Diet-induced changes in the colonic microenvironment reduce polyp development in APC ^Min/+ Msh2 ^-/- mice by triggering ER stress

CRC development is a complex disease driven by the interplay between genetic mutations, diet, gut microbiota and inflammation. However, how these factors work together to exert their effect on disease initiation and progression is still unclear. In this study, we investigated the effects of a 10% low carbohydrate (10% LC) diet and a normal diet supplemented with 10% pectin from apple (ND+10% Pec) on CRC progression and colonic homeostasis. We showed that although these dietary regimens had differential effects on the gut microbiota and the production of butyrate, they both reduced CRC development in the APC ^Min/+ Msh2 ^-/- mouse model. 10% LC diet strongly reduced the number of goblet cells while ND+10% Pec had no such effect, but both regimens induced upregulation of Muc-2 . The changes in the gut microbiota, butyrate levels and increased Muc-2 expression, however, trigger endoplasmic reticulum (ER) stress. Our results show that a 10% LC diet triggered endoplasmic reticulum stress (ER stress) via induction of the PERK pathway, while ND+10% Pec also increased the splicing of the XBP1. In addition, both diets induced dramatic expression of the heat shock proteins Hsp27 and Hsp70, further resulting in increased barrier function. These events are likely to protect the cells and help them cope with environmental changes. However, the induced cellular stress conditions, known to suppress cell proliferation, could be a mechanism through which these regimens attenuate CRC.