RE and Probiotics in MAFLD/NAFLD

This project aims to evaluate the roles of the autonomic nervous system (ANS) and gut microbiota as correlates of clinical improvement in metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic fatty liver disease (NAFLD) in response to a therapeutic regimen comprising resistance exercise and probiotic supplementation. The primary objective is to investigate the effects of these non-pharmacological interventions on MAFLD/NAFLD and to identify patient phenotypes based on baseline ANS profiles and gut microbiota composition that predict clinical responses.

The human microbiome, understood here as the collective community of microorganisms, their genetic material, and metabolic products that colonize the body from birth, is particularly concentrated in the gut. The gut microbiome, dominated primarily by anaerobic bacteria, encompasses thousands of species and millions of genes distributed among the major phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Recent research has increasingly focused on the gut microbiome due to its dysbiosis being linked to numerous diseases that may be modifiable through diet, supplementation, or physical activity. Dysbiosis of the gut microbiome has also been implicated in MAFLD and NAFLD, which are the most prevalent liver diseases globally, affecting approximately 35% of the adult population, with this prevalence expected to rise. The gut-liver axis has been extensively studied in relation to MAFLD/NAFLD due to the bidirectional interactions between the gut microbiota and hepatic function. The portal vein, which supplies approximately 70% of the liver's blood flow, facilitates this interaction by connecting the intestines to the liver. Patients with NAFLD/MAFLD typically exhibit increased intestinal permeability compared to healthy individuals, thereby increasing the liver's exposure to gut-derived bacteria, endotoxins, bacterial products, and inflammatory mediators.

Probiotics, defined as live microorganisms that confer health benefits to the host, have been shown in previous studies to enhance the integrity of the intestinal barrier, regulate the gut microbiota, reduce intestinal permeability, and mitigate immune and metabolic disturbances. These effects are particularly relevant in patients with NAFLD/MAFLD, where probiotics have been observed to reduce hepatic steatosis and inflammation-related damage.

Physical exercise, particularly structured programs, has been demonstrated to significantly improve liver function in patients with NAFLD/MAFLD and positively modulate the gut microbiota. Exercise may attenuate the production of reactive oxygen species (ROS) and other oxidative agents in NAFLD by regulating antioxidant enzymes and anti-inflammatory mediators. Additionally, exercise interventions in these patients have been shown to improve blood lipid profiles, including triglycerides, cholesterol, AST, and ALT levels, offering substantial clinical benefits. Although the existing literature predominantly emphasizes aerobic training, this study seeks to compare the effects of resistance training and probiotic supplementation in patients with NAFLD/MAFLD and to assess potential changes in clinical outcomes. Furthermore, the study will explore the influence of baseline ANS and gut microbiota profiles on the patients' responses to these non-pharmacological therapies.

Eligibility Criteria:
Inclusion Criteria:

• NAFLD/MAFLD or NASH diagnosis

Exclusion Criteria:

* significant (structural) limitation of movement of the upper and/or lower limbs
* Not fluent in English or Polish
* Have participated in any trial or research project within 3 months
* history of following alternative diets within 3 months before the study or alternating diet during the trial,
* nervous system disorders
* cognitive function impairment and dementia
* pregnancy or nurturing
* significant (structural) limitation of movement of the upper and/or lower limbs
* osteoporosis/osteopenia
* unable to understand instructions
* receiving insulin
* unregulated diabetes
* stage 3 hypertension
* orthostatic intolerance
* chronic diseases of the cardiovascular system
* shift work
* those who will be found to have any concomitant liver disease
* Participants with liver steatosis and regular alcohol consumption of \> 30 g/day
* anticoagulants/antiplatelet therapy, immunosuppressants, antibiotics, corticosteroids, valproic acid, amiodarone, tamoxifen.Medication use of steroids, methotrexate, metformin. Use of agents such as vitamin E, omega-3 fatty acids, or medications with evidence for effects on NAFLD (pioglitazone, GLP-1 analogs, dipeptidyl peptidase IV inhibitors, ursodeoxycholic acid)
* prolonged compromised immunity (e.g. recent cytotoxic chemotherapy, HIV infection with a CD4 count \< 240)
* active or prior history of invasive malignancy (except for curatively treated in situ carcinomas \[e.g., cervix\] or non-melanoma skin cancer) unless a complete remission was achieved
* previous surgery (bariatric, gastric, intestinal resection)
* parenteral nutrition (TPN) for the last 6 months
* active thyroid disorder
* Cushing's syndrome
* anticoagulant therapy
* antibiotics in the 3 months before inclusion
* regular use of a probiotic or prebiotic supplement within 3 months before enrollment;
* inclusion in a drug interventional trial in the previous 3 months
* Known allergy to probiotics
* Any implanted battery operated device (i.e. AICD, pacemaker, loop recorder, cochlear implant)