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Abstract Iron deficiencies are the most common nonenteric syndromes observed in patients with inflammatory bowel disease, but little is known about their impacts on immune tolerance. Here we show that homeostasis of regulatory T cells in the intestine was dependent on high cellular iron levels, which were fostered by pentanoate, a short-chain fatty acid produced by intestinal microbiota. Iron deficiencies in Treg caused by the depletion of Transferrin receptor 1, a major iron transporter, result in the abrogation of Treg in the intestine and lethal autoimmune disease. Transferrin receptor 1 is required for differentiation of c-Maf+ Treg, major constituents of intestinal Treg. Mechanistically, iron enhances the translation of HIF-2α mRNA, and HIF-2α in turn induces c-Maf expression. Importantly, microbiota-produced pentanoate promotes iron uptake and Treg differentiation in the intestine. This subsequently restores immune tolerance and ameliorated iron deficiencies in mice with colitis. Our results thus reveal an association between nutrient uptake and immune tolerance in the intestine.

Parabacteroides levels are reported to be low in obese individuals, and this genus has shown an anti-obesity capacity in animal studies. Nevertheless, the relationship between Parabacteroides and obesity in different subpopulations, e.g., with respect to age and sex, and its association with subsequent weight change have rarely been explored. The cross-sectional associations of Parabacteroides genus- and species-level OTU abundance with obesity were explored in the Guangdong Gut Microbiome Project (GGMP), which included 5843 adults, and replicated in the Guangzhou Nutrition and Health Study (GNSH), which included 1637 individuals. Furthermore, we assessed the prospective associations of Parabacteroides and its main OTUs’ abundance with the subsequent changes in body mass index (BMI) in the GNSH. We found that Parabacteroides was inversely associated with obesity among females and participants aged 40–69 years in the GGMP and the replicated cohort in the GNSH. After a 3-year follow-up, there was no significant correlation between Parabacteroides and the subsequent changes in BMI. However, Seq4172 (P. johnsonii) showed a negative correlation with subsequent BMI changes in the female and middle-aged (40–69 years) subpopulations. Overall, our results indicate that Parabacteroides have an inverse relationship with obesity and that Seq4172 (P. johnsonii) have a negative association with subsequent changes in BMI among females and middle-aged populations in perspective analyses.

Abstract Background Omega-3 polyunsaturated fatty acids (PUFAs) were proposed to have potential effects against inflammation and cancer. However, results from epidemiology studies remain inconsistent. We aimed to explore the associations of plasma PUFAs with EC recurrence and all-cause mortality. Method Women diagnosed with endometrial cancer (EC) between 2008 and 2013 and underwent surgery at Fudan University Shanghai Cancer Center of China were recruited. Survival status was followed up through September 2017. EC recurrence and total cause deaths were identified through medical record and telephone interview. In total, 202 patients with enough plasma samples at time of surgery were included. There were 195 patients who provided baseline plasma and survival information included in the current study. Plasma omega-3 PUFAs were measured by GC-FID. Cox Proportional Hazard model adjusted for potential cofounders was used to estimate HRs and 95% CIs. Results Median follow-up time for patients was 58 months after surgery. A total of 13 recurrences and 11 all-cause deaths, of which, 2 deaths from EC, were identified. Level of plasma EPA was higher in recurrent patients than total patients (0.78% vs 0.51%, P = 0.015). Higher plasma eicosapentaenoic acid (EPA) level trended to have positive association with EC recurrence (P-trend = 0.04), although comparing to the lowest tertile, the highest tertile of EPA level was not significantly associated with increased risk of EC recurrence (HRT3vsT1 = 6.02; 95%CI = 0.7–52.06). The association between total omega-3 PUFA and EC recurrence tended to be stronger among patients with deeper myometrial invasion (OR = 3.41; 95%CI = 1.06–10.95; P-interaction = 0.04). Conclusions Higher plasma EPA level was significantly associated with EC recurrence. Further studies are warranted to confirm these findings. Trial registration ChiCTR1900025418 ; Retrospectively registered (26 August 2019); Chinses Clinical Trial Registry.

BackgroundObservational studies have shown an inverse association between circulating linoleic acid (LA) and risk of ischemic stroke (IS).ObjectiveThe aim of this study was to explore whether genetic variants predicting levels of circulating LA are associated with IS and its subtypes using a two-sample Mendelian randomization (MR) analysis.MethodsLA-related single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of 8,631 participants, and summary statistics of IS and IS subtypes were obtained from the MEGASTROKE consortium. MR analysis was performed using the inverse-variance weighted (IVW) method complemented with other approaches, including weighted-median, weighted-mode, MR Pleiotropy RESidual Sum and Outlier test and MR-Egger regression, to test for the robustness of the association. Moreover, we conducted bidirectional MR analysis to assess the impact of IS-associated SNPs on circulating LA levels. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsWe found that genetically predicted circulating LA levels were inversely associated with the risk of IS by the IVW method (OR = 0.98, 95% CI: 0.97–0.99, and P = 0.003). Subgroup analyses showed a statistically significant association between LA and risk of large artery stroke (LAS; OR = 0.95, 95% CI: 0.92–0.98, and P = 0.004), but not for other IS subtypes. The results were stable in sensitivity analyses, and no evidence of reverse association between LA and risk of IS, or LAS was observed.ConclusionOur study supports a potential inverse association of genetically predicted circulating LA levels with risk of IS, particularly LAS.

Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

The present study was designed to investigate the anti-inflammatory activity and mechanism of a lipid extract from hard-shelled mussel (Mytilus coruscus) on adjuvant-induced (AIA) and collagen-induced arthritis (CIA) in rats. AIA and CIA rats that received hard-shelled mussel lipid extract (HMLE group) at a dose of 100 mg/kg demonstrated significantly lower paw swelling and arthritic index, but higher body weight gain than those which received olive oil (control group). Similar results were found in arthritic rats that received New Zealand green-lipped mussel lipid extract (GMLE) at the same dosage. The levels of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) in the serum, and interleukin-1β (IL-1β), IL-6, interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) in the ankle joint synovial fluids of HMLE group rats were significantly lower than those of control group. However, the levels of IL-4 and IL-10 in HMLE group rats were significantly higher than those in the control group. Decreased mRNA expressions of matrix metalloproteinase 1 (MMP1) and MMP13, but increased tissue inhibitor of metalloproteinase 1 (TIMP1) were observed in the knee joint synovium tissues of HMLE group rats when compared with the control group. No hepatotoxicity was observed in both HMLE and GMLE group rats. The present results indicated that HMLE had a similarly strong anti-inflammatory activity as GMLE. Such a strong efficacy could result from the suppression of inflammatory mediators (LTB4, PGE2, TXB2), pro-inflammatory cytokines (IL-1β, IL-6, INF-γ, TNF-α) and MMPs (MMP1, MMP13), and the promotion of anti-inflammatory cytokines (IL-4, IL-10) and TIMPs (TIMP1) productions.

BackgroundWhether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.Methods and findingsPlasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.ConclusionsThese large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.

BACKGROUND:Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and leukotriene B4 (LTB4) through systematic review and meta-analysis of randomized controlled trials. METHOD AND FINDINGS:A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE2, TXB2 and LTB4 in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB2 in serum/plasma in subjects with high risk of cardiovascular diseases (SMD:-1.26; 95% CI: -1.65, -0.86) and LTB4 in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) (SMD:-0.59: 95% CI: -1.02, -0.16). Subgroup analyses showed a significant reduction of LTB4 in subjects with rheumatoid arthritis (SMD: -0.83; 95% CI: -1.37, -0.29), but not in non-autoimmune chronic disease patients (SMD: -0.33; 95% CI: -0.97, 0.31). No significant publication bias was shown in the meta-analysis. CONCLUSIONS:Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB2 in blood of subjects with high risk of CVD as well as LTB4 in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB4 content with supplementation of marine-derived n-3 PUFA.

BackgroundPrevious studies did not draw a consistent conclusion about the effects of marine-derived n-3 polyunsaturated fatty acids (PUFAs) on fasting blood level of C-reactive protein (CRP), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α).Methods and findingsA comprehensive search of Web of Science, PubMed, Embase and Medline (from 1950 to 2013) and bibliographies of relevant articles was undertaken. Sixty-eight RCTs with a total of 4601 subjects were included in the meta-analysis. Marine-derived n-3 PUFAs supplementation showed a lowering effect on Marine-derived n-3 PUFAs supplementation had a significant lowering effect on TNF-α, IL-6 and CRP in three groups of subjects (subjects with chronic non-autoimmune disease, subjects with chronic autoimmune disease and healthy subjects). A significant negative linear relationship between duration and effect size of marine-derived n-3 PUFAs supplementation on fasting blood levels of TNF-α and IL-6 in subjects with chronic non-autoimmune disease was observed, indicating that longer duration of supplementation could lead to a greater lowering effect. A similar linear relationship was also observed for IL-6 levels in healthy subjects. Restricted cubic spline analysis and subgroup analysis showed that the lowering effect of marine-derived n-3 PUFAs on CRP, IL-6 and TNF-α in subjects with chronic non-autoimmune disease became weakened when body mass index was greater than 30 kg/m². The effect of marine-derived n-3 PUFAs from dietary intake was only assessed in subjects with chronic non-autoimmune disease, and a significant lowering effect was observed on IL-6, but not on CRP and TNF-α.ConclusionsMarine-derived n-3 PUFAs supplementation had a significant lowering effect on CRP, IL-6 and TNF-α level. The lowering effect was most effective in non-obese subjects and consecutive long-term supplementation was recommended.

Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for genemacronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting genemacronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate countryspecific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria (n, 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction, 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions. [ABSTRACT FROM AUTHOR]