Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46−RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.

Background: The perception of smell and taste, though present early in development, is not routinely considered in the care of preterm infants. Smell and taste are known to increase gut motility, insulin secretion, and the release of appetite, digestive and metabolic hormones. Objective: We aimed to investigate the effect of regular smell and taste on the time from birth to full enteral feeds, and the feasibility of the study protocol in very preterm infants. Methods: In a randomized controlled trial, infants <29 weeks' postmenstrual age (PA) were assigned to receive either the smell and taste of milk before each feed or to have no exposure to the smell and taste of milk (control). Results: Infants in the treatment group (n = 28) and control group (n = 23) were born at a mean (SD) PA of 26.7 (1.5) and 27.2 (1.4) weeks, respectively. They reached full enteral feeds at a median (IQR) of 13.5 (10.0-19.0) and 15.5 (11.0-22.0) days, respectively. Survival analysis showed an adjusted hazard ratio of 1.63 (95% confidence interval 0.91-2.91; p = 0.10) for the effect on the time to establish full enteral feeds. Repeated-measures analysis indicated significant group differences in weight z scores at 36 weeks' PA and at discharge in favor of the intervention (p < 0.05). Conclusion: These data indicate that the smell and taste of milk may improve milk tolerance and weight in preterm infants. The role of regular smell and taste in promoting enteral nutrition and growth in preterm infants merits a larger trial powered to detect important outcomes.

Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.