Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease, Investigation of the Interactions with Uremic Toxins, Inflammation and Oxidative Stress.

Elisabetta Margiotta,Francesco Miragoli,Silvia Armelloni,Lara Caldiroli,Simone Vettoretti,Vittoria Rizzo,Francesca Zanoni,Maria Luisa Callegari,Piergiorgio Messa

doi:10.3390/toxins13070472

Abstract

Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m2, not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.

Highlights

Sarcopenia is defined as a loss of skeletal muscle mass and function
Two uremic toxins, indoxyl sulphate (IS) and p-cresyl sulphate (PCs), are produced by proteolytic bacterial fermentation in the gut [4,5] and retained in the serum of Chronic Kidney Disease (CKD) patients owing to both increased intestinal production and reduced glomerular filtration and proximal tubular secretion [6,7,8]
Clinical parameters did not differ between sarcopenic and not-sarcopenic patients, except for BMI, which was higher in the not-sarcopenic ones. (Table 1)

Summary

Introduction

In Chronic Kidney Disease (CKD) patients, sarcopenia is highly prevalent and it is associated with physical disability, low quality of life and increased mortality [1] In these patients, sarcopenia is determined by a series of complex mechanisms, such as malnutrition, systemic inflammation, uremic toxins retention, metabolic acidosis, vitamin D deficiency, insulin resistance and some other hormonal factors often present in CKD patients [2]. IS has been shown to be associated with aortic calcification and vascular smooth muscle cell proliferation in rats and humans [6,9,10]; elevated PCs has been associated with insulin resistance [7] and vascular disease [8] Both toxins play an important role in inducing muscular atrophy through various mechanisms (e.g., pro-inflammatory cytokines release or activation of some pathways, such as aryl hydrocarbon receptor (AhR), NFκB and SRAA) [11]. In patients with end stage renal disease in dialysis, there is a significant inverse association between plasma IS and skeletal muscle mass [11], but this association was not observed in older patients with advanced CKD not yet in dialysis [13]

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Conclusion