kotler and Samuelson, {Linda C.} and Sandoval, {Darleen A.} and {Ben-Haroush Schyr}, Rachel and Danny Ben-Zvi",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-56135-y",

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volume = "16",

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Elad, A, Moalem, B, Sender, D, Bardugo, A, Kim, KS, Arad, Y, Benhayon, H, Gal Etzyoni, A, Greenstein, N, Halfon, A, Knapp, S, Malis, M, Peck, B, Samuel, I, Kupietzky, A, Daher, S, Forkosh, E, Hakimian, D, Hershcovici, T, Ilani, N, Katz, L, Rottenstreich, M, Vainer, E, Ishay, Y, Zlotnick, E, Nasereddin, A, Shiff, I, Benson, A, Grinbaum, R, Mishra, S, Kotler, S, Samuelson, LC, Sandoval, DA, Ben-Haroush Schyr, R & Ben-Zvi, D 2025, 'Sleeve gastrectomy reveals the plasticity of the human gastric epithelium', Nature Communications, vol. 16, no. 1, 869. https://doi.org/10.1038/s41467-025-56135-y

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AU - Elad, Amit

AU - Moalem, Botros

AU - Sender, Dana

AU - Bardugo, Aya

AU - Kim, Ki Suk

AU - Arad, Yhara

AU - Benhayon, Haya

AU - Gal Etzyoni, Ayelet

AU - Greenstein, Nehemia

AU - Halfon, Aviv

AU - Knapp, Sarah

AU - Malis, Michelle

AU - Peck, Bailey

AU - Samuel, Itia

AU - Kupietzky, Amram

AU - Daher, Saleh

AU - Forkosh, Esther

AU - Hakimian, David

AU - Hershcovici, Tiberiu

AU - Ilani, Nadav

AU - Katz, Lior

AU - Rottenstreich, Moshe

AU - Vainer, Elez

AU - Ishay, Yuval

AU - Zlotnick, Eitan

AU - Nasereddin, Abed

AU - Shiff, Idid

AU - Benson, Ariel

AU - Grinbaum, Ronit

AU - Mishra, Siddhartha

AU - Kotler, Shlomi

AU - Samuelson, Linda C.

AU - Sandoval, Darleen A.

AU - Ben-Haroush Schyr, Rachel

AU - Ben-Zvi, Danny

PY - 2025/12

Y1 - 2025/12

N2 - Gastrin is secreted following a rise in gastric pH, leading to gastric acid secretion. Sleeve gastrectomy (SG), a bariatric surgery where 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. Using histology, and single-cell RNA sequencing of the gastric epithelium in 12 women, we observed that SG is associated with an increase in a sub-population of acid-secreting parietal cells that overexpress respiratory enzymes and an increase in histamine-secreting enterochromaffin-like cells (ECLs). ECLs of SG-operated patients overexpressed genes coding for biosynthesis of neuropeptides and serotonin. Mathematical modeling showed that pH homeostasis by gastrin is analogous to non-linear proportional and integral control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative model predictions were validated in patients. The results demonstrate human gastric epithelium remodeling following SG at the molecular and cellular levels, and more generally how trophic hormones enable robust adaptation of tissue function to meet physiological demand.

AB - Gastrin is secreted following a rise in gastric pH, leading to gastric acid secretion. Sleeve gastrectomy (SG), a bariatric surgery where 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. Using histology, and single-cell RNA sequencing of the gastric epithelium in 12 women, we observed that SG is associated with an increase in a sub-population of acid-secreting parietal cells that overexpress respiratory enzymes and an increase in histamine-secreting enterochromaffin-like cells (ECLs). ECLs of SG-operated patients overexpressed genes coding for biosynthesis of neuropeptides and serotonin. Mathematical modeling showed that pH homeostasis by gastrin is analogous to non-linear proportional and integral control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative model predictions were validated in patients. The results demonstrate human gastric epithelium remodeling following SG at the molecular and cellular levels, and more generally how trophic hormones enable robust adaptation of tissue function to meet physiological demand.

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Sleeve gastrectomy reveals the plasticity of the human gastric epithelium

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