SUMMARY Herpes Zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. While a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax®. Vaccination induces robust antigen-specific antibody, plasmablasts and CD4+ T cells, yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets such as transcriptomic and metabolomics signatures, cell populations and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity, and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors (including the nuclear receptor for BAs, FXR) play integral roles in regulating whole body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally-restricted Apical Sodium-dependent BA Transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high fat diet (HFD)-fed mice. Administration of this ASBTi increased fecal BA excretion and mRNA expression of BA synthesis genes in liver, and reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis, Fibroblast Growth Factor 15 (FGF15). ASBT inhibition resulted in a marked shift in hepatic BA composition, with a reduction in hydrophilic, FXR antagonistic species and an increase in FXR agonistic BAs. ASBT inhibition restored glucose tolerance, reduced hepatic triglyceride and total cholesterol concentrations, and improved NAFLD Activity Score (NAS) in HFD-fed mice. These changes were associated with reduced hepatic expression of lipid synthesis genes (including LXR target genes), and normalized expression of the central lipogenic transcription factor, Srebp1c. Accumulation of hepatic lipids and SREBP1 protein were markedly reduced in HFD-fed Asbt−/− mice, providing genetic evidence for a protective role mediated by interruption of the enterohepatic BA circulation. Taken together, these studies suggest that blocking ASBT function with a luminally-restricted inhibitor can improve both hepatic and whole body aspects of NAFLD.

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Objective To conduct an untargeted, high resolution exploration of metabolic pathways that were altered in association with hepatic steatosis in adolescents. Study design This prospective, case control study included 39 Hispanic-American, obese adolescents aged 11–17 years evaluated for hepatic steatosis using magnetic resonance spectroscopy. Of these 39 individuals, 30 had hepatic steatosis ≥ 5% and 9 were matched controls with hepatic steatosis < 5%). Fasting plasma samples were analyzed in triplicate using ultra-high resolution metabolomics on a Thermo Fisher Q Exactive mass spectrometer, coupled with C18 reverse phase liquid chromatography. Differences in plasma metabolites between adolescents with and without NAFLD was determined by independent t-tests and visualized using Manhattan plots. Untargeted pathway analyses using Mummichog were performed among the significant metabolites to identify pathways that were most dysregulated in NAFLD. Results The metabolomics analysis yielded 9,583 metabolites, and 7,711 with 80% presence across all samples remained for statistical testing. Of these, 478 metabolites were associated with the presence of NAFLD compared with the matched controls. Pathway analysis revealed that along with lipid metabolism, several major amino acid pathways were dysregulated in NAFLD, with tyrosine metabolism being the most affected. Conclusions Metabolic pathways of several amino acids are significantly disturbed in adolescents with elevated hepatic steatosis. This is a novel finding and suggests that these pathways may be integral in the mechanisms of NAFLD.

Inhalation of cadmium (Cd) is associated with lung diseases, but less is known concerning pulmonary effects of Cd found in the diet. Cd has a decades‐long half‐life in humans and significant bioaccumulation occurs with chronic dietary intake. We exposed mice to low‐dose CdCl2 (10 mg/L in drinking water) for 20 weeks, which increased lung Cd to a level similar to that of nonoccupationally exposed adult humans. Cd‐treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung. In contrast to higher doses, low‐dose Cd did not elicit increased metallothionein transcripts in lung. To identify pathways most affected by Cd, gene set enrichment of transcripts was analyzed. Results showed that major inducible targets of low‐dose Cd were neuronal receptors represented by enriched olfactory, glutamatergic, cholinergic, and serotonergic gene sets. Olfactory receptors regulate chemosensory function and airway hypersensitivity, and these gene sets were the most enriched. Targeted metabolomics analysis showed that Cd treatment also increased metabolites in pathways of glutamatergic (glutamate), serotonergic (tryptophan), cholinergic (choline), and catecholaminergic (tyrosine) receptors in the lung tissue. Protein abundance measurements showed that the glutamate receptor GRIN2A was increased in mouse lung tissue. Together, these results show that in mice, oral low‐dose Cd increased lung Cd to levels comparable to humans, increased airway hyperresponsiveness and disrupted neuronal pathways regulating bronchial tone. Therefore, dietary Cd may promote or worsen airway hyperresponsiveness in multiple lung diseases including asthma.