Gut Microbial and Metabolic Profiling Reveal the Lingering Effects of Infantile Iron Deficiency Unless Treated with Iron.

SCOPE: Iron deficiency (ID) compromises the health of infants worldwide. Although readily treated with iron, concerns remain about the persistence of some effects. Metabolic and gut microbial consequences of infantile ID were investigated in juvenile monkeys after natural recovery (pID) from iron deficiency or post-treatment with iron dextran and B vitamins (pID+Fe). METHODS AND RESULTS: Metabolomic profiling of urine and plasma is conducted with 1 H nuclear magnetic resonance (NMR) spectroscopy. Gut microbiota are characterized from rectal swabs by amplicon sequencing of the 16S rRNA gene. Urinary metabolic profiles of pID monkeys significantly differed from pID+Fe and continuously iron-sufficient controls (IS) with higher maltose and lower amounts of microbial-derived metabolites. Persistent differences in energy metabolism are apparent from the plasma metabolic phenotypes with greater reliance on anaerobic glycolysis in pID monkeys. Microbial profiling indicated higher abundances of Methanobrevibacter, Lachnobacterium, and Ruminococcus in pID monkeys and any history of ID resulted in a lower Prevotella abundance compared to the IS controls. CONCLUSIONS: Lingering metabolic and microbial effects are found after natural recovery from ID. These long-term biochemical derangements are not present in the pID+Fe animals emphasizing the importance of the early detection and treatment of early-life ID to ameliorate its chronic metabolic effects.

Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term.

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28Si, influences hippocampal neurogenesis and function. To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/µ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67+, BrdU+, BrdU+NeuN+ and DCX+ cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67+, BrdU+ and DCX+ cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67+ and DCX+ cells in 0.2 Gy group relative to control group and fewer BrdU+ and DCX+ cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU+ cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU+ cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU+ cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28Si-radiation exposure damages neurogenesis, but to a lesser extent than 56Fe radiation and that low-dose 28Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.

Genetic and environmental determinants of population variation in interleukin-6, its soluble receptor and C-reactive protein: insights from identical and fraternal twins.

Interleukin-6 and C-reactive protein are commonly assessed biomarkers linked to illness, obesity, and stressful life events. However, relatively little is known about their heritability. By comparing Caucasian twins from the Midlife in the US project (MIDUS), we estimated the heritability of IL-6, its soluble receptor, and CRP. Based on the hypothesis that adiposity might contribute more to IL-6 than to sIL-6r, we fit heritability models quantifying the extent to which each reflected genetic and environmental factors shared with obesity. Genetic influences on IL-6 and its receptor proved to be distinct. Further, the appearance of a heritable basis for IL-6 was mediated largely via shared paths with obesity. Supporting this conclusion, we confirmed that when unrelated adult controls are carefully matched to twin participants on BMI, age, gender and socioeconomic indices, their IL-6 is similar to the corresponding twins. In contrast, the effect of BMI on CRP was split between shared genetics and environmental influences. In conclusion, IL-6 is strongly affected by factors associated with obesity accounting for its lability and responsiveness to diet, life style and contemporaneous events.

Acute and fractionated exposure to high-LET (56)Fe HZE-particle radiation both result in similar long-term deficits in adult hippocampal neurogenesis.

Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreER(T2)/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy (56)Fe-particle exposure or five fractionated 20 cGy (56)Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of (56)Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed.