Loss of Slfn3 induces a sex-dependent repair vulnerability after 50% bowel resection

Abstract

Bowel resection accelerates enterocyte proliferation in the remaining gut that may have suboptimal absorptive and digestive capacity because of proliferation-associated decrease in functional differentiation markers. We hypothesized that although Slfn3 is an important regulator of murine enterocytic differentiation, Slfn3 would have less impact on the bowel resection adaptation where accelerated proliferation takes priority over differentiation. We assessed proliferation, cell shedding, and enterocyte differentiation markers of mucosa from resected and postoperative bowel of wild type (WT) and Slfn3 knockout (Slfn3KO) mice. Villus length and crypt depth were increased in WT mice and was even longer in Slfn3KO mice, while female Slfn3KO mice displayed even deeper crypts than both WT sexes after resection. Mitotic marker, Phh3+, and proliferation marker expression of Lgr5, FoxL1, and PDGFRα were increased after resection in male WT but this effect was blunted in male Slfn3KO mice. Cell shedding regulators Villin1 and TNFα were downregulated in female mice and male WT mice only, while Gelsolin and EGFR increased expression in all mice. Slfn3 expression increased after resection in WT mice but differentiation markers sucrase isomaltase, Dpp4, Glut2, and SGLT1 were all decreased. This suggests that enterocytic differentiation effort is incompatible with a rapid proliferation shift in intestinal adaptation. Slfn3 absence potentiates villus length and crypt depth, suggesting that the differentiating stimulus of Slfn3 signaling may restrain mucosal mass increase through regulating Villin1, Gelsolin, EGFR, TNFα, and proliferation markers. Slfn3 may therefore be an important regulator not only of "normal" enterocytic differentiation but also the response to bowel resection.

Microbiome diversity declines while distinct expansions of Th17, iNKT, and dendritic cell subpopulations emerge after anastomosis surgery

“…An end-to-end or Roux-en-Y anastomosis was made starting 5 cm from the pyloric orifice of the stomach using 8–0 Nylon suture (Unify, ADSurgical, black thread, taper point, 3/8 6.4 mm curved needle) (Fig. 1 ) [ 52 ]. The Roux-en-Y limb was approximately 2–3 cm long.…”

Systematic review reveals sexually antagonistic knockouts in model organisms

“…Our review also reveals the first validated example of a sexually antagonistic gene, the Slfn3 ( Schlafen 3 ) knockout in mice, where effects on villi length were replicated in two independent studies from the same laboratory (Vomhof‐DeKrey et al, 2019 , 2021 ). The knockout has sex‐opposite effects on different aspects of bowel histology (villi length and muscle layer thickness; Table 1 ).…”

“…Coloring of the points follows A. Individual points from the current study are also labeled: a–e synthetic variants; f and g natural variants (a: Thomson et al, 2021 , Mouse; b: Vomhof‐Dekrey et al, 2021 , mouse; c: Lee et al, 2020 , Japanese quail; d: Kichev et al, 2018 , Mouse; e: Schroeder et al, 2021 , Drosophila melanogaster ; f: Dachtler et al, 2016 , Mouse; g: Barson et al, 2015 , Salmon).…”

Vil-Cre specific Schlafen 3 knockout mice exhibit sex-specific differences in intestinal differentiation markers and Schlafen family members expression levels

“…Pan-Slfn3KO mice only exhibited an increase in ileal SGLT1 in males and a decrease in ileal Glut2 in females [ 32 ]. Alternatively, in 50% bowel-resected pan-Slfn3KO mice, SI, Dpp4, Glut2, and SGLT1 are all decreased [ 38 ]. Additionally, a more correlative effect was seen in temporarily blocked jejunal regions of rats that were injected intraluminally with either adenoviral Slfn3 or Slfn3 siRNA.…”