Effects of polyphenol supplementation on hepatic steatosis, intima-media thickness and non-invasive vascular elastography in obese adolescents: a pilot study protocol.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent in obese adolescents. Increased systemic inflammation and decreased gut microbial diversity linked to obesity affect the liver and are also associated with cardiovascular diseases in adulthood. However, NAFLD and vascular alterations are reversible. METHODS AND ANALYSIS: This pilot study evaluated the feasibility of a prospective open-label randomised controlled trial evaluating the effects of polyphenols on NAFLD and vascular parameters in obese adolescents. Children aged 12-18 years with hepatic steatosis (n=60) will be recruited. The participants will be randomised with a 1:1 allocation ratio to receive polyphenol supplementation one time per day for 8 weeks along with the clinician-prescribed treatment (group B, n=30) or to continue the prescribed treatment without taking any polyphenols (group A, n=30). The outcome measures will be collected from both the groups at day 1 before starting polyphenol supplementation, at day 60 after 8 weeks of supplementation and at day 120, that is, 60 days after supplementation. The changes in hepatic steatosis and vascular parameters will be measured using liver and vascular imaging. Furthermore, anthropometric measures, blood tests and stool samples for gut microbiome analysis will be collected. After evaluating the study's feasibility, we hypothesise that, as a secondary outcome, compared with group A, the adolescents in group B will have improved NAFLD, vascular parameters, systemic inflammation and gut microbiome. ETHICS AND DISSEMINATION: This study is approved by Health Canada and the hospital ethics. Participants and their parents/tutors will both provide consent. Trial results will be communicated to the collaborating gastroenterologists who follow the enrolled participants. Abstracts and scientific articles will be submitted to high-impact radiological societies and journals. CLINICALTRIALS: gov ID: NCT03994029. Health Canada authorisation referral number: 250 811. Protocole version 13, 2 June 2023. TRIAL REGISTRATION NUMBER: NCT03994029.

Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders.

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.

Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.

Cranberry polyphenols and agave agavins impact gut immune response and microbiota composition while improving gut barrier function, inflammation, and glucose metabolism in mice fed an obesogenic diet.

The consumption of plant-based bioactive compounds modulates the gut microbiota and interacts with the innate and adaptive immune responses associated with metabolic disorders. The present study aimed to evaluate the effect of cranberry polyphenols (CP), rich in flavonoids, and agavins (AG), a highly branched agave-derived neo-fructans, on cardiometabolic response, gut microbiota composition, metabolic endotoxemia, and mucosal immunomodulation of C57BL6 male mice fed an obesogenic high-fat and high-sucrose (HFHS) diet for 9 weeks. Interestingly, CP+AG-fed mice had improved glucose homeostasis. Oral supplementation with CP selectively and robustly (five-fold) increases the relative abundance of Akkermansia muciniphila, a beneficial bacteria associated with metabolic health. AG, either alone or combined with CP (CP+AG), mainly stimulated the glycan-degrading bacteria Muribaculum intestinale, Faecalibaculum rodentium, Bacteroides uniformis, and Bacteroides acidifaciens. This increase of glycan-degrading bacteria was consistent with a significantly increased level of butyrate in obese mice receiving AG, as compared to untreated counterparts. CP+AG-supplemented HFHS-fed mice had significantly lower levels of plasma LBP than HFHS-fed controls, suggesting blunted metabolic endotoxemia and improved intestinal barrier function. Gut microbiota and derived metabolites interact with the immunological factors to improve intestinal epithelium barrier function. Oral administration of CP and AG to obese mice contributed to dampen the pro-inflammatory immune response through different signaling pathways. CP and AG, alone or combined, increased toll-like receptor (TLR)-2 (Tlr2) expression, while decreasing the expression of interleukin 1ß (ILß1) in obese mice. Moreover, AG selectively promoted the anti-inflammatory marker Foxp3, while CP increased the expression of NOD-like receptor family pyrin domain containing 6 (Nlrp6) inflammasome. The intestinal immune system was also shaped by dietary factor recognition. Indeed, the combination of CP+AG significantly increased the expression of aryl hydrocarbon receptors (Ahr). Altogether, both CP and AG can shape gut microbiota composition and regulate key mucosal markers involved in the repair of epithelial barrier integrity, thereby attenuating obesity-associated gut dysbiosis and metabolic inflammation and improving glucose homeostasis.

Specialized Pro-Resolving Mediators Derived from N-3 Polyunsaturated Fatty Acids: Role in Metabolic Syndrome and Related Complications.

Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS. Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids. Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD. Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54-83.

The postnatal window is critical for the development of sex-specific metabolic and gut microbiota outcomes in offspring.

The Developmental Origins of Health and Disease (DOHaD) concept has been proposed to explain the influence of environmental conditions during critical developmental stages on the risk of diseases in adulthood. The aim of this study was to compare the impact of the prenatal vs. postnatal environment on the gut microbiota in dams during the preconception, gestation and lactation periods and their consequences on metabolic outcomes in offspring. Here we used the cross-fostering technique, e.g. the exchange of pups following birth to a foster dam, to decipher the metabolic effects of the intrauterine versus postnatal environmental exposures to a polyphenol-rich cranberry extract (CE). CE administration to high-fat high-sucrose (HFHS)-fed dams improved glucose homeostasis and reduced liver steatosis in association with a shift in the maternal gut microbiota composition. Unexpectedly, we observed that the postnatal environment contributed to metabolic outcomes in female offspring, as revealed by adverse effects on adiposity and glucose metabolism, while no effect was observed in male offspring. In addition to the strong sexual dimorphism, we found a significant influence of the nursing mother on the community structure of the gut microbiota based on α-diversity and ß-diversity indices in offspring. Gut microbiota transplantation (GMT) experiments partly reproduced the observed phenotype in female offspring. Our data support the concept that the postnatal environment represents a critical window to influence future sex-dependent metabolic outcomes in offspring that are causally but partly linked with gut microbiome alterations.

Cholecalciferol Supplementation Does Not Prevent the Development of Metabolic Syndrome or Enhance the Beneficial Effects of Omega-3 Fatty Acids in Obese Mice.

BACKGROUND: Cholecalciferol (D3) may improve inflammation, and thus provide protection from cardiometabolic diseases (CMD), although controversy remains. Omega-3 fatty acids (ω-3FA) may also prevent the development of CMD, but the combined effects of ω-3FA and D3 are not fully understood. OBJECTIVES: We determined the chronic independent and combined effects of D3 and ω-3FA on body weight, glucose homeostasis, and markers of inflammation in obese mice. METHODS: We gave 8-week-old male C57BL/6J mice, which had been fed a high-fat, high-sucrose (HF) diet (65.5% kcal fat, 19.8% kcal carbohydrate, and 14% kcal protein) for 12 weeks, either a standard D3 dose (+SD3; 1400 IU D3/kg diet) or a high D3 dose (+HD3; 15,000 IU D3/kg diet). We fed 1 +SD3 group and 1 +HD3 group with 4.36% (w/w) fish oil (+ω-3FA; 44% eicosapentaenoic acid, 25% docosahexaenoic acid), and fed the other 2 groups with corn oil [+omega-6 fatty acids (ω-6FA)]. A fifth group was fed a low-fat (LF; 15.5% kcal) diet. LF and HF+ω-6+SD3 differences were tested by a Student's t-test and HF treatment differences were tested by a 2-way ANOVA. RESULTS: D3 supplementation in the +HD3 groups did not significantly increase plasma total 25-hydroxyvitamin D and 25-hydroxyvitamin D3 [25(OH)D3] versus the +SD3 groups, but it increased 3-epi-25-hydroxyvitamin D3 levels by 3.4 ng/mL in the HF+ω-6+HD3 group and 4.0 ng/mL in the HF+ω-3+HD3 group, representing 30% and 70%, respectively, of the total 25(OH)D3 increase. Energy expenditure increased in those mice fed diets +ω-3FA, by 3.9% in the HF+ω-3+SD3 group and 7.4% in the HF+ω-3+HD3 group, but it did not translate into lower body weight. The glucose tolerance curves of the HF+ω-3+SD3 and HF+ω-3+HD3 groups were improved by 11% and 17%, respectively, as compared to the respective +ω-6FA groups. D3 supplementation, within the ω-3FA groups, altered the gut microbiota by increasing the abundance of S24-7 and Lachnospiraceae taxa compared to the standard dose, while within the ω-6FA groups, D3 supplementation did not modulate specific taxa. CONCLUSIONS: Overall, D3 supplementation does not prevent CMD or enhance the beneficial effects of ω-3FA in vitamin D-sufficient obese mice.

Efficacy of Polyphenols in the Management of Dyslipidemia: A Focus on Clinical Studies.

Polyphenols (PLPs), phytochemicals found in a wide range of plant-based foods, have gained extensive attention in view of their antioxidant, anti-inflammatory, immunomodulatory and several additional beneficial activities. The health-promoting effects noted in animal models of various non-communicable diseases explain the growing interest in these molecules. In particular, in vitro and animal studies reported an attenuation of lipid disorders in response to PLPs. However, despite promising preclinical investigations, the effectiveness of PLPs in human dyslipidemia (DLP) is less clear and necessitates revision of available literature. Therefore, the present review analyzes the role of PLPs in managing clinical DLP, notably by dissecting their potential in ameliorating lipid/lipoprotein metabolism and alleviating hyperlipidemia, both postprandially and in long-term interventions. To this end, PubMed was used for article search. The search terms included polyphenols, lipids, triglycerides, cholesterol, LDL-cholesterol and /or HDL-cholesterol. The critical examination of the trials published to date illustrates certain benefits on blood lipids along with co-morbidities in participant's health status. However, inconsistent results document significant research gaps, potentially owing to study heterogeneity and lack of rigor in establishing PLP bioavailability during supplementation. This underlines the need for further efforts in order to elucidate and support a potential role of PLPs in fighting DLP.

Intestinal protection by proanthocyanidins involves anti-oxidative and anti-inflammatory actions in association with an improvement of insulin sensitivity, lipid and glucose homeostasis.

Recent advances have added another dimension to the complexity of cardiometabolic disorders (CMD) by directly implicating the gastrointestinal tract as a key player. In fact, multiple factors could interfere with intestinal homeostasis and elicit extra-intestinal CMD. As oxidative stress (OxS), inflammation, insulin resistance and lipid abnormalities are among the most disruptive events, the aim of the present study is to explore whether proanthocyanidins (PACs) exert protective effects against these disorders. To this end, fully differentiated intestinal Caco-2/15 cells were pre-incubated with PACs with and without the pro-oxidant and pro-inflammatory iron/ascorbate (Fe/Asc). PACs significantly reduce malondialdehyde, a biomarker of lipid peroxidation, and raise antioxidant SOD2 and GPx via the increase of NRF2/Keap1 ratio. Likewise, PACs decrease the inflammatory agents TNFα and COX2 through abrogation of NF-κB. Moreover, according to crucial biomarkers, PACs result in lipid homeostasis improvement as reflected by enhanced fatty acid ß-oxidation, diminished lipogenesis, and lowered gluconeogenesis as a result of PPARα, γ and SREBP1c modulation. Since these metabolic routes are mainly regulated by insulin sensitivity, we have examined the insulin signaling pathway and found an upregulation of phosphoPI3K/Akt and downregulation of p38-MAPK expressions, indicating beneficial effects in response to PACs. Taken together, PACs display the potential to counterbalance OxS and inflammation in Fe/Asc-exposed intestinal cells, in association with an improvement of insulin sensitivity, which ameliorates lipid and glucose homeostasis.

The Role of Oxidative Stress and Inflammation in Cardiometabolic Health of Children During Cancer Treatment and Potential Impact of Key Nutrients.

Significance: The 5-year survival rate of childhood cancers is now reaching 84%. However, treatments cause numerous acute and long-term side effects. These include cardiometabolic complications, namely hypertension, dyslipidemia, hyperglycemia, insulin resistance, and increased fat mass. Recent Advances: Many antineoplastic treatments can induce oxidative stress (OxS) and trigger an inflammatory response, which may cause acute and chronic side effects. Critical Issues: Clinical studies have reported a state of heightened OxS and inflammation during cancer treatment in children as the result of treatment cytotoxic action on both cancerous and noncancerous cells. Higher levels of OxS and inflammation are associated with treatment side effects and with the development of cardiometabolic complications. Key nutrients (omega-3 polyunsaturated fatty acids, dietary antioxidants, probiotics, and prebiotics) have the potential to modulate inflammatory and oxidative responses and, therefore, could be considered in the search for adverse complication prevention means as long as antineoplastic treatment efficiency is maintained. Future Directions: There is a need to better understand the relationship between cardiometabolic complications, OxS, inflammation and diet during pediatric cancer treatment, which represents the ultimate goal of this review. Antioxid. Redox Signal. 35, 293-318.

Can phytotherapy with polyphenols serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)?

Much more serious than the previous severe acute respiratory syndrome (SARS) coronavirus (CoV) outbreaks, the novel SARS-CoV-2 infection has spread speedily, affecting 213 countries and causing ∼17,300,000 cases and ∼672,000 (∼+1,500/day) deaths globally (as of July 31, 2020). The potentially fatal coronavirus disease (COVID-19), caused by air droplets and airborne as the main transmission modes, clearly induces a spectrum of respiratory clinical manifestations, but it also affects the immune, gastrointestinal, hematological, nervous, and renal systems. The dramatic scale of disorders and complications arises from the inadequacy of current treatments and absence of a vaccine and specific anti-COVID-19 drugs to suppress viral replication, inflammation, and additional pathogenic conditions. This highlights the importance of understanding the SARS-CoV-2 mechanisms of actions and the urgent need of prospecting for new or alternative treatment options. The main objective of the present review is to discuss the challenging issue relative to the clinical utility of plants-derived polyphenols in fighting viral infections. Not only is the strong capacity of polyphenols highlighted in magnifying health benefits, but the underlying mechanisms are also stressed. Finally, emphasis is placed on the potential ability of polyphenols to combat SARS-CoV-2 infection via the regulation of its molecular targets of human cellular binding and replication, as well as through the resulting host inflammation, oxidative stress, and signaling pathways.

Blueberry proanthocyanidins and anthocyanins improve metabolic health through a gut microbiota-dependent mechanism in diet-induced obese mice.

Blueberry consumption can prevent obesity-linked metabolic diseases, and it has been proposed that the polyphenol content of blueberries may contribute to these effects. Polyphenols have been shown to favorably impact metabolic health, but the role of specific polyphenol classes and whether the gut microbiota is linked to these effects remain unclear. We aimed to evaluate the impact of whole blueberry powder and blueberry polyphenols on the development of obesity and insulin resistance and to determine the potential role of gut microbes in these effects by using fecal microbiota transplantation (FMT). Sixty-eight C57BL/6 male mice were assigned to one of the following diets for 12 wk: balanced diet (Chow); high-fat, high-sucrose diet (HFHS); or HFHS supplemented with whole blueberry powder (BB), anthocyanidin (ANT)-rich extract, or proanthocyanidin (PAC)-rich extract. After 8 wk, mice were housed in metabolic cages, and an oral glucose tolerance test (OGTT) was performed. Sixty germ-free mice fed HFHS diet received FMT from one of the above groups biweekly for 8 wk, followed by an OGTT. PAC-treated mice were leaner than HFHS controls although they had the same energy intake and were more physically active. This observation was reproduced in germ-free mice receiving FMT from PAC-treated mice. PAC- and ANT-treated mice showed improved insulin responses during OGTT, and this finding was also reproduced in germ-free mice following FMT. These results show that blueberry PAC and ANT polyphenols can reduce diet-induced body weight and improve insulin sensitivity and that at least part of these beneficial effects are explained by modulation of the gut microbiota.

Wild blueberry proanthocyanidins shape distinct gut microbiota profile and influence glucose homeostasis and intestinal phenotypes in high-fat high-sucrose fed mice.

Blueberries are a rich source of polyphenols, widely studied for the prevention or attenuation of metabolic diseases. However, the health contribution and mechanisms of action of polyphenols depend on their type and structure. Here, we evaluated the effects of a wild blueberry polyphenolic extract (WBE) (Vaccinium angustifolium Aiton) on cardiometabolic parameters, gut microbiota composition and gut epithelium histology of high-fat high-sucrose (HFHS) diet-induced obese mice and determined which constitutive polyphenolic fractions (BPF) was responsible for the observed effects. To do so, the whole extract was separated in three fractions, F1) Anthocyanins and phenolic acids, F2) oligomeric proanthocyanidins (PACs), phenolic acids and flavonols (PACs degree of polymerization DP < 4), and F3) PACs polymers (PACs DP > 4) and supplied at their respective concentration in the whole extract. After 8 weeks, WBE reduced OGTT AUC by 18.3% compared to the HFHS treated rodents and the F3 fraction  contributed the most to this effect. The anthocyanin rich F1 fraction did not reproduce this response. WBE and the BPF restored the colonic mucus layer. Particularly, the polymeric PACs-rich F3 fraction increased the mucin-secreting goblet cells number. WBE caused a significant 2-fold higher proportion of Adlercreutzia equolifaciens whereas oligomeric PACs-rich F2 fraction increased by 2.5-fold the proportion of Akkermansia muciniphila. This study reveals the key role of WBE PACs in modulating the gut microbiota and restoring colonic epithelial mucus layer, providing a suitable ecological niche for mucosa-associated symbiotic bacteria, which may be crucial in triggering health effects of blueberry polyphenols.

Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.

Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.

Non-alcoholic fatty liver disease severity and metabolic complications in obese children: impact of omega-3 fatty acids.

Although n-3 polyunsaturated fatty acids (PUFA) revealed promising therapeutic results in non-alcoholic fatty liver disease (NAFLD), which is considered as the most prevalent cause of chronic hepatic disease, inconsistencies are calling for further confirmatory trials to demonstrate therapeutic efficacy and safety. The study, registered as NCT02201160 on www.clinicaltrials.gov, was designed to compare two groups of NAFLD with a different severity, and to evaluate the efficacy of n-3 PUFA supplementation. Twenty young male participants of French Canadian origin with NAFLD were enrolled and classified into moderate (mNAFLD) and severe (sNAFLD) fatty liver groups, according to transaminase levels, ultrasonography, NAFLD Activity Score and Fatty Liver Index (FLI). The sNAFLD patients were assigned to consume 2 g of n-3 PUFA for 6 months. sNAFLD patients displayed higher insulinemia, insulin resistance (IR), oxidative stress (OxS), systolic blood pressure and the risk lipid indicators of cardiovascular diseases. Supplementation of n-3 PUFA for 6 months resulted in a significant increase in concentrations of eicosapentaenoic and docosahexaenoic acids in red blood cells along with an attenuation of hepatic steatosis as reflected by the reduction of the FLI, ALT and ALT/AST ratio. Moreover, the n-3 PUFA improved the lipid profile and carotid intima-media thickness, while reducing metabolic and OxS markers as well as raising adiponectin. In conclusion, NAFLD severity was essentially related to IR. Treatment with n-3 PUFA has an evidently beneficial effect on liver steatosis and related metabolic abnormalities. Furthermore, the cross association of omega-3 index with cardiometabolic markers may serve as a predictor for cardiovascular risk disorders in NAFLD.

Saturated Fats from Butter but Not from Cheese Increase HDL-Mediated Cholesterol Efflux Capacity from J774 Macrophages in Men and Women with Abdominal Obesity.

Background: Recent evidence suggests that the association between dietary saturated fatty acids (SFAs) and coronary artery disease risk varies according to food sources. How SFAs from butter and cheese influence HDL-mediated cholesterol efflux capacity (CEC), a key process in reverse cholesterol transport, is currently unknown. Objective: In a predefined secondary analysis of a previously published trial, we have examined how diets rich in SFAs from either cheese or butter influence HDL-mediated CEC, compared with diets rich in either monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). Methods: In a randomized crossover controlled consumption trial, 46 men and women with abdominal obesity consumed 5 isocaloric diets, each for 4 wk. Two diets were rich in SFAs either from cheese (CHEESE) or butter (BUTTER) [12.4-12.6% of energy (%E) as SFAs, 32%E as fat, 52%E as carbohydrates]. In 2 other diets, SFAs (5.8%E) were replaced with either MUFAs from refined olive oil (MUFA) or PUFAs from corn oil (PUFA). Finally, a lower fat and carbohydrate diet was used as a control (5.8%E as SFAs, 25.0%E as fat, 59%E as carbohydrates; CHO). Post-diet HDL-mediated CEC was determined ex vivo using radiolabelled J774 macrophages incubated with apolipoprotein B-depleted serum from the participants. Results: Mean (±SD) age was 41.4 ± 14.2 y, and waist circumference was 107.6 ± 11.5 cm in men and 94.3 ± 12.4 cm in women. BUTTER and MUFA increased HDL-mediated CEC compared with CHEESE (+4.3%, P = 0.026 and +4.7%, P = 0.031, respectively). Exploring the significant diet × sex interaction (P = 0.044) revealed that the increase in HDL-mediated CEC after BUTTER compared with CHEESE was significant among men (+6.0%, P = 0.047) but not women (+2.9%, P = 0.19), whereas the increase after MUFA compared with CHEESE was significant among women (+9.1%, P = 0.008) but not men (-0.6%, P = 0.99). Conclusion: These results provide evidence of a food matrix effect modulating the impact of dairy SFAs on HDL-mediated CEC with potential sex-related differences that deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02106208.

A polyphenol-rich cranberry extract reverses insulin resistance and hepatic steatosis independently of body weight loss.

OBJECTIVE: Previous studies have reported that polyphenol-rich extracts from various sources can prevent obesity and associated gastro-hepatic and metabolic disorders in diet-induced obese (DIO) mice. However, whether such extracts can reverse obesity-linked metabolic alterations remains unknown. In the present study, we aimed to investigate the potential of a polyphenol-rich extract from cranberry (CE) to reverse obesity and associated metabolic disorders in DIO-mice. METHODS: Mice were pre-fed either a Chow or a High Fat-High Sucrose (HFHS) diet for 13 weeks to induce obesity and then treated either with CE (200 mg/kg, Chow + CE, HFHS + CE) or vehicle (Chow, HFHS) for 8 additional weeks. RESULTS: CE did not reverse weight gain or fat mass accretion in Chow- or HFHS-fed mice. However, HFHS + CE fully reversed hepatic steatosis and this was linked to upregulation of genes involved in lipid catabolism (e.g., PPARα) and downregulation of several pro-inflammatory genes (eg, COX2, TNFα) in the liver. These findings were associated with improved glucose tolerance and normalization of insulin sensitivity in HFHS + CE mice. The gut microbiota of HFHS + CE mice was characterized by lower Firmicutes to Bacteroidetes ratio and a drastic expansion of Akkermansia muciniphila and, to a lesser extent, of Barnesiella spp, as compared to HFHS controls. CONCLUSIONS: Taken together, our findings demonstrate that CE, without impacting body weight or adiposity, can fully reverse HFHS diet-induced insulin resistance and hepatic steatosis while triggering A. muciniphila blooming in the gut microbiota, thus underscoring the gut-liver axis as a primary target of cranberry polyphenols.

Vitamin D Reduces Colitis- and Inflammation-Associated Colorectal Cancer in Mice Independent of NOD2.

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer (CRC). Vitamin D (vD) induces NOD2 gene expression, enhancing immunity, while deficiency impairs intestinal epithelial integrity, increasing inflammation. This study investigated the effect of vD on CRC in colitis, and if preventive benefits are mediated via NOD2. Inflammation-associated CRC was induced by treating C57BL/6J and Nod2-/- mice with azoxymethane (AOM) and dextran sodium sulfate (DSS) cycles (×3). vD-deficient mice displayed more severe colitis compared to vD-supplemented mice, with greater weight loss, higher colitis activity index, increased colonic weight/length ratios, and lower survival rates. Increased histological inflammation score and increased IL-6 were observed in the mucosa of vD-deficient mice. Overall incidence of colonic tumors was not significantly different between vD-deficient and vD-supplemented mice. Higher tumor multiplicity was observed in vD-deficient vs vD-supplemented groups (both mouse strains). After AOM/DSS treatment, decreased plasma 25(OH)D3 levels and downregulation of vD target genes Cyp24 and Vdr were observed in both mice strains (vD-deficient or vD-supplemented diet), compared to saline-treated controls on the vD-deficient diet. In conclusion, vD supplementation reduced colitis severity and decreased the number of inflammation-associated colorectal tumors in both C57BL/6J and Nod2-/- mice, independent of NOD2.

Apple peel polyphenols: a key player in the prevention and treatment of experimental inflammatory bowel disease.

Diets rich in fruits and vegetables may reduce oxidative stress (OxS) and inflammation via several mechanisms. These beneficial effects may be due to their high polyphenol content. The aims of the present study are to evaluate the preventive and therapeutic aspects of polyphenols in dried apple peel powder (DAPP) on intestinal inflammation while elucidating the underlying mechanisms and clinical benefits. Induction of intestinal inflammation in mice was performed by oral administration of the inflammatory agent dextran sulfate sodium (DSS) at 2.5% for 10 days. Physiological and supraphysiological doses of DAPP (200 and 400 mg/kg/day respectively) were administered by gavage for 10 days pre- and post-DSS treatment. DSS-mediated inflammation caused weight loss, shortening of the colon, dystrophic detachment of the epithelium, and infiltration of mono- and poly-morphonuclear cells in the colon. DSS induced an increase in lipid peroxidation, a down-regulation of antioxidant enzymes, an augmented expression of myeloperoxidase (MPO) and cyclooxygenase-2 (COX-2), an elevated production of prostaglandin E2 (PGE2) and a shift in mucosa-associated microbial composition. However, DAPP normalized most of these abnormalities in preventive or therapeutic situations in addition to lowering inflammatory cytokines while stimulating antioxidant transcription factors and modulating other potential healing pathways. The supraphysiological dose of DAPP in therapeutic situations also improved mitochondrial dysfunction. Relative abundance of Peptostreptococcaceae and Enterobacteriaceae bacteria was slightly decreased in DAPP-treated mice. In conclusion, DAPP exhibits powerful antioxidant and anti-inflammatory action in the intestine and is associated with the regulation of cellular signalling pathways and changes in microbiota composition. Evaluation of preventive and therapeutic effects of DAPP may be clinically feasible in individuals with intestinal inflammatory bowel diseases.

Triggering Akkermansia with dietary polyphenols: A new weapon to combat the metabolic syndrome?

The gut and its bacterial colonizers are now well characterized as key players in whole-body metabolism, opening new avenues of research and generating great expectation for new treatments against obesity and its cardiometabolic complications. As diet is the main environmental factor affecting the gut microbiota, it has been suggested that fruits and vegetables, whose consumption is strongly associated with a healthy lifestyle, may carry phytochemicals that could help maintain intestinal homeostasis and metabolic health. We recently demonstrated that oral administration of a cranberry extract rich in polyphenols prevented diet-induced obesity and several detrimental features of the metabolic syndrome in association with a remarkable increase in the abundance of the mucin-degrading bacterium Akkermansia in the gut microbiota of mice. This addendum provides an extended discussion in light of recent discoveries suggesting a mechanistic link between polyphenols and Akkermansia, also contemplating how this unique microorganism may be exploited to fight the metabolic syndrome.