Sleeve Gastrectomy Reveals the Plasticity of the Human Gastric Epithelium

Gastric acidity is essential for the function of the human stomach. pH homeostasis is facilitated by gastrin, a hormone secreted from the gastric antrum in response to a rise in pH, leading to acid secretion from the gastric corpus. Sleeve gastrectomy (SG), a bariatric surgery in which 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. We used histology and single-cell RNA sequencing to study the gastric antrum and corpus epithelium of naïve patients, and of patients who underwent SG years earlier. SG was associated with an increase in a sub-population of acid-secreting parietal cells which overexpress respiratory enzymes and carbonic anhydrase, and an increase in the fraction of histamine-secreting enterochromaffin-like cells (ECLs). Notably, ECLs of SG-operated patients over-expressed genes coding for biosynthesis of neuropeptides and of serotonin. Mathematical modeling of pH homeostasis by gastrin showed that fasting pH is not sensitive to nearly all model parameters. Robustness is a result of the ability of gastrin to induce acid secretion as well as increase the number of ECLs and parietal cells, a feedback analogous to a non-linear proportional and integral feedback control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative predictions of the model on the gastric response to SG were validated in patients: SG induced a 5-fold increase in blood gastrin levels as early as one day post-surgery, and an over 30% increase in the number of parietal cells and ECLs per gland years after surgery. Together, these empirical and modeling data demonstrate how the human gastric epithelium remodels following SG at the molecular and cellular levels, and more generally how trophic hormones such as gastrin enable robust adaptation of tissue function to meet physiological demand.