Scope: We previously showed that two hydrogenated xanthohumol (XN) derivatives, α,βdihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a dietinduced obese murine model. We hypothesized that improvements in obesity and MetS are linked to changes in the composition of the gut microbiota, bile acid metabolism, intestinal barrier function and inflammation. Methods and results: To test this hypothesis, we sequenced 16S rRNA genes and measured bile acids in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. We measured the expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism, in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreased intestinal microbiota diversity and abundance, specifically Bacteroidetes and Tenericutes, altered bile acid metabolism, and reduced inflammation. In WAT, TXN supplementation decreased pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connected changes in the microbiota to improvements in MetS in the host. Conclusion: Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.

Scope The cathelicidin antimicrobial peptide (CAMP) gene is induced by 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), lithocholic acid, curcumin, nicotinamide and butyrate. Discovering additional small molecules that regulate its expression will identify new molecular mechanisms involved in CAMP regulation and increase understanding of how diet and nutrition can improve immune function. Methods and results We discovered that two stilbenoids, resveratrol and pterostilbene, induced CAMP promoter-luciferase expression. Synergistic activation was observed when either stilbenoid was combined with 1α,25(OH)2D3. Both stilbenoids increased CAMP mRNA and protein levels in the monocyte cell line U937 and synergy was observed in both U937 and the keratinocyte cell line, HaCaT. Inhibition of resveratrol targets sirtuin-1, cyclic AMP production and the c-Jun N-terminal, phophoinositide 3 and AMP-activated kinases did not block induction of CAMP by resveratrol or synergy with 1α,25(OH)2D3. Nevertheless, inhibition of the extracellular signal-regulated 1/2 and p38 mitogen-activated protein kinases, increased CAMP gene expression in combination with 1α,25(OH)2D3 suggesting that inhibition of these kinases by resveratrol may explain, in part, its synergy with vitamin D. Conclusions Our findings demonstrate for the first time that stilbenoid compounds may have the potential to boost the innate immune response by increasing CAMP gene expression particularly in combination with 1α,25(OH)2D3.

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Older adults are at increased risk for vitamin and mineral deficiencies that contribute to age-related immune system decline. Several lines of evidence suggest that taking a multi-vitamin and mineral supplement (MVM) could improve immune function in individuals 55 and older. To test this hypothesis, we provided healthy older adults with either an MVM supplement formulated to improve immune function (Redoxon® VI, Singapore) or an identical, inactive placebo control to take daily for 12 weeks. Prior to and after treatment, we measured (1) their blood mineral and vitamin status (i.e., vitamin C, zinc and vitamin D); (2) immune function (i.e., whole blood bacterial killing activity, neutrophil phagocytic activity, and reactive oxygen species production); (3) immune status (salivary IgA and plasma cytokine/chemokine levels); and (4) self-reported health status. MVM supplementation improved vitamin C and zinc status in blood and self-reported health-status without altering measures of immune function or status or vitamin D levels, suggesting that healthy older adults may benefit from MVM supplementation. Further development of functional assays and larger study populations should improve detection of specific changes in immune function after supplementation in healthy older adults. Clinical Trials Registration: ClinicalTrials.gov #NCT02876315.

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