Probiotics with Standard Medical Treatment versus Standard Medical Treatment alone in patients with Frailty in Decompensated Cirrhosis: An Open Label Randomised Trial

Cirrhosis of the liver represents an advanced stage of liver disease characterized by progressive necro-inflammation within the liver, leading to liver fibrosis and vascular remodelling. Histologically, cirrhosis is defined by nodule formation surrounded by dense fibrotic septa, resulting in the distortion of liver architecture (1-2). Cirrhosis carries a high mortality risk due to complications such as jaundice, ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and gastrointestinal bleeding. It is increasingly recognized as a leading cause of morbidity and mortality related to liver diseases (1). Frailty is clinically defined as a state of reduced physiological reserve and increased vulnerability to health stressors (3). It is characterized by impaired muscle contractile function and is influenced by mechanisms such as oxidative stress, dysregulation of inflammatory cytokines, malnutrition, physical inactivity, and muscle apoptosis. Sarcopenia, a progressive skeletal muscle disorder, is closely associated with frailty and increases the risk of adverse outcomes such as falls, fractures, disability, and mortality (4). The prevalence of sarcopenia in cirrhosis ranges from 40% to 70%, while frailty ranges from 18% to 43% (5-6). Physical frailty encompasses multiple dimensions of muscle health, including sarcopenia, disability, reduced energy expenditure, and malnutrition. Recent discussions in the American Society of Transplantation consensus statement highlight that frailty includes broader aspects such as muscle function and the subjective experience of frailty by patients (7). Numerous studies underscore physical frailty as a robust independent predictor of transplant waitlist and post-transplant mortality, mortality after hospitalization, hospital length of stay, and discharge location (6-12).Frailty in cirrhosis has emerged as an independent predictor of outcomes such as transplant waitlist mortality, post-transplant mortality, mortality following hospitalization, length of hospital stay, and discharge destination (6-12). One of the primary risk factors contributing to frailty in cirrhosis is compromised liver function itself. The liver plays essential roles in metabolism, detoxification, and protein synthesis. As liver function declines in cirrhosis, these critical processes are disrupted, leading to malnutrition, muscle wasting, and metabolic disturbances. These physiological changes reduce overall physical reserve and functional capacity, predisposing patients to frailty. Malnutrition is another significant contributor to frailty in cirrhotic patients. The liver’s impaired ability to metabolize and store nutrients results in deficiencies of essential vitamins, minerals, and proteins. This nutritional imbalance exacerbates muscle wasting, compromises immune function, and delays wound healing—key features of frailty. Poor dietary intake, often compounded by appetite loss and dietary restrictions, further increases the risk of malnutrition in these patients.(13) The presence of comorbidities commonly seen in cirrhosis, such as diabetes mellitus,cardiovascular disease, and chronic kidney disease, also contributes to frailty. These conditions not only complicate the management of cirrhosis but also independently increasethe risk of functional decline and disability.(14) Emerging evidence suggests that alterations in gut microbiota composition and function can contribute to the development and progression of liver frailty through several mechanisms: 1. Intestinal Barrier Dysfunction: The gut microbiota helps maintain the integrity of the intestinal barrier. Dysbiosis can lead to increased gut permeability (leaky gut), allowing microbial products such as lipopolysaccharides (LPS) to translocate from thegut lumen into systemic circulation. Elevated LPS levels trigger immune responses and inflammation, which can promote liver injury and fibrosis.(15) 2. Microbial Metabolites: Gut microbes metabolize dietary components into bioactive metabolites, such as short-chain fatty acids (SCFAs), bile acids, and trimethylamine- N-oxide (TMAO). These metabolites can influence liver function directly or indirectly. For example, SCFAs possess anti-inflammatory properties and may help protect against liver damage, while TMAO has been associated with cardiovascular and liver diseases.(16) 3. Immune Modulation: The gut microbiota plays a crucial role in shaping the development and function of the immune system. Dysbiosis can disrupt immune homeostasis, leading to chronic inflammation and immune activation, which contribute to liver inflammation, fibrosis, and cirrhosis.(17)  4. Metabolic Syndrome and NAFLD: Dysbiosis is linked to metabolic syndrome,characterized by obesity, insulin resistance, dyslipidaemia, and hypertension. These metabolic abnormalities are risk factors for non-alcoholic fatty liver disease(NAFLD), a prevalent cause of liver disease globally. Gut dysbiosis may promote hepatic lipid accumulation and inflammation, exacerbating NAFLD progression.(18) 5. Hepatic Encephalopathy: In patients with liver cirrhosis, gut-derived toxins like ammonia and mercaptans bypass liver detoxification and accumulate in the brain, causing hepatic encephalopathy. Alterations in gut microbiota composition and function contribute to increased ammonia production and impaired gut barrier function, worsening neurological symptoms(19). Probiotics, as defined by the World Health Organization (WHO), are living organisms that, when administered in adequate amounts, confer health benefits to the host (20). Studies have demonstrated that probiotics act on the gut-liver axis, resulting in reduced ammonia production and improved intestinal permeability. This mechanism ultimately leads to decreased hyperammonaemia and improvement in hepatic encephalopathy. (21).

Probiotics have also been shown to reduce the levels of inflammatory cytokines (IL-6, IL-1) in skeletal muscle (18). Experimental and clinical evidence suggests that probiotics could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis. This modulation can interfere with major pathophysiological events underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections (22). Long-term treatment with probiotics appears to consistently reduce the rate of hepatic encephalopathy-related and all-cause hospitalizations, without increasing the risk of adverse events. Probiotics also show a low propensity for selecting resistant bacterial mutants, indicating no increased risk of infection with prolonged exposure (23). However, the effects of probiotics alone on frailty progression in patients with cirrhosis remain unclear. Hence, this study is planned to investigate the effect of probiotics on frailty in decompensated cirrhosis.