Treatment of bile acid malabsorption using ileal stem cell transplantation

Abstract

Purpose: To determine if ileal stem cells transplanted into a segment of jejunum can be used to treat bile acid malabsorption. Methods: In adult Lewis rats, a 15-cm segment of jejunum was isolated with its blood circulation left intact and partially stripped of enterocytes using luminal high-velocity perfusions with 3 mM EDTA solutions. Continuity was restored by anastomosing the proximal and distal gut. Ileal stem cell clusters were harvested from neo-natal Lewis rats and transplanted into these segments. After 4 weeks, rats underwent an ileectomy and the isolated segment was anastomosed in its place. After an additional 4 weeks, a 48 hour stool collection was performed. The engrafted segment was harvested for taurocholate uptake studies, ileal bile acid transporter (IBAT) protein (by immunohistomorphometry) and IBAT mRNA quantitation (by RT-PCR). Data was analyzed by ANOVA/t-test. Rats undergoing ileectomy, jejunectomy or sham operation served as controls. Results: Total bile acid loss in the stool was significantly lower in rats with a neo-ileum compared to rats with an ileectomy (p < 0.004; Fig. 1). Na+-dependent taurocholate uptake was significantly increased in the neo-ileum compared to the jejunum (p < 0.001). IBAT protein signal intensity was significantly higher in the neo-ileum compared to jejunum (p < 0.001). IBAT mRNA amounts were significantly higher (p < 0.004) than in the jejunum however comparable to the ileum. Conclusion: Ileal stem cells were used to establish a new zone of active bile acid uptake and IBAT expression in a jejunal segment. This neo-ileum eliminated loss of bile acids in the stool after ileectomy. This is the first time intestinal stem cell transplantation has been shown to correct a clinical malabsorption syndrome.