| |
Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial
|
| |
| |
Dowload the PDF here
In the current study, we demonstrated that the prevalence of NAFLD was reduced in half by the strategy of exercise and green-MED diet enriched with Mankai and walnuts and restricted in red and processed meat, as reflected by increased plasma polyphenols and serum folate. Also, we found an independent association between 18-month IHF% reduction and beneficial changes in cardiometabolic, inflammatory parameters, specific gut bacteria and with global microbiota composition, which was also found to have a mediatory role in the association between lifestyle intervention and liver fat reduction. Following our previous trials suggesting that the MED diet is favourable to a low-fat diet in terms of cardiometabolic risk13 34 and IHF loss,18 this clinical trial may suggest an effective nutritional tool for the treatment of NAFLD beyond weight loss, a predicament that very little, if any effect, pharmacological treatment exists for.
In conclusion, a green-MED diet, enriched with specific polyphenols and decreased red and processed meat consumption, amplifies the beneficial effect of the MED diet on hepatic fat reduction, beyond weight loss. The results of this study may suggest an improved dietary protocol to treat NAFLD.
AASLD: What Are the Current Treatment Options for our Patients with NAFLD/NASH ? - (12/01/20)
Cancer Risk in Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study - (05/3/21)
Forty-one (12%) of PWH without viral hepatitis had elevated LSM assessed by transient elastography compared to 154 (7%) population controls. - Non-Viral Liver Disease in HIV+ - Increased Prevalence of Liver Fibrosis in PLWH Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls - (03/02/21)
Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study - (02/10/21)
In this large community-based sample of middle-aged and older adults unselected for liver disease, we observed that 8.8% of participants, a substantial minority, exceeded the threshold of potentially clinically significant hepatic fibrosis, defined by LSM ≥ 8.2 kPa. Hepatic fibrosis was associated with multiple obesity-related, glucose-related, vascular-related, and cholesterol-related traits; however, most associations were confounded, at least in part, by general adiposity or hepatic steatosis because the associations were mostly attenuated when BMI or CAP was added to the multivariable model. Notably, hepatic fibrosis remained significantly associated with obesity-related traits, hypertension, low HDL cholesterol, and, most strongly, with diabetes, with 2.5 times increased odds, even after accounting for CAP, which suggests an association between hepatic fibrosis and cardiometabolic disease in addition too the association with hepatic steatosis.
AASLD: PREVALENCE AND RISK FACTORS OF HEPATIC STEATOSIS AND FIBROSIS IN AMERICAN ADULTS: A POPULATION-BASED STUDY - (12/21/20) Age, male, BMI≥30, diabetes, and low HDL were associated with having S≥S3. Age, male, BMI≥35, diabetes, hepatitis B or C, other liver disease, and steatosis ≥67% were associated with having F≥F3. Being Black was protective of both severe steatosis and advanced fibrosis. Conclusion: Steatosis (≥5% liver fat) is widespread among U.S. adults. Almost 1 in 4 patients with hepatitis B or C and 1 in 10 patients with fatty liver had advanced fibrosis.
Abstract
Objective To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss.
Design For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided).
The green-MED group further consumed green tea (3-4 cups/day) and Mankai (a Wolffia globosa aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided).
IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS).
Results
Participants (age=51 years; 88% men; body mass index=31.3 kg/m2; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS.
Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups.
Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (-38.9% proportionally), as compared with MED (-19.6% proportionally; p=0.035 weight loss adjusted) and HDG (-12.2% proportionally; p<0.001).
After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of Naringenin and 2-5-dihydroxybenzoic-acid in green-MED.
Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p<0.05 for all).
Conclusion The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half.
In conclusion, a green-MED diet, enriched with specific polyphenols and decreased red and processed meat consumption, amplifies the beneficial effect of the MED diet on hepatic fat reduction, beyond weight loss. The results of this study may suggest an improved dietary protocol to treat NAFLD....
Introduction
Intrahepatic fat (IHF) accumulation, a result of intracellular triglyceride (TG) deposition in the liver, is promoted by bodily adipose tissue dysfunction and insulin resistance.1 IHF that exceeds 5%, in the absence of alcohol abuse, defines non-alcoholic fatty liver disease (NAFLD).2 IHF accumulation is associated with elevated liver enzymes, insulin resistance, type 2 diabetes, cardiovascular risk and extrahepatic malignancies.2 3 In recent years, the gut microbiome was suggested to have a pivotal role in NAFLD pathogenesis. This association is presumably due to the modulation of hepatic carbohydrate and lipid metabolism, with dysbiosis, that is, aberrant composition of the microbiome community, being a hallmark of the disease.4 5 NAFLD affects about a quarter of the world population6 and can progress to the development of steatohepatitis, liver-cirrhosis and hepatocellular carcinoma.2 7 The current evidence-based treatment strategy consists of weight-loss through lifestyle interventions,8 without specific dietary recommendations, although strong evidence points toward recommending the Mediterranean (MED) diet.9 MED diet, relatively rich in plant food sources, has been associated with reduced prevalence of NAFLD,10 improves cardiometabolic and cardiovascular biomarkers, and reduces all-cause mortality.11-13
Polyphenols, secondary metabolites of plants with antioxidant properties, are involved in the defence against ultraviolet radiation and pathogenic insults in the plants and have been suggested, in humans, to be protective against several malignancies, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases,14 as well as reducing hepatic steatosis.15 The main groups of polyphenols are classified by the number of phenol rings they contain and structural elements and include phenolic acids, flavonoids, stilbenes and lignans.14 The MED diet has a relatively high content of polyphenols. In the traditional Spanish MED diet, the mean polyphenol intake was estimated to be between ∼2500 and 3000 mg/day16 as compared with ∼1000 mg/day in a western-style diet.17 We, and others, reported a greater decrease in NAFLD with MED diet, as compared with a low-fat diet.3 18 19 Adherence to vegetarian and plant-based diets was also associated with a lower incidence of NAFLD.20 21
In the current 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT PLUS), we aimed to examine the effect of MED diet, further enriched with polyphenols and lower in red and processed meat ('green-MED'), on IHF changes, as measured by proton magnetic resonance spectroscopy (H-MRS). Our a priori hypothesis was that a green-MED diet may promote further effectiveness in treating NAFLD, beyond the expected beneficial effects of the MED diet.
Discussion
In the current study, we demonstrated that the prevalence of NAFLD was reduced in half by the strategy of exercise and green-MED diet enriched with Mankai and walnuts and restricted in red and processed meat, as reflected by increased plasma polyphenols and serum folate. Also, we found an independent association between 18-month IHF% reduction and beneficial changes in cardiometabolic, inflammatory parameters, specific gut bacteria and with global microbiota composition, which was also found to have a mediatory role in the association between lifestyle intervention and liver fat reduction. Following our previous trials suggesting that the MED diet is favourable to a low-fat diet in terms of cardiometabolic risk13 34 and IHF loss,18 this clinical trial may suggest an effective nutritional tool for the treatment of NAFLD beyond weight loss, a predicament that very little, if any effect, pharmacological treatment exists for.
Several limitations of this study should be considered. First, we had a high proportion of male participants, reflecting the profile of the workplace. This limits our ability to extrapolate our results to women. In addition, NAFLD is almost as prevalent in women as compared with men, and thus gender aspects are not fulfilled by this trial. Also, this study's results may not be extrapolated to a population that is not abdominally obese and/or with dyslipidaemia, or a population with a lower prevalence of NAFLD than seen among our participants. Yet, the high prevalence of liver steatosis is probably a reflection of a sedentary lifestyle and unhealthy eating pattern, as our participants did not report any alcohol abuse. Second, we assessed adherence to the intervention mainly by participants' self-reports. However, serum folate analysis, reflecting green leaf consumption29 and correlate well with nutritional self-reports,28 enabled us to objectively estimate green products' intake. Although we measured plasma polyphenols, these measurements are limited in reflecting polyphenol intake, as only a few phenolic acids, derived from dietary polyphenol metabolism, will be present in overnight, fasted blood samples.35 The strengths of the study include the closed workplace environment, which enabled monitoring of the provided lunch, the presence of an on-site clinic at the participants' workplace; intense dietary guidance and group meetings with multidisciplinary guidance; access to free-of-charge provided polyphenols; relatively large sample size; high retention rate; and the use of an accurate imaging technique,30 as compared with other non-invasive methods36 with high reproducibility between measurements,37 to quantify IHF%.
According to current guidelines, obese or overweight individuals are advised to undergo a moderate 5%-10% weight reduction by energy restriction.8 9 NAFLD patients are advised to change their diet (ie, reduce added sugar and reduce saturated fat) and engage in PA, both aerobic and resistance.8 In our study, participants who were instructed for HDG reduced both WC and IHF%, in accordance with a previous publication,38 whereas aerobic PA interventions in obese men and women, without weight loss, was found to be useful in the reduction of liver steatosis. The MED intervention in our study had greater efficacy in promoting adiposity (WC and weight) reduction, in addition to IHF% loss, similarly to data previously reported by us,3 18where some fat depots, and more specifically IHF%, were effectively reduced by the MED/low carbohydrate diet than the low-fat diet, independently of VAT changes. The green-MED diet achieved the highest IHF loss, within similar weight loss as observed in the MED group, suggesting that diet composition has an effect beyond weight loss. We now add to this knowledge by demonstrating an additional benefit from the green-MED regimen, differed from the MED diet by being rich in green polyphenols and restricted in red and processed meat.
Polyphenols might play a role in reducing liver steatosis by preventing hepatocellular damage through several possible mechanisms, including reducing de novo lipogenesis, increasing fatty acid oxidation and reducing oxidative stress.15 The MED eating pattern is based mainly on increasing plant-based foods, including olive oil, along with restricted meat consumption. In our trial, we further enriched the diet with provided polyphenols, in addition to the polyphenols naturally found in the MED diet. Participants in the green-MED group were instructed to consume 3-4 cups/day of green tea containing mostly EGCG, associated with reducing liver fat, as well as liver enzymes levels, fibrosis, and inflammation39 and a daily Mankai green shake containing a mixture of flavonoids, shown to increase fatty acid oxidation in the liver, reduce inflammation by inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells, to increase adiponectin, and to reduce BP.40 Both MED groups received 28 g/day of walnuts, rich in ellagic acid, shown to improve hepatic status due to antihepatotoxic properties.41 The participants of the green-MED group had a specific detection of Naringenin (demonstrated to have a beneficial effect in liver diseases42) and 2-5-dihydroxybenzoic acid (a catabolite of the plant hormone salicylic acid43).
In addition to a greater reduction in IHF following a higher intake of polyphenols rich Mankai shake and walnuts, a decrease in red/processed meat and increased folate (probably reflecting Mankai consumption) also led to greater IHF reduction. Folate is an essential vitamin of the B vitamins family, with several important biological roles (eg, involvement in the DNA synthesis).44 Low folate levels were previously recognised as an independent risk factor of NAFLD,45 probably by affecting the expression of genes that might contribute to the accumulation of lipids in the liver.44 These results suggest that a higher intake of specific polyphenol-serum folate-rich components, in addition to a decrease in red/processed meat, might mediate a reduction of liver fat. We observed known associations of IHF% at baseline with some cardiometabolic-related biomarkers in accordance with our previous report,3 and an association between IHF change and change in FGF21 (elevated in conditions of obesity and NAFLD46). Due to our study's nature, we cannot determine whether the change observed in these markers resulted from the reduction in IHF% and improvement in liver status or is merely a reflection of overall cardiometabolic improvement.
Previous studies have established the role of the gut microbiome in fat storage regulation in general,47 and NAFLD induction through hepatic fat storage specifically.5We described an association between IHF% and microbiome composition at baseline, with a homogenous dysbiotic pattern among the two higher IHF% tertiles (>4.3% IHF) of our cohort. This observation is in accordance with prior evidence, associating NAFLD (>5% IHF) and gut dysbiosis.4 The family Ruminococcaceae has been consistently reported as less abundant in NAFLD,48 49 a finding we were able to reproduce at baseline in our cohort. Interestingly enough, during our trial IHF reduction was positively correlated with changes in specific Ruminococcaceae genera (Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-009) and negatively correlated with change of a specific genus (Ruminococcaceae_UCG-008). This finding warrants further investigation as to the role of Ruminococcaceae in NAFLD pathogenesis and resolution. We further report a novel observation, linking IHF% change with a compositional shift in the microbiome over 18 months. This shift, in turn, partially mediated the effect of lifestyle interventions on IHF%. This mediatory effect of gut microbiome composition on IHF reduction constitutes an advancement of the observations made by others, establishing the association between the gut microbiome composition and NAFLD susceptibility.50
In conclusion, a green-MED diet, enriched with specific polyphenols and decreased red and processed meat consumption, amplifies the beneficial effect of the MED diet on hepatic fat reduction, beyond weight loss. The results of this study may suggest an improved dietary protocol to treat NAFLD.
| |
| |
| |
|
|
|
