Objective: Diets rich in fermentable fibres provide an array of health benefits; however, many patients with IBD report poor tolerance to fermentable fibre-rich foods. Intervention studies with dietary fibres in murine models of colonic inflammation have yielded conflicting results on whether fibres ameliorate or exacerbate IBD. Herein, we examined how replacing the insoluble fibre, cellulose, with the fermentable fibres, inulin or pectin, impacted murine colitis resulting from immune dysregulation via inhibition of interleukin (IL)-10 signalling and/or innate immune deficiency (Tlr5KO). Design: Mice were fed with diet containing either cellulose, inulin or pectin and subjected to weekly injections of an IL-10 receptor (αIL-10R) neutralising antibody. Colitis development was examined by serological, biochemical, histological and immunological parameters. Results: Inulin potentiated the severity of αIL10R-induced colitis, while pectin ameliorated the disease. Such exacerbation of colitis following inulin feeding was associated with enrichment of butyrate-producing bacteria and elevated levels of caecal butyrate. Blockade of butyrate production by either metronidazole or hops β-acids ameliorated colitis severity in inulin-fed mice, whereas augmenting caecal butyrate via tributyrin increased colitis severity in cellulose containing diet-fed mice. Elevated butyrate levels were associated with increased IL-1β activity, while inhibition of the NOD-like receptor protein 3 by genetic, pharmacologic or dietary means markedly reduced colitis. Conclusion: These results not only support the notion that fermentable fibres have the potential to ameliorate colitis but also caution that, in some contexts, prebiotic fibres can lead to gut dysbiosis and surfeit colonic butyrate that might exacerbate IBD.

Supplemental long-chain omega-3 (n–3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. Deidentified data from 1422 individuals from 14 published n–3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.

Obesity is associated with chronic inflammation and is a risk factor for insufficient milk production. Inflammation-mediated suppression of lipoprotein lipase could inhibit mammary uptake of long-chain fatty acids (LCFAs, >16C). In an ancillary case control analysis, we investigated whether women with low milk production despite regular breast emptying have elevated inflammation and disrupted transfer of LCFAs from plasma into milk. Data and specimens from a low milk supply study and an exclusively breastfeeding control group were analyzed, with milk production measured by 24-hour test-weighing at 2–10 weeks postpartum. Low milk supply groups were defined as very low (VL, 5 mg/L, 57%, 15%, 22%, respectively, p = 0.004), detectable milk TNF-α (67%, 32%, 33%, respectively, p = 0.04), and obesity (78%, 40%, 22%, respectively, p = 0.003). VL cases had lower LCFAs in milk (Mean[±SD], 60[±3%]) compared to MOD (65[±4%]) and controls (66[±5%]; (p < 0.001). Milk and serum LCFAs were strongly correlated in controls (r = 0.82, p < 0.001), but not in MOD (r = 0.25, p = 0.30) or VL (r = 0.20, p = 0.41) groups (p_int < 0.001). Mothers with very low milk production have significantly higher obesity and inflammatory biomarkers, lower LFCAs in milk, and disrupted association between plasma and milk LCFAs. These data support the hypothesis that inflammation disrupts normal mammary gland fatty acid uptake. Further research should address impacts of inflammation and obesity on mammary fatty acid uptake for milk production.

Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A₂α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.