SHP‐2 Phosphatase Prevents Colonic Inflammation by Controlling Secretory Cell Differentiation and Maintaining Host‐Microbiota Homeostasis

Abstract

Polymorphisms in the PTPN11 gene encoding for the tyrosine phosphatase SHP-2 were described in patients with ulcerative colitis. We have recently demonstrated that mice with an intestinal epithelial cell-specific deletion of SHP-2 (SHP-2IEC-KO) develop severe colitis 1 month after birth. However, the mechanisms by which SHP-2 deletion induces colonic inflammation remain to be elucidated. We generated SHP-2IEC-KO mice lacking Myd88 exclusively in the intestinal epithelium. The colonic phenotype was histologically analyzed and cell differentiation was determined by electron microscopy and lysozyme or Alcian blue staining. Microbiota composition was analyzed by 16S sequencing. Results show that innate defense genes including those specific to Paneth cells were strongly up-regulated in SHP-2-deficient colons. Expansion of intermediate cells (common progenitors of the Goblet and Paneth cell lineages) was found in the colon of SHP-2IEC-KO mice whereas Goblet cell number was clearly diminished. These alterations in Goblet/intermediate cell ratio were noticed 2 weeks after birth, before the onset of inflammation and were associated with significant alterations in microbiota composition. Indeed, an increase in Enterobacteriaceae and a decrease in Firmicutes were observed in the colon of these mice, indicating that dysbiosis also occurred prior to inflammation. Importantly, loss of epithelial Myd88 expression inhibited colitis development in SHP-2IEC-KO mice, rescued Goblet/intermediate cell ratio, and prevented NFκB hyperactivation and inflammation. These data indicate that SHP-2 is functionally important for the maintenance of appropriate barrier function and host-microbiota homeostasis in the large intestine.

The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration

“…Alcian blue staining revealed a marked increase in goblet cell numbers in Braf V600E murine colons as opposed to controls and the goblet cell reduction observed in Shp-2 IEC-KO mice was rescued in Shp-2 IEC-KO ;Braf V600E mice ( Figure 4D). Additionally, we did not find lysozyme-positive cells in Shp-2 IEC-KO ;Braf V600E colons, in contrast to Shp-2 IEC-KO colons (Figure 4E, see arrows) [21]. Of importance, we found increased phosphorylated ERK1/2 MAPK in colonic epithelial enrichments from Shp-2 IEC-E76K mice ( Figure 4F).…”

“…Intestinal mucosa disruption with crypt abscesses and immune cell infiltration indicate that the Shp‐2 IEC‐KO phenotype is similar to the phenotype observed in UC patients as opposed to CD patients . Importantly, a marked reduction in goblet cell numbers is observed before the inflammation onset . Hence, the decrease in goblet cell numbers associated with reduced secretion of the protective mucus layer could explain the spontaneous colitis developed by Shp‐2 IEC‐KO mice .…”

Regulation of faecal biomarkers in inflammatory bowel disease patients treated with oral mastiha (Pistacia lentiscus) supplement: A double‐blind and placebo‐controlled randomised trial

“…When analysing lysozyme in UC or CD individually, significantly lower levels at follow‐up for the mastiha group in UC patients were reported. Lysozyme, an antimicrobial protein that regulates innate immune response, is expressed in both entities, CD and UC, mainly in small intestine but markedly also in the colon, as shown in both experimental animals (Coulombe et al, ) and humans (Fahlgren, Hammarström, Danielsson, & Hammarström, ; Rubio, ). Because increased lysozyme expression is correlated with dysbiosis and with inflammation, herein, we could hypothesise that the effect of mastiha is rather a prebiotic one and possibly stronger in UC patients, related to the contained phenolic compounds and arabinogalactanes, both reported to have prebiotic activities (Dion, Chappuis, & Ripoll, ; Williamson & Clifford, ).…”

Novel insights into microbiome in colitis and colorectal cancer

“…Notably, Fx -/- mice sequentially developed colitis, dysplasia and adenocarcinoma, which can be prevented by antibiotic treatment (12). Similarly, mice with IEC-specific deletion of the IBD susceptibility gene Ptpn11 exhibit impaired goblet cell differentiation in the colon and dysbiotic microbiota which drive spontaneous colitis development (13). …”