Objective: In short bowel syndrome (SBS), although a remaining colon improves patient outcome, there is no direct evidence of a mucosal colonic adaptation in humans. This prospective study evaluates morphology, proliferation status, transporters expression level in the epithelium of the remaining colon of SBS adult patients compared to controls. The targeted transporters were Na⁺/H⁺ exchangers (NHE2 and 3) and oligopeptide transporter (PepT1). Methods: Twelve adult patients with a jejuno-colonic anastomosis were studied at least two years after the last surgery and compared to 11 healthy controls. The depth of crypts and number of epithelial cells per crypt were quantified. The proliferating and apoptotic cell contents were evaluated by revealing Ki67, PCNA and caspase 3. NHE2, NHE3, PepT1 mRNAs and PepT1 protein were quantified by quantitative RT-PCR and western blot respectively. Results: In SBS patients compared to controls: (a) hyperphagia and severe malabsorption were documented; (b) crypt depth and number of cells per crypt was 35 percent and 22 percent higher respectively (p<0.005) whereas the proliferation and apoptotic levels per crypt were unchanged; (c) NHE2 mRNA was unmodified; NHE3 mRNA was down-regulated near by the anastomosis and unmodified distally; PepT1 mRNA and protein were unmodified. Conclusion: In hyperphagic SBS patients with severe malabsorption, adaptive colonic changes include an increased absorptive surface with an unchanged proliferative/apoptotic ratio and well preserved absorptive NHE2, NHE3 and PepT1 transporters. This is the first study showing a controlled non pharmacological "hyperplasia" in the colon of SBS patients.