The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD.

Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability and constipation are typical features accompanying CKD progression and triggering chronic inflammation. In order to verify the efficacy of the innovative synbiotic formulation NATUREN G^® in modulating the levels of circulating UTs, intestinal permeability and gastrointestinal symptoms, we set up a randomized, single-blind, placebo-controlled, pilot trial in stage IIIb-IV CKD patients and in healthy controls. Two-month administration of the synbiotic resulted in a decrease of free IS, as compared with the placebo-treated arm, only in the CKD group. The other UTs did not significantly change, although different trends in time (increase in the placebo arm and decrease in the synbiotic arm) were observed. Moreover, after supplementation, reduction of small intestinal permeability and amelioration of abdominal pain and constipation syndromes were observed only in the CKD group. The obtained results suggest the specificity of action of NATUREN G^® in CKD and justify further validation in a wider study population.

Intestinal permeability (IP) is essential in maintaining gut-metabolic functions in health. An unequivocal evaluation of IP, as marker of intestinal barrier integrity, however, is missing in health and in several diseases. We aimed to assess IP in the whole gastrointestinal tract according to body mass index (BMI) and liver steatosis. In 120 patients (61F:59M; mean age 45 ± SEM 1.2 years, range: 18–75), IP was distinctively studied by urine recovery of orally administered sucrose (SO, stomach), lactulose/mannitol ratio (LA/MA, small intestine), and sucralose (SA, colon). By triple quadrupole mass-spectrometry and high-performance liquid chromatography, we measured urinary recovery of saccharide probes. Subjects were stratified according to BMI as normal weight, overweight, and obesity, and answered questionnaires regarding dietary habits and adherence to the Mediterranean Diet. Liver steatosis was assessed by ultrasonography. IP at every gastrointestinal tract was similar in both sexes and decreased with age. Stomach and small intestinal permeability did not differ according to BMI. Colonic permeability increased with BMI, waist, neck, and hip circumferences and was significantly higher in obese than in lean subjects. As determined by logistic regression, the odds ratio (OR) of BMI increment was significantly higher in subjects in the highest tertile of sucralose excretion, also after adjusting for age and consumption of junk food. The presence of liver steatosis was associated with increased colonic permeability. Patients with lower score of adherence to Mediterranean diet had a higher score of ‘junk food’. Intestinal permeability tended to increase in subjects with a lower adherence to Mediterranean diet. In conclusion, colonic (but not stomach and small intestinal) permeability seems to be linked to obesity and liver steatosis independently from dietary habits, age, and physical activity. The exact role of these last factors, however, requires specific studies focusing on intestinal permeability. Results should pave the way to both primary prevention measures and new therapeutic strategies in metabolic and liver diseases.

Physical activity encompasses a series of overall benefits on cardiovascular health and metabolic disorders. Research has recently focused on the hepatobiliary tract, as an additional target of the health-related outcomes of different types of physical exercise. Here, we focus on the global features of physical activity with respect to exercise modality and intensity, and on studies linking physical activity to lipid metabolism, gallbladder diseases (gallstones, symptoms, complications and health-related quality of life), gallbladder motor-function, enterohepatic circulation of bile acids, and systemic metabolic inflammation. Additional studies need to unravel the pathophysiological mechanisms involved in both beneficial and harmful effects of physical activity in populations with different metabolic conditions.

Background/Objectives: Yeast-based probiotic candidates are increasingly investigated as potential modulators of gut ecology, although evidence in healthy individuals remains limited. This randomized, single-blind, crossover study primarily evaluated the tolerability of ATECREM Serius containing Saccharomyces uvarum SERIUS strain (>10¹⁰ CFU/g) and explored its effect on human gut microbiota. Methods: Forty-four volunteers completed the crossover intervention consisting of 2 months of ATECREM Serius (TRT1) and 2 months of placebo (PLT1), separated by 2 weeks of wash-out. Fecal microbiota was profiled by 16S rRNA gene sequencing, while fecal and urinary volatile organic compounds (VOCs) were profiled by GC–MS. Fecal free amino acids (FAAs) were also measured. Results: ATECREM Serius was well tolerated, with no treatment-related adverse events. Differences were observed for three out of five α-diversity indices, while β-diversity differed between TRT1 and PLT1. The relative abundance and prevalence of Bifidobacteriaceae and Bacteroides were increased in TRT1, whereas Enterobacteriaceae and clostridia sensu stricto were limited compared to placebo. Fecal metabolomics indicated an enrichment of organic acids, particularly SCFAs, in TRT1, whereas propanoic acid was reduced in PLT1. Fecal tryptophan and histidine decreased in TRT1, and urinary metabolomics showed a clearer clustering between TRT0 and TRT1, including a significant decrease of 2,5-dimethylfuran. Conclusions: In adults, ATECREM Serius was well tolerated within the investigated population and intervention period. Secondary exploratory analyses identified treatment-associated differences in selected gut microbial taxa and metabolomic features, including the increase in Bifidobacterium abundance compared to placebo. These findings are hypothesis-generating and require confirmation in larger, adequately powered studies.