Prophylactic use of meloxicam and paracetamol in peripartal sows suffering from postpartum dysgalactia syndrome

Postpartum dysgalactia syndrome (PPDS) is a major economic problem in modern sow farms. General treatment of PPDS consists of the use of oxytocin to promote milk ejection and non-steroidal anti-inflammatory drugs (NSAIDs) to alleviate inflammatory processes. So far, studies investigated the use of a single administration of NSAIDs after parturition in healthy and non-healthy sows. The current study investigated whether administration of meloxicam or paracetamol in sows prior to parturition improves sow and piglet health as well as performance in a farm with PPDS problems in sows. Sixty sows and 978 piglets from a Belgian farrow-to-finish farm were enrolled. Sows were randomly divided into three groups: a non-treated control group, a meloxicam-treated group and a paracetamol-treated group. Treatment was administered orally for 7 days from gestation day 113 onwards. Performance and health parameters investigated in sows were gestation length, farrowing duration, litter characteristics, colostrum yield and quality (Immunoglobulin G), litter weight gain, weaning-to-estrus interval, pregnancy rate, rectal temperature, acute phase proteins and inflammatory markers serum amyloid A, haptoglobin, interferon γ, interleukin 1β and 6 backfat, constipation and feed refusal. Performance and health parameters in piglets were birthweight, average daily weight gain, colostrum intake and mortality. Paracetamol-treated sows showed a significantly (P = 0.04) lower rectal temperature (mean ± SD: 38.09 ± 0.18°C) than the meloxicam-treated sows (38.24 ± 0.18°C), but not than the control group (38.22 ± 0.18°C). Sows of the paracetamol-treated group had a significantly (P = 0.001) longer gestation length (116.3 ± 0.9 days) than sows of the control group (115.3 ± 0.6 days), but not than meloxicam-treated sows (115.9 ± 0.9 days). No significant differences between the three groups were found for all the other parameters. In conclusion, the prophylactic oral administration of either meloxicam or paracetamol for 7 days starting 2 days prior to farrowing did not show beneficial effects on both health and performance parameters of sows and piglets

Executioner caspases 3 and 7 are dispensable for intestinal epithelium turnover and homeostasis at steady state

Apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, thereby shaping the overall architecture of the gastrointestinal tract, but also regulating tolerance induction, pinpointing a role of apoptosis intestinal epithelial cell (IEC) turnover and maintenance of barrier function, and in maintaining immune homeostasis. To experimentally address this concept, we generated IEC-specific knockout mice that lack both executioner caspase-3 and caspase-7 (Casp3/7(Delta IEC)), which are the converging point of the extrinsic and intrinsic apoptotic pathway. Surprisingly, the overall architecture, cellular landscape, and proliferation rate remained unchanged in these mice. However, nonapoptotic cell extrusion was increased in Casp3/7(Delta IEC) mice, compensating apoptosis deficiency, maintaining the same physiological level of IEC shedding. Microbiome richness and composition stayed unaffected, bearing no sign of dysbiosis. Transcriptome and single-cell RNA sequencing analyses of IECs and immune cells revealed no differences in signaling pathways of differentiation and inflammation. These findings demonstrate that during homeostasis, apoptosis per se is dispensable for IEC turnover at the top of intestinal villi intestinal tissue dynamics, microbiome, and immune cell composition

XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells

Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In Xiap-/- mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of Clostridia species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which Tnfr2 expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of Xiap-/- mice. Consequently, both Tnfr1-/-Xiap-/- and Tnfr2-/-Xiap-/- mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed Xiap-/- mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis

XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells

Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In Xiap-/- mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of Clostridia species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which Tnfr2 expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of Xiap-/- mice. Consequently, both Tnfr1-/-Xiap-/- and Tnfr2-/-Xiap-/- mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed Xiap-/- mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis