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Five years ago, with the editorial board of Frontiers in Nutrition, we took a leap of faith to outline the Goals for Nutrition Science - the way we see it (1). Now, in 2020, we can put ourselves to the test and take a look back. Without a doubt we got it right with several of the key directions. To name a few, Sustainable Development Goals (SDGs) for Food and Nutrition are part of the global public agenda, and the SDGs contribute to the structuring of international science and research. Nutritional Science has become a critical element in strengthening work on the SDGs, and the development of appropriate methodologies is built on the groundwork of acquiring and analyzing big datasets. Investigation of the Human Microbiome is providing novel insight on the interrelationship between nutrition, the immune system and disease. Finally, with an advanced definition of the gut-brain-axis we are getting a glimpse into the potential for Nutrition and Brain Health. Various milestones have been achieved, and any look into the future will have to consider the lessons learned from Covid-19 and the sobering awareness about the frailty of our food systems in ensuring global food security. With a view into the coming 5 years from 2020 to 2025, the editorial board has taken a slightly different approach as compared to the previous Goals article. A mind map has been created to outline the key topics in nutrition science. Not surprisingly, when looking ahead, the majority of scientific investigation required will be in the areas of health and sustainability. Johannes le Coutre, Field Chief Editor, Frontiers in Nutrition.

Five years ago, with the editorial board of Frontiers in Nutrition, we took a leap of faith to outline the Goals for Nutrition Science - the way we see it (1). Now, in 2020, we can put ourselves to the test and take a look back. Without a doubt we got it right with several of the key directions. To name a few, Sustainable Development Goals (SDGs) for Food and Nutrition are part of the global public agenda, and the SDGs contribute to the structuring of international science and research. Nutritional Science has become a critical element in strengthening work on the SDGs, and the development of appropriate methodologies is built on the groundwork of acquiring and analyzing big datasets. Investigation of the Human Microbiome is providing novel insight on the interrelationship between nutrition, the immune system and disease. Finally, with an advanced definition of the gut-brain-axis we are getting a glimpse into the potential for Nutrition and Brain Health. Various milestones have been achieved, and any look into the future will have to consider the lessons learned from Covid-19 and the sobering awareness about the frailty of our food systems in ensuring global food security. With a view into the coming 5 years from 2020 to 2025, the editorial board has taken a slightly different approach as compared to the previous Goals article. A mind map has been created to outline the key topics in nutrition science. Not surprisingly, when looking ahead, the majority of scientific investigation required will be in the areas of health and sustainability. Johannes le Coutre, Field Chief Editor, Frontiers in Nutrition.

Emergent responses of the immune system result from the integration of molecular and cellular networks over time and across multiple organs. High-content and high-throughput analysis technologies, concomitantly with data-driven and mechanistic modeling, hold promise for the systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. Here, we present the perspectives that emerged from the National Institute of Allergy and Infectious Disease (NIAID) workshop 'Complex Systems Science, Modeling and Immunity' and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling, and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies.

Conjugated linoleic acid (CLA) exerts a protective effect on experimental inflammatory bowel disease and shows promise as a chemopreventive agent against colorectal cancer (CRC) in mice, although the mechanisms by which it exerts its beneficial effects against malignancies in the gut are not completely understood. Mice lacking PPAR[gamma], in immune and epithelial cells and PPAR[gamma]/-expressing littermates were fed either control or CLA-supplemented (1 g CLA/100 g) diets to determine the role of PPAR[gamma], in inflammation-induced CRC. To induce tumor formation and colitis, mice were treated with azoxymethane and then challenged with 2% dextran sodium sulfate, respectively. Dietary CLA ameliorated disease activity, decreased colitis, and prevented adenocarcinoma formation in the PPAR[gamma],-expressing floxed mice but not in the tissue-specific PPAR[gamma]-null mice. Dietary CLA supplementation significantly decreased the percentages of macrophages in the mesenteric lymph nodes (MLN) regardless of the genotype and increased regulatory T cell numbers in MLN of PPAR[gamma]expressing, but not in the tissue-specific, PPAR-),-null mice. Colonic tumor necrosis factor-[alpha] mRNA expression was significantly suppressed in CLA-fed, PPAR[gamma]-expressing mice. This study suggests CLA ameliorates colitis and prevents tumor formation in part through a PPAR[gamma]-dependent mechanism. doi: 10.3945/jn.109.115642.

We investigated the cellular and molecular immunoregulatory actions of conjugated linoleic acid (CLA) of relevance to viral disease pathogenesis and antiviral responses. To test the hypothesis that CLA ameliorates viral disease, we developed a viral challenge model by infecting pigs with type-2 porcine circovirus (PCV2). After 42 d of dietary supplementation with either soybean oil (n = 16) or CLA (n = 16), half of the pigs in each group were challenged with PCV2. We examined the effect of CLA on the development of lesions (i.e., lymphoid depletion and pneumonia) and observed the kinetics of the immune responses against PCV2. The viral infection depleted immature B cells (Ig[M.sup.+]SWC[3.sup.+]) and favored proapoptotic mRNA expression profiles [i.e., suppressed B-cell leukemia/lymphoma-xl (Bcl-xl) and stimulated Bcl-2 homologous antagonist/killer (Bak)] in the external inguinal lymph nodes. B-cell depletion was more accentuated in pigs fed the control diet, whereas interleukin (IL)-2 mRNA expression was downregulated. Histopathological examination of the lungs revealed that the interstitial pneumonia tended to be more severe in infected pigs fed the control diet, which were also affected by growth retardation. CD[8.sup.+] T cells were the primary cellular targets of CLA action in peripheral blood (CD[8.sup.+]CD[29.sup.low] and CD[8.sup.+]CD45R[C.sup.+]) and thymus (CD[8.sup.+] and CD[4.sup.+]CD[8.sup.+]). CLA interacted with PCV2 to increase the proliferation of CD[8.sup.+] T cells and to suppress PCV2-specific interferon (IFN)-[gamma] production in CD[4.sup.+] T cells. At the molecular level, these cellular immunoregulatory properties were associated with differential patterns of peroxisome proliferator-activated receptor ([alpha] and [gamma]) mRNA expression between diets in virally infected pigs. J. Nutr. 133: 3204-3214, 2003. KEY WORDS: * lipid nutrition * lymphoid depletion * growth suppression * conjugated linoleic acid

Excessive intake of saturated fatty acids and/or linoleic acid favors the induction of an array of lipid mediators and cytokines enhancing inflammatory responses. Conversely, dietary supplementation with (n-3) fatty acids or vitamin D ameliorates inflammation and autoimmune diseases. Although it was well accepted that conjugated linoleic acid (CLA) prevented diseases with a common inflammatory pathogenesis (i.e., cancer and atherosclerosis), no studies were available on the roles of CLA in mucosal inflammation. The present study was designed to investigate the anti-inflammatory actions and molecular mechanisms underlying the regulation of colonic health by CLA. We hypothesized that colonic inflammation can be ameliorated by dietary CLA supplementation. To test this hypothesis, inflammation of the colonic mucosa was triggered by challenging pigs fed either soybean oil-supplemented or CLA-supplemented diets with an enteric bacterial pathogen (i.e., Brachyspira hyodysenteriae). Immunoregulatory cytokines and peroxisome proliferator-actirated receptor-[gamma] (PPAR-[gamma]) mRNA expression were assayed in colonic lymph nodes and colon of pigs. Colonic mucosal lesions and lymphocyte subset distribution were evaluated by histology and immunohistochemistry. Supplementation of CLA in the diet before the induction of colitis decreased mucosal damage; maintained cytokine profiles (i.e., interferon-[gamma] and interleukin-10) and lymphocyte subset distributions (i.e., CD[4.sup.+] and CD[8.sup.+]), resembling those of noninfected pigs; enhanced colonic expression of PPAR-[gamma]; and attenuated growth failure. Therefore, CIA fed preventively before the onset of enteric disease attenuated inflammatory lesion development and growth failure. J. Nutr. 132: 2019-2027, 2002. KEY WORDS: * lipid nutrition, colitis * conjugated linoleicacid * interferon-[gamma] * PPAR-[gamma] * growth suppression

Abstract Background The prevalence of diabetes is increasing worldwide. It has been long known that increased rates of inflammatory diseases, such as obesity (OBS), hypertension (HT) and cardiovascular diseases (CVD) are highly associated with type 2 diabetes (T2D). T2D and/or OBS can develop independently, due to genetic, behavioral or lifestyle-related variables but both lead to oxidative stress generation. The underlying mechanisms by which theses complications arise and manifest together remain poorly understood. Protein-protein interactions regulate nearly every living process. Availability of high-throughput genomic data has enabled unprecedented views of gene and protein co-expression, co-regulations and interactions in cellular systems. Methods The present work, applied a systems biology approach to develop gene interaction network models, comprised of high throughput genomic and PPI data for T2D. The genes differentially regulated through T2D were 'mined' and their 'wirings' were studied to get a more complete understanding of the overall gene network topology and their role in disease progression. Results By analyzing the genes related to T2D, HT and OBS, a highly regulated gene-disease integrated network model has been developed that provides useful functional linkages among groups of genes and thus addressing how different inflammatory diseases are connected and propagated at genetic level. Based on the investigations around the 'hubs' that provided more meaningful insights about the cross-talk within gene-disease networks in terms of disease phenotype association with oxidative stress and inflammation, a hypothetical co-regulation disease mechanism model been proposed. The results from this study revealed that the oxidative stress mediated regulation cascade is the common mechanistic link among the pathogenesis of T2D, HT and other inflammatory diseases such as OBS. Conclusion The findings provide a novel comprehensive approach for understanding the pathogenesis of various co-associated chronic inflammatory diseases by combining the power of pathway analysis with gene regulatory network evaluation.

Abstract Background Peroxisome proliferator-activated receptor γ (PPAR γ) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. Methods PPAR γ flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. Results The deficiency of PPAR γ in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+FoxP3+ regulatory T cells (Treg) and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR γ in T cells. Conclusions The expression of PPAR γ in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive sites.

Abstract Background It has been shown previously that administration of Francisella tularensis (Ft) Live Vaccine Strain (LVS) lipopolysaccharide (LPS) protects mice against subsequent challenge with Ft LVS and blunts the pro-inflammatory cytokine response. Methods To further investigate the molecular mechanisms that underlie Ft LVS LPS-mediated protection, we profiled global hepatic gene expression following Ft LVS LPS or saline pre-treatment and subsequent Ft LVS challenge using Affymetrix arrays. Results A large number of genes (> 3,000) were differentially expressed at 48 hours post-infection. The degree of modulation of inflammatory genes by infection was clearly attenuated by pre-treatment with Ft LVS LPS in the surviving mice. However, Ft LVS LPS alone had a subtle effect on the gene expression profile of the uninfected mice. By employing gene set enrichment analysis, we discovered significant up-regulation of the fatty acid metabolism pathway, which is regulated by peroxisome proliferator activated receptors (PPARs). Conclusions We hypothesize that the LPS-induced blunting of pro-inflammatory response in mouse is, in part, mediated by PPARs (α and γ).