the associations between early growth and markers of ageing suggest that in some systems, ageing may be programmed by events in early life. A potential mechanism is the impaired development of repair systems.

Rotavirus (RV) causes significant morbidity and mortality in children worldwide. The intestinal microbiota plays an important role in modulating host-pathogen interactions, but little is known about the impact of commonly used probiotics on human RV (HRV) infection. In this study, we compared the immunomodulatory effects of Gram-positive [Lactobacillus rhamnosus strain GG (LGG)] and Gram-negative [Escherichia coli Nissle (EcN)] probiotic bacteria on virulent human rotavirus (VirHRV) infection and immunity using neonatal gnotobiotic (Gn) piglets. Gn piglets were colonized with EcN, LGG, EcN+LGG or uncolonized and challenged with VirHRV. Mean peak virus shedding titers and mean cumulative fecal scores were significantly lower in EcN-colonized compared to LGG-colonized or uncolonized piglets. Reduced viral shedding titers were correlated with significantly reduced small intestinal HRV IgA antibody responses in EcN-colonized compared to uncolonized piglets post-VirHRV challenge. However the total IgA levels post-VirHRV challenge in the intestine and pre-VirHRV challenge in serum were significantly higher in EcN-colonized than in LGG-colonized piglets. In vitro treatment of mononuclear cells (MNCs) with these probiotics demonstrated that EcN, but not LGG, induced IL-6, IL-10, and IgA, with the latter partially dependent on IL-10. However, addition of exogenous recombinant porcine IL-10 + IL-6 to MNCs co-cultured with LGG significantly enhanced IgA responses. The greater effectiveness of EcN in moderating HRV infection, may also be explained by the binding of EcN, but not LGG to Wa HRV particles or HRV 2/4/6 virus-like particles (VLP) but not 2/6 VLP. Results suggest that EcN and LGG differentially modulate RV infection and B cell responses.

Gram-positive lactic acid-producing bacteria including Lactobacillus rhamnosus GG (LGG) are commonly used as probiotics, while fewer gram-negative probiotics including Escherichia coli Nissle 1917 (EcN) are characterized. A mechanistic understanding of their individual and interactive effects on human rotavirus (HRV) disease and immunity is lacking. Noncolonized, EcN, LGG and EcN+LGG-colonized neonatal gnotobiotic (Gn) pigs were challenged with HRV. EcN colonization associated with greater protection against HRV, also induced the highest frequencies of plasmacytoid dendritic cells (DC), significantly increased natural killer (NK) cell function and decreased frequencies of apoptotic and TLR4+ mononuclear cells (MNCs). Consistent with the highest NK cell activity, splenic CD172+ MNCs (DC enriched fraction) of EcN colonized pigs produced the highest levels of IL-12 (activates NK cells) in vitro. LGG colonization had little effect on the above parameters, and those of EcN+LGG colonized pigs were intermediate, suggesting that the probiotics modulate each other’s effects. Additionally, in vitro EcN-treated splenic or intestinal MNCs produced a higher but balanced cytokine repertoire (IFN-α, IL-12 and IL-10), as compared to that of pigs treated with LGG. These results indicate that the EcN-mediated greater protection against HRV was associated with potent stimulation of the innate immune system and activation of the DC-IL-12-NK immune axis.

Narrower bifurcation angles are associated with increased circulatory energy costs and may be related to a lower than normal microvascular density. Our finding of differences in retinal microvascular architecture might reflect a persistent alteration in vascular architecture as a result of an impairment of foetal development and could provide a mechanistic link between low birth weight and subsequently increased cardiovascular risk.

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