Characterization of the Gut-Liver-Muscle Axis in Cirrhotic Patients With Sarcopenia

Francesca Romana Ponziani; Anna Picca; Emanuele Marzetti; Riccardo Calvani; Giorgia Conta; Federica Del Chierico; Giorgio Capuani; Mariella Faccia; Francesca Fianchi; Barbara Funaro; Helio Josè Coelho-Junior; Valentina Petito; Emanuele Rinninella; Francesco Paroni Sterbini; Sofia Reddel; Pamela Vernocchi; Maria Cristina Mele; Alfredo Miccheli; Lorenza Putignani; Maurizio Sanguinetti; Maurizio Pompili; Antonio Gasbarrini

Disclosures

Liver International. 2021;41(6):1320-1334. 

In This Article

Abstract and Introduction

Abstract

Background & Aim: Sarcopenia is frequent in cirrhosis and is associated with unfavourable outcomes. The role of the gut-liver-muscle axis in this setting has been poorly investigated. The aim of this study was to identify gut microbiota, metabolic and inflammatory signatures associated with sarcopenia in cirrhotic patients.

Methods: Fifty cirrhotic patients assessed for the presence of sarcopenia by the quantification of muscle mass and strength were compared with age- and sex-matched controls. A multiomic analysis, including gut microbiota composition and metabolomics, serum myokines and systemic and intestinal inflammatory mediators, was performed.

Results: The gut microbiota of sarcopenic cirrhotic patients was poor in bacteria associated with physical function (Methanobrevibacter, Prevotella and Akkermansia), and was enriched in Eggerthella, a gut microbial marker of frailty. The abundance of potentially pathogenic bacteria, such as Klebsiella, was also increased, to the detriment of autochthonous ones. Sarcopenia was associated with elevated serum levels of pro-inflammatory mediators and of fibroblast growth factor 21 (FGF21) in cirrhotic patients. Gut microbiota metabolic pathways involved in amino acid, protein and branched-chain amino acid metabolism were up-regulated, in addition to ethanol, trimethylamine and dimethylamine production. Correlation networks and clusters of variables associated with sarcopenia were identified, including one centred on Klebsiella/ethanol/FGF21/Eggerthella/Prevotella.

Conclusions: Alterations in the gut-liver-muscle axis are associated with sarcopenia in patients with cirrhosis. Detrimental but also compensatory functions are involved in this complex network.

Introduction

Muscle wasting and physical function impairment affect 30%–70% of patients with cirrhosis.[1] Several factors are invoked in the pathogenesis of muscle atrophy in this patient population. Reduced use of carbohydrates as a source of energy at the expense of proteins, hormonal changes, malnutrition, gastrointestinal dysfunction, increased resting energy expenditure and low physical activity are responsible of the loss of muscle mass in cirrhotic patients.[2]

Sarcopenia has been associated with poor quality of life and has been shown to independently predict negative outcomes, including reduced survival, in patients with cirrhosis.[3] Interestingly, while liver transplantation can cure cirrhosis, its effects on sarcopenia are variable with either improvement, stability or worsening being reported in literature.[3,4] Therefore, a better understanding of the pathophysiology of sarcopenia in this setting is needed to plan targeted therapeutic interventions.[5]

In older adults, sarcopenia has been associated with a state of chronic, low-grade inflammation, termed inflamm-ageing. This condition shares the same pathophysiological traits of meta-inflammation, which is typical of metabolic disorders and is associated with changes in the gut microbiota.[6] Cirrhosis is a paradigm of chronic inflammation driven by gut dysbiosis and increased intestinal permeability. However, whether alterations in gut microbiota are associated with sarcopenia in cirrhotic patients has yet to be established.

To fill this gap in knowledge, the present study aimed at characterizing the gut-liver-muscle axis and identifying gut microbial, metabolic and inflammatory signatures of sarcopenia in patients with cirrhosis.

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