Tis7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome

Abstract

Effective therapies are limited for patients with parenteral nutrition-dependent short bowel syndrome. We previously showed that intestinal expression of the transcriptional coregulator tetradecanoyl phorbol acetate-induced sequence 7 ( tis7) is markedly increased during the adaptive response following massive small bowel resection and tis7 plays a role in normal gut lipid metabolism. Here, we further explore the functional implications of tis7 deletion in intestinal lipid metabolism and the adaptive response following small bowel resection. Intestinal tis7 transgenic ( tis7tg), tis7−/−, and wild-type (WT) littermates were subjected to 50% small bowel resection. Mice were fed a control or a high-saturated-fat (42% energy) diet for 21 days. Survival, body weight recovery, lipid absorption, mucosal lipid analysis, and the morphometric adaptive response were analyzed. Quantitative real-time PCR was performed to identify tis7 downstream gene targets. Postresection survival was markedly reduced in high-fat, but not control, diet-fed tis7−/− mice. Decreased survival was associated with anastomotic inflammation and intestinal obstruction postresection. High-fat, but not control, diet-fed tis7−/− mice had increased intestinal IL-6 expression. Intestinal lipid trafficking was altered in tis7−/− compared with WT mice postresection. In contrast, high-fat diet-fed tis7tg mice had improved survival postresection compared with WT littermates. High-fat diet feeding in the setting of tis7 deletion resulted in postresection anastomotic inflammation and small bowel obstruction. Tolerance of a calorie-rich, high-fat diet postresection may require tis7 and its target genes. The presence of luminal fat in the setting of tis7 deletion promotes an intestinal inflammatory response postresection.

Nutritional strategies to enhance adaptation in intestinal failure

“…Only recently genuine host factors have been identified that may influence adaptation. Tetradecanoyl phorbol acetate-induced sequence 7 (Tis7) has been characterized to mediate adaptive responses in the intestine and deletion of Tis7 reduces survival in a mouse model of short bowel syndrome [18]. Based on findings in two intestinal transplantation cohorts we have found an increased frequency of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations in patients with short bowel syndrome who did not have Crohn's disease, suggesting that NOD2 plays a role in adaptation [19][20][21].…”

Proline Absorption and SGK1 Expression are Inhibited in Intestinal Tis7 Transgenic Mice

“…The protocols for intestinal resection surgery and for the provision of a liquid high fat diet (42% kcals from fat, Modified, High Fat AIN-93M purified liquid diet 710147, Dyets Inc, Bethlehem PA) for 3 weeks post-op were as described [7]. Briefly, two days prior to surgery mice were acclimated to a liquid control diet nutritionally equivalent to standard rodent chow (described below).…”

The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)

“…On the other hand, we have shown that as a result of impaired intestinal lipid absorption TIS7 knockout mice displayed lower body adiposity 11 . Compared with wild type (WT) littermates, TIS7 knockout mice do not gain weight when chronically fed a HFD and TIS7 deletion results in delayed lipid absorption and altered intestinal and hepatic lipid trafficking, with reduced intestinal TG, cholesterol, and free fatty acid mucosal levels in the jejunum 11,12 . However, at this point, the precise mechanism of TIS7 action in the regulation of lipid absorption and metabolism on the molecular level was unclear.…”