The implementation of a non-pharmacological multimodal intervention program-including physical exercise, nutritional counseling, and psychological support-is expected to improve fatigue in patients with primary biliary cholangitis. Consequently, this improvement is anticipated to enhance quality of life and cognitive symptoms, while also positively impacting emotional, social, and occupational aspects.

From a pathophysiological perspective, it is hypothesized that chronic cholestasis and/or immune system activation, with the release of pro-inflammatory cytokines, leads to both central and peripheral alterations causing fatigue.

At the central level, systemic inflammation may induce neuronal senescence in the basal ganglia, resulting in altered functional connectivity networks dependent on these regions and/or structural and connectivity changes in areas involved in interoception, such as the insula and anterior cingulate cortex.

At the peripheral level, the hypothesis is that chronic inflammation mediated by anti-mitochondrial antibodies causes mitochondrial metabolic dysfunction in muscle cells, which would be reflected in changes observed in the gene expression analysis of these cells.

Improvement in fatigue following the multimodal intervention program is expected to be associated with normalization of the immunological profile, enhanced functional brain connectivity, and improved mitochondrial metabolism in muscle.

Primary biliary cholangitis (PBC) is a rare autoimmune disease that damages the small bile ducts and primarily affects women. Although it is a liver disease, its most common symptom is fatigue, affecting up to 60% of patients. Fatigue is a debilitating symptom, described by patients as "a brain fog" that causes concentration problems and memory loss, along with "a lack of energy" that leads to poor exercise tolerance and early exhaustion. This significantly impacts quality of life, negatively affecting family, social, and work-related activities. To the frustration of both patients and healthcare providers, fatigue is not correlated with the severity of liver disease, and there is currently no effective treatment.

Ursodeoxycholic acid (UDCA), the first-line treatment for PBC, has been shown to improve disease survival, but it does not appear to have an effect on fatigue, as demonstrated by a meta-analysis. Other treatments, such as bezafibrate, have also failed to show improvement in fatigue. Several clinical trials have tested treatments targeting different pathophysiological mechanisms, including selective serotonin reuptake inhibitors (SSRIs), stimulants like modafinil, and immunomodulatory therapies such as rituximab, all with negative results.

Currently, new drugs have been approved as second-line treatments for PBC, such as elafibranor and seladelpar. The latter may have some impact on fatigue; however, this was not the primary objective of the study, and the mechanisms associated with this improvement remain unclear.

One of the main reasons why no treatment exists is the lack of understanding of the underlying mechanisms. Fatigue is a complex and likely multifactorial symptom. It has been hypothesized that chronic immune system activation, leading to excessive production of inflammatory substances, could be a trigger. Additionally, it remains unknown whether alterations in bile acid composition, which are molecules with potent biological effects on multiple organs, could worsen fatigue. Furthermore, this chronic inflammation may induce changes in both the brain and muscles, contributing to the development of fatigue.

It has been demonstrated that physical exercise reduces systemic inflammation by lowering inflammatory substances and can also improve abnormalities in muscle energy production. Studies conducted in patients with other diseases associated with fatigue, such as multiple sclerosis, have shown that exercise programs can be beneficial for fatigue management.

At present, experience with physical training programs for PBC patients with fatigue is very limited. The results of a study conducted in the United Kingdom and another in Canada suggest that a home-based exercise program may improve fatigue. However, both studies have certain limitations, as the follow-up was remote, there was no supervision to ensure proper execution of the exercises or that they were performed at the prescribed intensity. Additionally, the effective exercise duration was only about 15 minutes, which, along with its moderate intensity, is unlikely to induce specific adaptations in mitochondrial biogenesis and efficiency. On the other hand, while patients with liver diseases generally express positive attitudes toward the benefits of supervised exercise, they also acknowledge a lack of confidence in initiating it independently.

Based on this evidence, an integrated exercise program is proposed, consisting of two phases: an initial supervised phase lasting eight weeks and a subsequent remote phase, combined with nutritional counseling and psychological support. It is hypothesized that this program will improve fatigue and consequently enhance quality of life, as well as alleviate associated cognitive symptoms (such as depression and sleep disturbances).

To better understand the changes occurring in the organs involved in fatigue, the investigators aim to analyze immune responses and bile acids to determine their potential association with fatigue, as has been observed in other autoimmune diseases. Additionally, potential alterations at both the brain and muscle levels will be explored.

At the neurological level, functional connectivity alterations in brain regions involved in fatigue will be studied using functional magnetic resonance imaging (fMRI). At the muscular level, changes in muscle metabolism will be analyzed by studying gene expression in muscle fibers. Muscle samples will be obtained using a minimally invasive technique called muscle microbiopsy, which involves a fine-needle puncture of a muscle and is not associated with complications. These studies will be conducted before and after the exercise program, aiming to observe the positive changes expected at all levels.

These studies will be conducted before and after the training program.

Inclusion Criteria:

• Age ≥18 years
• PBC diagnosis according to EASL guidelines
• Moderate - severe fatigue defined by ≥ 29 points in PBC-40 questionnaire

Exclusion Criteria:

• Age > 80 years
• Severe pruritus
• Decompensated cirrhosis
• Other causes of liver disease than PBC
• Liver transplant (LT) o placement on a waiting-list for LT
• Uncontrolled thyroid disesase
• Anemia with haemoglobin <11g/dl
• Uncontrolled cardiovascular risk factors
• BMI > 35,
• Acute myocardial infarct or unstable angina the past 6 months
• Muscle disease or systemic disease with potential muscle involvement
• Dysautonomy
• Untreated osteoporosis
• Untreated celiac disease
• Alcohol consumption > 14 standard drinks (SD) in women and >21 (SD) in men per week
• Chronic kidney disease ≥ 4 KDIGO stage
• Malignancy in the past two years (except for non melanoma skin cancer and in situ cervical carcinoma)
• Not capable of performing or following the prehabilitation program
• Involvement in a clinical trial the previous 2 months
• Refusal of informed consent

For the study of the pathophysiology of fatigue, additional exclusion criteria will be established: Severe depression or neuropsychiatric disease, 2) Treatment with centrally acting drugs, 3) Muscular or systemic disease with potential muscle involvement, 4) Immunosuppressive treatment, 5) Sleep disorder, 6) Obesity (BMI >30).