RESUMO
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.
Assuntos
Envelhecimento/imunologia , Suplementos Nutricionais , Ingestão de Alimentos/imunologia , Fenômenos Fisiológicos da Nutrição do Idoso/imunologia , Minerais/administração & dosagem , Vitaminas/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Citocinas/sangue , Método Duplo-Cego , Ingestão de Alimentos/fisiologia , Fenômenos Fisiológicos da Nutrição do Idoso/fisiologia , Feminino , Humanos , Imunoglobulina A/metabolismo , Masculino , Minerais/sangue , Neutrófilos/imunologia , Fagocitose , Espécies Reativas de Oxigênio , Vitaminas/sangueRESUMO
In humans and other primates, 1,25(OH)2vitamin D3 regulates the expression of the cathelicidin antimicrobial peptide (CAMP) gene via toll-like receptor (TLR) signaling that activates the vitamin D pathway. Mice and other mammals lack the vitamin D response element (VDRE) in their CAMP promoters. To elucidate the biological importance of this pathway, we generated transgenic mice that carry a genomic DNA fragment encompassing the entire human CAMP gene and crossed them with Camp knockout (KO) mice. We observed expression of the human transgene in various tissues and innate immune cells. However, in mouse CAMP transgenic macrophages, TLR activation in the presence of 25(OH)D3 did not induce expression of either CAMP or CYP27B1 as would normally occur in human macrophages, reinforcing important species differences in the actions of vitamin D. Transgenic mice did show increased resistance to colonization by Salmonella typhimurium in the gut. Furthermore, the human CAMP gene restored wound healing in the skin of Camp KO mice. Topical application of 1,25(OH)2vitamin D3 to the skin of CAMP transgenic mice induced CAMP expression and increased killing of Staphylococcus aureus in a wound infection model. Our model can help elucidate the biological importance of the vitamin D-cathelicidin pathway in both pathogenic and non-pathogenic states.
Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções Estafilocócicas/prevenção & controle , Vitamina D/farmacologia , Animais , Colecalciferol/farmacologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Lipopolissacarídeos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Fagócitos/metabolismo , Fagocitose , Salmonella typhimurium , Transdução de Sinais , Pele/efeitos dos fármacos , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Transgenes , Elemento de Resposta à Vitamina D , CatelicidinasRESUMO
SCOPE: Two hydrogenated xanthohumol (XN) derivatives, α,ß-dihydro-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 diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation. METHODS AND RESULTS: To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance-specifically Bacteroidetes and Tenericutes-alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects 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.
Assuntos
Ácidos e Sais Biliares/metabolismo , Flavonoides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Propiofenonas/farmacologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/genética , Dieta Hiperlipídica/efeitos adversos , Fezes/química , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/microbiologia , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Paniculite/tratamento farmacológico , Paniculite/etiologia , RNA Ribossômico 16SRESUMO
SCOPE: The cathelicidin antimicrobial peptide (CAMP) gene is induced by 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3), 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)2 D3. 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, phosphoinositide 3 and AMP-activated kinases did not block induction of CAMP by resveratrol or synergy with 1α,25(OH)2 D3. 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)2 D3 suggesting that inhibition of these kinases by resveratrol may explain, in part, its synergy with vitamin D. CONCLUSION: 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)2 D3.
Assuntos
Catelicidinas/genética , Estilbenos/farmacologia , Vitamina D/análogos & derivados , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/metabolismo , Linhagem Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Vitamina D/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Antimicrobial peptides (AMPs) are synthesized and secreted by immune and epithelial cells that are constantly exposed to environmental microbes. AMPs are essential for barrier defense, and deficiencies lead to increased susceptibility to infection. In addition to their ability to disrupt the integrity of bacterial, viral and fungal membranes, AMPs bind lipopolysaccharides, act as chemoattractants for immune cells and bind to cellular receptors and modulate the expression of cytokines and chemokines. These additional biological activities may explain the role of AMPs in inflammatory diseases and cancer. Modulating the endogenous expression of AMPs offers potential therapeutic treatments for infection and disease. METHODS: The present review examines the published data from both in vitro and in vivo studies reporting the effects of nutrients and by-products of microbial metabolism on the expression of antimicrobial peptide genes in order to highlight an emerging appreciation for the role of dietary compounds in modulating the innate immune response. RESULTS: Vitamins A and D, dietary histone deacetylases and by-products of intestinal microbial metabolism (butyrate and secondary bile acids) have been found to regulate the expression of AMPs in humans. Vitamin D deficiency correlates with increased susceptibility to infection, and supplementation studies indicate an improvement in defense against infection. Animal and human clinical studies with butyrate indicate that increasing expression of AMPs in the colon protects against infection. CONCLUSION: These findings suggest that diet and/or consumption of nutritional supplements may be used to improve and/or modulate immune function. In addition, by-products of gut microbe metabolism could be important for communicating with intestinal epithelial and immune cells, thus affecting the expression of AMPs. This interaction may help establish a mucosal barrier to prevent invasion of the intestinal epithelium by either mutualistic or pathogenic microorganisms.