Gender Differences in Liver Steatosis and Fibrosis in Overweight and Obese Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease before and after 8 Weeks of Very Low-Calorie Ketogenic Diet.

Obesity and metabolic syndrome are linked to steatotic liver disease (SLD), the most common form of chronic liver disease. Lifestyle modifications and dieting are strategies that can prevent metabolic dysfunction-associated steatotic liver disease (MASLD). The very low-calorie ketogenic diet (VLCKD) is a helpful treatment for MASLD and has been recommended for people affected by obesity; we evaluated the effect of gender on steatosis and fibrosis in a cohort of 112 overweight or obese patients undergoing an eight-week treatment with a VLCKD. Differences between the genders in terms of anthropometric measures, body composition, and metabolic indicators were examined before, during, and after the nutritional intervention. At baseline, there were significant differences between men and women in terms of anthropometric parameters, blood pressure, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting insulin, hepatic markers, and lipid profile. Men had considerably higher levels of liver steatosis (measured by CAP) and liver stiffness (measured by E) under basal conditions than women. After the VLCKD, there were reductions in both genders of controlled attenuation parameter (CAP), body weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, insulin resistance, fat mass (FM), free fat mass (FFM), and fasting blood glucose, insulin, glycated hemoglobin (HbA1c), triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, alanine transaminase (ALT), gamma-glutamyl transferase (γGT), and uric acid levels. Only in men, liver stiffness, aspartate aminotransferase (AST), creatinine, and C-reactive protein (CRP) levels significantly decreased. Moreover, men had significantly greater levels of liver steatosis: the male gender featured an increase of 23.96 points of the Fibroscan CAP. Men exhibited higher levels of steatosis and fibrosis than women, and these differences persist despite VLCKD. These gender-specific variations in steatosis and fibrosis levels could be caused by hormonal and metabolic factors, suggesting that different therapeutic strategies might be required depending on the gender.

Higher-Level Steatosis Is Associated with a Greater Decrease in Metabolic Dysfunction-Associated Steatoic Liver Disease after Eight Weeks of a Very Low-Calorie Ketogenic Diet (VLCKD) in Subjects Affected by Overweight and Obesity.

The most common form of chronic liver disease, recently defined as MASLD, is strongly linked to obesity and metabolic syndrome. Lifestyle changes are part of MASLD prevention. The very low-calorie ketogenic diet (VLCKD) is a useful option for treating MASLD and reducing liver steatosis in patients with obesity. We assessed whether a greater degree of steatosis could have a positive or negative impact on how well 8 weeks of using the VLCKD improve steatosis and fibrosis in a patient population of overweight and obese individuals. Anthropometric parameters, along with changes in hormone and metabolic biomarkers, were also assessed both before and after the dietary change. The study population included 111 overweight (14.41%) or obese subjects (85.59%) aged between 18 and 64 years; the 75 women and 36 men involved were not taking any medicine. In both the raw (0.37 95% CI 0.21; 0.52) and the multivariate models (model a: 0.439 95% CI 0.26; 0.62; model b: 0.437 95% CI 0.25; 0.63), there was a positive and statistically significant correlation between the CAP delta value and the CAP before using the VLCKD. Additionally, the liver stiffness delta was found to be positively and statistically significantly correlated with liver stiffness before the use of the VLCKD in both models: the multivariate model (model a: 0.560 95% CI 0.40; 0.71; model b: 0.498 95% CI 0.34; 0.65) and the raw model (0.52 95% CI 0.39; 0.65). Systolic and diastolic blood pressure, insulin resistance (measured by HOMA-IR), insulin, HbA1c, fasting blood glucose, total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, BMI, waist circumference, and fat mass, were all decreased (p < 0.001) following the use of the VLCKD. However, following the use of the VLCKD, there was an increase in vitamin D levels. (p < 0.001). We found that using the VLCKD for 8 weeks has a greater effect on improving steatosis and fibrosis in subjects who initially have more severe forms of these conditions.

Effects of Egg Consumption on Subjects with SLD or Hypertension: A MICOL Study.

BACKGROUND: Steatotic liver disease (SLD) is defined as a fat accumulation in more than 5% of hepatocytes; it can progress to non-alcoholic steatohepatitis (NASH), associated with an increased state of inflammation. The aim of this study was to explore the protective effects of eating eggs and any association with SLD and hypertension (HTN). METHODS: The study cohort included 908 participants assessed in the fourth recall of the MICOL study, grouped into four groups, based on NALFD and/or HTN. RESULTS: The prevalence of HTN and SLD among participants was 31.61%. Overall, the results indicated a statistical significance of egg consumption, showing a protective role against the two disease conditions, in both the raw and adjusted models (RRR = 0.34, p = 0.009, 0.15 to 0.76 95% C.I.). CONCLUSIONS: Many differences were found among the groups, and the protective role of eating eggs was amply demonstrated. We can conclude that it is unwise to demonize the intake of this food and its nutritional properties, in contrast with previous reports in the literature.

Galad Score as a Prognostic Marker for Patients with Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for more than 75% of primary liver cancers, which are the second leading cause of cancer-related deaths. The GALAD (gender, age, AFP-L3, AFP, and des-carboxy-prothrombin) score is a diagnostic tool developed based on gender, age, alpha-fetoprotein, alpha-fetoprotein L3, and des-gamma-carboxy prothrombin, originally designed as a diagnostic tool for HCC in high-risk patients. METHODS: We analyzed 212 patients with and without cirrhosis. The population study was divided into patients with liver cirrhosis without evidence of HCC at the time of serum sample collection for GALAD score determination and patients with liver cirrhosis and a confirmed diagnosis of HCC at the time of serum sample collection for GALAD score determination. Patients were followed up until death or liver transplantation. The association between variables and HCC mortality risk was performed, and the results were presented as hazard ratio (HR). The receiver operating characteristic (ROC) curve was used to assess the performance of the GALAD HCC diagnosis. The survival probability was explored using the non-parametric test, and the equality of survival amongst categories was assessed with the log-rank test. RESULTS: Biomarkers were higher in the HCC group compared to cirrhosis. Kaplan-Meier survival probability analysis for individual GALAD categories revealed that a high GALAD level was associated with decreased survival during follow-up, and the difference between the curves was statistically significant (p = 0.01). CONCLUSIONS: Our findings suggest that the GALAD score has promise as a prognostic tool, with implications for improving patient management and treatment strategies for HCC.

Effects of an Eight Week Very Low-Calorie Ketogenic Diet (VLCKD) on White Blood Cell and Platelet Counts in Relation to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in Subjects with Overweight and Obesity.

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are frequently associated conditions characterized by low-grade inflammation. Very low-calorie ketogenic diet (VLCKD) strategies are commonly used to simultaneously obtain weight loss and an improvement of liver steatosis. We evaluated the efficacy of 8 weeks' VLCKD in decreasing the white blood cell (WBC) and platelet (PLT) counts, as well as liver steatosis and fibrosis, diagnosed using transient elastography (FibroScan). Metabolic and anthropometric parameters commonly associated with MASLD were also evaluated. This study included 87 participants; 58 women and 29 men aged between 18 and 64 years with overweight (18%) or obesity (82%), but not taking any medication. Anthropometric measurements, bioimpedance analysis, and biochemical assays were performed before and after the dietary intervention. BMI (kg/m2) (p-value < 0.001), waist circumference (cm) (p-value < 0.001), and fat mass (kg) (p-value < 0.001) were significantly decreased following VLCKD. After VLCKD, the FibroScan parameter CAP (db/m), which measures the accumulation of fatty liver, significantly decreased (p-value < 0.001), as did liver stiffness (kPA), the FibroScan parameter quantifying liver fibrosis (p-value < 0.05). Seemingly, WBC (p-value < 0.001) and PLT (p-value < 0.001) counts were lowered by VLCKD in the whole group; however, the decrease in WBC and platelet counts were significant only in patients with steatosis (CAP ≥ 215 dB/m). Fasting blood glucose (p-value < 0.001), insulin (p-value < 0.001), HbA1c (p-value < 0.001), triglycerides (p-value < 0.001), total cholesterol (p-value < 0.001), LDL-cholesterol (p-value < 0.001), HDL-cholesterol (p-value < 0.001); γGT (p-value < 0.001) blood levels and insulin resistance (as measured by HOMAIR) (p-value < 0.001); and systolic (p-value < 0.001), and diastolic (p-value < 0.001) blood pressure levels, were all significantly lower after VLCKD. In contrast, blood levels of vitamin D were higher following the diet (p-value < 0.001). We conclude that treating subjects with overweight and obesity with VLCKD is followed by a simultaneous reduction in WBCs and platelets, the expression of low-grade inflammation, and of liver steatosis and fibrosis. Therefore, we can hypothesize that VLCKD decreases general and liver low-grade inflammation, thus improving liver health.

The oleic/palmitic acid imbalance in exosomes isolated from NAFLD patients induces necroptosis of liver cells via the elongase-6/RIP-1 pathway.

Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression. Aim of the study was to highlight the PA/OA imbalance within circulating exosomes, the subsequent intracellular alterations, and the impact on NALFD. Liver cells were challenged with exosomes isolated from both healthy subjects and NAFLD patients. The exosomal PA/OA ratio was artificially modified, and biological effects were evaluated. A NAFLD-derived exosomal PA/OA imbalance impacts liver cell cycle and cell viability. OA-modified NAFLD-derived exosomes restored cellular viability and proliferation, whereas the inclusion of PA into healthy subjects-derived exosomes negatively affected cell viability. Moreover, while OA reduced the phosphorylation and activation of the necroptosis marker, Receptor-interacting protein 1 (phospho-RIP-1), PA induced the opposite outcome, alongside increased levels of stress fibers, such as vimentin and fibronectin. Administration of NAFLD-derived exosomes led to increased expression of Elongase 6 (ELOVL6), Stearoyl-CoA desaturase 1 (SCD1), Tumor necrosis factor α (TNF-α), Mixed-lineage-kinase-domain-like-protein (MLKL) and RIP-1 in the hepatocytes, comparable to mRNA levels in the hepatocytes of NAFLD patients reported in the Gene Expression Omnibus (GEO) database. Genetic and pharmacological abrogation of ELOVL6 elicited a reduced expression of downstream molecules TNF-α, phospho-RIP-1, and phospho-MLKL upon administration of NAFLD-derived exosomes. Lastly, mice fed with high-fat diet exhibited higher phospho-RIP-1 than mice fed with control diet. Targeting the Elongase 6-RIP-1 signaling pathway offers a novel therapeutic approach for the treatment of the NALFD-induced exosomal PA/OA imbalance.

Plasma Bacterial DNA Load as a Potential Biomarker for the Early Detection of Colorectal Cancer: A Case-Control Study.

The gut microbiota has gained increasing attention in recent years due to its significant impact on colorectal cancer (CRC) development and progression. The recent detection of bacterial DNA load in plasma holds promise as a potential non-invasive approach for early cancer detection. The aim of this study was to examine the quantity of bacterial DNA present in the plasma of 50 patients who have CRC in comparison to 40 neoplastic disease-free patients, as well as to determine if there is a correlation between the amount of plasma bacterial DNA and various clinical parameters. Plasma bacterial DNA levels were found to be elevated in the CRC group compared to the control group. As it emerged from the logistic analysis (adjusted for age and gender), these levels were strongly associated with the risk of CRC (OR = 1.02, p < 0.001, 95% C.I.: 1.01-1.03). Moreover, an association was identified between a reduction in tumor mass and the highest tertile of plasma bacterial DNA. Our findings indicate that individuals with CRC displayed a higher plasma bacterial DNA load compared to healthy controls. This observation lends support to the theory of heightened bacterial migration from the gastrointestinal tract to the bloodstream in CRC. Furthermore, our results establish a link between this phenomenon and the size of the tumor mass.

Age-Related Dietary Habits and Blood Biochemical Parameters in Patients with and without Steatosis-MICOL Cohort.

BACKGROUND: Steatosis is now the most common liver disease in the world, present in approximately 25% of the global population. The aim of this study was to study the association between food intake and liver disease and evaluate the differences in blood parameters in age classes and steatosic condition. METHODS: The present study included 1483 participants assessed in the fourth recall of the MICOL study. Patients were subdivided by age (65 years) and administered a validated food frequency questionnaire (FFQ) with 28 food groups. RESULTS: The prevalence of steatosis was 55.92% in the adult group and 55.88% in the elderly group. Overall, the results indicated many statistically significant blood parameters and dietary habits. Analysis of food choices with a machine learning algorithm revealed that in the adult group, olive oil, grains, processed meat, and sweets were associated with steatosis, while the elderly group preferred red meat, dairy, seafood, and fruiting vegetables. Furthermore, the latter ate less as compared with the adult group. CONCLUSIONS: Many differences were found between the two age groups, both in blood parameters and food intake. The random forest also revealed different foods predicted steatosis in the two groups. Future analysis will be useful to understand the molecular basis of these differences and how different food intake causes steatosis in people of different ages.

GALAD outperforms aMAP and ALBI for predicting HCC in patients with compensated advanced chronic liver disease: A 12-year prospective study.

BACKGROUND AND AIMS: Surveillance programs are strongly recommended in patients with liver cirrhosis for early detection of HCC development. Six-monthly ultrasound sonography is the most reliable and commonly used technique, especially when associated with serum determination of α-fetoprotein, but different score systems have been proposed to overcome the unsatisfactory diagnostic accuracy of α-fetoprotein. The aim of this 12-year prospective study is to compare the gender, age, AFP-L3, AFP, des-gamma-carboxy prothrombin (GALAD) versus age, gender, bilirubin, albumin, and platelets and albumin-bilirubin scores in predicting HCC onset. APPROACH AND RESULTS: A cohort of 545 consecutive patients with compensated advanced chronic liver disease without suspected focal lesions was followed up every 6 months by liver imaging and α-fetoprotein to detect HCC occurrence. Harrell's C-index for censored data was employed to evaluate the performance of any parameters or scores helping to predict HCC development. ROC curve analysis showed that the GALAD score was more accurate in evaluating HCC development than albumin-bilirubin and age, gender, bilirubin, albumin, and platelets. The AUC ranged from 0.7268 to 0.6851 at 5 and 10 years, both in the total cohort and in the sub-cohorts (viral hepatitis, NASH, and alcohol). The HCC Risk model was constructed using univariate and multivariate Cox proportional hazard regression analysis, showing a strong association of GALAD with HR > 1, p < 0.05, in the total and sub-cohorts, and a better risk prediction in the alcohol cohort, both alone and standardized with other blood parameters. CONCLUSIONS: GALAD is the most reliable and accurate score system to detect HCC risk of development in patients with compensated advanced chronic liver disease.

Food Network Analysis in Non-Obese Patients with or without Steatosis.

BACKGROUND: Steatosis is the most common liver disease worldwide and the leading cause of liver-associated morbidity and mortality. The aim of this study was to explore the differences in blood parameters and dietary habits in non-obese patients with and without steatosis. METHODS: The present study included 987 participants with BMI < 30, assessed in the fourth recall of the MICOL study. Patients were divided by steatosis grade, and a validated food frequency questionnaire (FFQ) with 28 food groups was administered. RESULTS: The prevalence of non-obese participants with steatosis was 42.86%. Overall, the results indicated many statistically significant blood parameters and dietary habits. Analysis of dietary habits revealed that non-obese people with or without steatosis had similar dietary habits, although higher daily amounts of red meat, processed meat, ready meals, and alcohol were recorded in participants with liver disease (p < 0.05). CONCLUSIONS: Many differences were found in non-obese people with and without steatosis, but in light of a network analysis, the two groups demonstrated similar dietary habits, proving that pathophysiological, genetic, and hormonal patterns are probably the basis of their liver status, regardless of weight. Future genetic analyses will be performed to analyze the expression of genes involved in the development of steatosis in our cohort.

Diet and Exercise Exert a Differential Effect on Glucose Metabolism Markers According to the Degree of NAFLD Severity.

BACKGROUND: Non-Alcoholic Fatty Liver Disease (NAFLD) and Type 2 Diabetes (T2D) are highly prevalent diseases worldwide. Insulin Resistance (IR) is the common denominator of the two conditions even if the precise timing of onset is unknown. Lifestyle change remains the most effective treatment to manage NAFLD. This study aimed to estimate the effect of the Low Glycemic Index Mediterranean Diet (LGIMD) and exercise (aerobic and resistance) over a one-year period on the longitudinal trajectories of glucose metabolism regulatory pathways. MATERIALS AND METHODS: In this observational study, 58 subjects (aged 18-65) with different degrees of NAFLD severity were enrolled by the National Institute of Gastroenterology-IRCCS "S. de Bellis", to follow a 12-month program of combined exercise and diet. RESULTS: The mean age was 55 ± 7 years old. Gender was equally distributed among NAFLD categories. There was a statistically significant main effect of time for glycosylated hemoglobin (Hb1Ac) over the whole period (-5.41, 95% CI: -7.51; -3.32). There was a steady, statistically significant decrease of HbA1c in participants with moderate and severe NAFLD whereas this effect was observed after the 9th month in those with mild NAFLD. CONCLUSIONS: The proposed program significantly improves glucose metabolism parameters, especially HbA1c.

The Replacement of Only One Portion of Starchy Carbohydrates with Green Leafy Vegetables Regresses Mid and Advanced Stages of NAFLD: Results from a Prospective Pilot Study.

The gold standard treatment for NAFLD is weight loss and lifestyle interventions, which require a diet enriched in fiber and reduced in sugars and saturated fats. Fibres may be advantageous for NAFLD patients since they reduce and slow the absorption of carbohydrates, lipids, and proteins, lowering the energy density of the meal and increasing their sense of satiety. Furthermore, the polyphenol content and other bioactive compounds of vegetables have antioxidant and anti-inflammatory properties preventing disease progression. The aim of this study is to ascertain the effects of a diet enriched by green leafy vegetables and with a moderate restriction of carbohydrate intake in patients with NAFLD over a three month period. Among the forty patients screened, twenty four patients completed the clinical trial consisting of swapping one portion of carbohydrate-rich food for one portion of green leafy vegetables, and liver and metabolic markers of NAFLD were evaluated. All patients underwent routine blood tests, anthropometric measurements, bioelectrical impedance analysis, fibroscan, and fatty liver index (FLI) evaluation before and at the end of the study. The population under study (n = 24) had a median age of 47.5 (41.5-52.5) years and included mainly women (70.8%). We found that FLI, which is used to predict fatty liver (73 (33-89) vs. 85 (54-95), p < 0.0001) and the FAST score, which is a fibroscan-derived parameter identifying patients at risk of progressive NASH (0.03 (0.02-0.09) vs. 0.05 (0.02-0.15), p = 0.007), were both improved after changes in diet. The BMI (33.3 (28.6-37.3) vs. 35.3 (31.2-39.0), p < 0.0001), WC (106.5 (95.0-112.5) vs. 110.0 (103.0-124.0), p < 0.0001), neck circumference (38.0 (35.0-41.5) vs. 39.5 (38.0-42.5), p < 0.0001), fat mass (32.3 (23.4-40.7) vs. 37.9 (27.7-43.5), p < 0.0001), and extracellular water (17.3 (15.2-20.8) vs. 18.3 (15.9-22.7), p = 0.03) were also all significantly lower after three months of diet. Metabolic parameters linked to NAFLD decreased: HbA1c (36.0 (33.5-39.0) vs. 38.0 (34.0-40.5), p = 0.01), triglycerides (72 (62-90) vs. 90 (64-132), p = 0.03), and the liver markers AST (17 (14-19) vs. 18 (15-27), p = 0.01) and γGT (16 (13-20) vs. 16 (14-27), p = 0.02). In conclusion, replacing only one portion of starchy carbohydrates with one portion of vegetables for a three month period is sufficient to regress, at least in part, both mid and advanced stages of NAFLD. This moderate adjustment of lifestyle habits is easily achievable.

Contribution of macro- and micronutrients intake to gastrointestinal cancer mortality in the ONCONUT cohort: Classical vs. modern approaches.

The aim of this study was to evaluate the contribution of macro- and micronutrients intake to mortality in patients with gastrointestinal cancer, comparing the classical statistical approaches with a new generation algorithm. In 1992, the ONCONUT project was started with the aim of evaluating the relationship between diet and cancer development in a Southern Italian elderly population. Patients who died of specific death causes (ICD-10 from 150.0 to 159.9) were included in the study (n = 3,505) and survival analysis was applied. This cohort was used to test the performance of different techniques, namely Cox proportional-hazards model, random survival forest (RSF), Survival Support Vector Machine (SSVM), and C-index, applied to quantify the performance. Lastly, the new prediction mode, denominated Shapley Additive Explanation (SHAP), was adopted. RSF had the best performance (0.7653711 and 0.7725246, for macro- and micronutrients, respectively), while SSVM had the worst C-index (0.5667753 and 0.545222). SHAP was helpful to understand the role of single patient features on mortality. Using SHAP together with RSF and classical CPH was most helpful, and shows promise for future clinical applications.

90K/Mac-2 BP Is a New Predictive Biomarker of Response to Infliximab Therapy in IBD Patients.

Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and Ulcerative Colitis (UC), are multifactorial disorders characterized by a chronic inflammatory status with the secretion of cytokines and immune mediators. Biologic drugs targeting pro-inflammatory cytokines, such as infliximab, are broadly used in the treatment of IBD patients, but some patients lose responsiveness after an initial success. The research into new biomarkers is crucial for advancing personalized therapies and monitoring the response to biologics. The aim of this single center, observational study is to analyze the relationship between serum levels of 90K/Mac-2 BP and the response to infliximab, in a cohort of 48 IBD patients (30 CD and 18 UC), enrolled from February 2017 to December 2018. In our IBD cohort, high 90K serum levels were found at baseline in patients who then developed anti-infliximab antibodies at the fifth infusion (22 weeks after the first), becoming non-responders (9.76 ± 4.65 µg/mL compared to 6.53 ± 3.29 µg/mL in responder patients, p = 0.005). This difference was significant in the total cohort and in CD, but not significant in UC. We then analyzed the relationship between serum levels of 90K, C-reactive protein (CRP), and Fecal calprotectin. A significant positive correlation was found at baseline between 90K and CRP, the most common serum inflammation marker (R = 0.42, p = 0.0032). We concluded that circulating 90K could be considered a new non-invasive biomarker for monitoring the response to infliximab. Furthermore, 90K serum level determination, before the first infliximab infusion, in association with other inflammatory markers such as CRP, could assist in the choice of biologics for the treatment of IBD patients, thereby obviating the need for a drug switch due to loss of response, and so improving clinical practice and patient care.

Effects of Different Biological Therapies on S1/S2 Antibody Response to SARS-CoV-2 Vaccination in a Cohort of Patients with Inflammatory Bowel Disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the entire planet. The objectives of our study were to compare responses to the vaccine (Pfizer-Biontech COMIRNATY) in a population of patients with intestinal bowel syndrome undergoing different biological therapies or conventional therapy. The study recruited 390 patients who received the first vaccination dose during the dedicated vaccination campaign for inflammatory bowel disease (IBD) patients. The inclusion criteria were a diagnosis of CD or UC and complete vaccination with the Pfizer-BioNTech COVID-19 (Comirnaty) vaccine. The exclusion criteria were other significant diseases or important therapies under way or contraindications to vaccination according to the European drug surveillance recommendations. Linear rank models were run to assess the association between the different therapies and S1/S2 antibodies at three different times. The models showed that in patients with IBD receiving Vedolizumab a significant increase in mean IgG levels was observed, independently of other therapies and confounding factors (ß: 57.45, 95% CI 19.62 to 19.00). This study confirmed the complete antibody response to vaccination against COVID-19 in patients with IBD undergoing biological therapy-particularly Vedolizumab treatment-but also a reduced immune response due to concomitant steroid therapy.

The Effect of Low Glycemic Index Mediterranean Diet and Combined Exercise Program on Metabolic-Associated Fatty Liver Disease: A Joint Modeling Approach.

BACKGROUND: Excessive caloric intake and reduced energy expenditure are associated with the onset of metabolic-associated fatty liver disease (MAFLD). The aim of this study was to probe the benefits of a low glycemic index Mediterranean diet (LGIMD) and a combined exercise program (CEP) on MAFLD by monitoring the clinical process through anthropometric measurement, body mass index (BMI), and specific biomarkers, such as the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). METHODS: The study was conducted at the National Institute of Gastroenterology, 'S. de Bellis', Italy. Subjects were invited to join the study for 12 months. RESULTS: 54 participants were enrolled. Joint modeling of longitudinal and time-to-event data was applied. Overall, a statistically significant direct effect of LGIMD/CEP adherence on ln (BMI), a statistically significant direct effect of LGIMD/CEP adherence on time-to-event and a strong statistically significant direct effect of log (BMI) on time-to-event were observed. In addition, a statistically significant direct effect of LGIMD/CEP adherence on ln(HOMA-IR), a statistically significant direct effect of LGIMD/CEP adherence on time-to-event and a statistically significant direct effect of ln(HOMA-IR) on time-to-event were observed. CONCLUSIONS: LGIMD/CEP significantly improved MAFLD status; in addition, longitudinal BMI and HOMA-IR were good predictors of the disappearance of diagnostic criteria for MAFLD.

A Low Glycemic Index Mediterranean Diet Combined with Aerobic Physical Activity Rearranges the Gut Microbiota Signature in NAFLD Patients.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, and its prevalence worldwide is increasing. Several studies support the pathophysiological role of the gut-liver axis, where specific signal pathways are finely tuned by intestinal microbiota both in the onset and progression of NAFLD. In the present study, we investigate the impact of different lifestyle interventions on the gut microbiota composition in 109 NAFLD patients randomly allocated to six lifestyle intervention groups: Low Glycemic Index Mediterranean Diet (LGIMD), aerobic activity program (ATFIS_1), combined activity program (ATFIS_2), LGIMD plus ATFIS_1 or ATFIS2 and Control Diet based on CREA-AN (INRAN). The relative abundances of microbial taxa at all taxonomic levels were explored in all the intervention groups and used to cluster samples based on a statistical approach, relying both on the discriminant analysis of principal components (DAPCs) and on a linear regression model. Our analyses reveal important differences when physical activity and the Mediterranean diet are merged as treatment and allow us to identify the most statistically significant taxa linked with liver protection. These findings agree with the decreased 'controlled attenuation parameter' (CAP) detected in the LGIMD-ATFIS_1 group, measured using FibroScan®. In conclusion, our study demonstrates the synergistic effect of lifestyle interventions (diet and/or physical activity programs) on the gut microbiota composition in NAFLD patients.

Exosomal FZD-7 Expression Is Modulated by Different Lifestyle Interventions in Patients with NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition characterized from hypertriglyceridemia and hepatic fat accumulation, in the absence of alcohol intake. NAFLD starts as steatosis (NAFL), and the continued injury relative to the toxic fat induces inflammation, steatohepatitis (NASH), and HCC. One of the factors determining liver degeneration during the evolution of NAFLD is a modification of Wnt/Frizzled (FZD) signaling. In particular, an inhibition of Wnt signaling and an overexpression of a specific FZD receptor protein, namely, the FZD7, have been observed in NAFLD. Actually, the prognosis and the follow-up of NAFLD is not easy, and the liver biopsy is the gold standard for an accurate detection of liver fibrosis. In this study, the modulation of the FZD7 expression levels in plasma-derived exosomes of NAFLD-affected patients, before and after specific lifestyle interventions, were experimentally evaluated by Western blotting analysis. The experimental data were analyzed by an accurate statistical study that indicated, in the exosomes derived from plasma of NAFLD patients with moderate or severe steatosis, an average expression level of FZD7 that was significantly higher than healthy subjects at baseline; conversely, the values were normalized after 90 days of specific lifestyle interventions. The overall results suggested that the FZD7 delivered by exosomes represents a good candidate as a new and effective biomarker for diagnosis and prognosis of NAFLD.

Nutritional Regimes Enriched with Antioxidants as an Efficient Adjuvant for IBD Patients under Infliximab Administration, a Pilot Study.

Antioxidants are privileged candidates for the development of adjuvants able to improve the efficiency of pharmacological therapies, particularly for chronic inflammatory syndromes. During the last 20 years, anti-TNFα (tumor necrosis factor alpha) monoclonal antibodies infusion has been the biological therapy most frequently administered but there is still large space for improvement in disease remission rates and maintenance. In this context, nutritional bioactive compounds contained in dietary patterns or included as supplements, may act as adjuvants for the induction and maintenance of IBD (inflammatory bowel diseases) remission. To verify this possibility, a single-center preliminary study (SI-CURA, Soluzioni Innovative per la gestione del paziente e il follow up terapeutico della Colite UlceRosA) was designed and carried out to evaluate whether a daily administration of purple corn supplement could improve the response to Infliximab (IFX) infusion of IBD patients with both Crohn's disease (CD) and ulcerative colitis (UC). A cohort of 47 patients was enrolled in the study. Biological samples were collected before the first and the third IFX infusion. All patients received nutritional guidelines, 27 of them received commercial red fruit tea with low anthocyanins content, while 20 received a purple corn supplement with a high anthocyanin content. Results show that the administration of an antioxidant-enriched purple corn supplement could improve IFX-mediated disease remission in terms of circulating inflammatory markers. Comparison between CD and UC patients revealed that, at this anthocyanin dosage, the purple corn extract administration improved the IFX response in CD but not in UC patients. Our results may pave the way for a new metacentric study of CD patients, recruiting a wider cohort and followed-up over a longer observational time.

Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer.

Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.