Deletion of Intestinal SHP Impairs Short-term Response to Cholic Acid Challenge in Male Mice

Small heterodimer partner (SHP) is a crucial regulator of bile acid (BA) transport and synthesis; however, its intestine-specific role is not fully understood. Here, we report that male intestine-specific Shp knockout (IShpKO) mice exhibit higher intestinal BA but not hepatic or serum BA levels compared with the f/f Shp animals when challenged with an acute (5-day) 1% cholic acid (CA) diet. We also found that BA synthetic genes Cyp7a1 and Cyp8b1 are not repressed to the same extent in IShpKO compared with control mice post-CA challenge. Loss of intestinal SHP did not alter Fxrα messenger RNA (mRNA) but increased Asbt (BA ileal uptake transporter) and Ostα (BA ileal efflux transporter) expression even under chow-fed conditions. Surprisingly, the acute CA diet in IShpKO did not elicit the expected induction of Fgf15 but was able to maintain the suppression of Asbt, and Ostα/β mRNA levels. At the protein level, apical sodium-dependent bile acid transporter (ASBT) was downregulated, while organic solute transporter-α/β (OSTα/β) expression was induced and maintained regardless of diet. Examination of ileal histology in IShpKO mice challenged with acute CA diet revealed reduced villi length and goblet cell numbers. However, no difference in villi length, and the expression of BA regulator and transporter genes, was seen between f/f Shp and IShpKO animals after a chronic (14-day) CA diet, suggesting a potential adaptive response. We found the upregulation of the Pparα-Ugt axis after 14 days of CA diet may reduce the BA burden and compensate for the ileal SHP function. Thus, our study reveals that ileal SHP expression contributes to both overall intestinal structure and BA homeostasis.