ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2019 and some content may be unavailable. To unlock all content for 2019, please visit the archives.

Abstract: TH-PO613

Uremic Dysbiosis Causes Sarcopenic Phenotype Through Reduction in Muscle Mitochondria and Attenuation of Insulin-Stimulated Muscle Protein Synthesis

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1300 Health Maintenance, Nutrition, and Metabolism

Authors

  • Uchiyama, Kiyotaka, Keio University, School of Medicine, Tokyo, Japan
  • Wakino, Shu, Keio University, School of Medicine, Tokyo, Japan
  • Tajima, Takaya, Keio University, School of Medicine, Tokyo, Japan
  • Itoh, Tomoaki, Keio University, School of Medicine, Tokyo, Japan
  • Oshima, Yoichi, Keio University, School of Medicine, Tokyo, Japan
  • Irie, Junichiro, Keio University, School of Medicine, Tokyo, Japan
  • Itoh, Hiroshi, Keio University, School of Medicine, Tokyo, Japan
Background

Chronic kidney disease (CKD) leads to clinically relevant sarcopenia, defined as reduced exercise endurance and muscle atrophy, which are novel risk factors associated with morbidity and mortality in CKD patients. However, the pathophysiology of uremic sarcopenia remains incompletely defined. Recent reports have shown alterations in the gut microbiota to be associated with the etiology of CKD. Using germ-free (GF) mice, we aimed to determine whether and how uremic dysbiosis causes uremic sarcopenia.

Methods

CKD was induced in specific-pathogen-free mice via an adenine-containing diet; control mice were fed a normal diet. Fecal microbiota transplantation (FMT) into GF mice was performed by oral gavage using cecal samples obtained from either control mice (control-FMT mice) or CKD mice (CKD-FMT mice). Vehicle mice were gavaged with sterile phosphate-buffered saline. Sarcopenic phenotype was evaluated after 2 weeks.

Results

Compared with control mice, CKD mice had sarcopenic phenotypes, including significant decrease in running distance, handgrip strength, and skeletal muscle mass. Sarcopenic phenotypes were reproduced in CKD-FMT mice as compared with control-FMT mice and were associated with reduced muscle mitochondria and attenuation in insulin-stimulated phosphorylation of S6 kinase beta-1, indicating reduced muscle protein synthesis. In addition, serum concentrations of indoxyl sulfate, phenyl sulfate, and hippuric acid among uremic solutes as well as fecal concentrations of indole and phenol among bacterial fermentation products were increased in CKD-FMT mice as compared with the concentrations in control-FMT mice. Gut microbiome analysis using 16S rRNA genes sequences revealed decrease in Lactobacillus and Lactonifactor and increase in Allobaculum, Clostridium cluster IV, and Alistipes in CKD mice as compared with those in control mice. All of these alterations in gut microbiome remained in CKD-FMT mice as compared with those in control-FMT mice.

Conclusion

Uremic dysbiosis can directly contribute to sarcopenic phenotypes even in the absence of the host CKD condition. Increased concentrations of microbiota-derived fecal putrefaction products, serum uremic solutes, and resultant insulin resistance can mediate the effects of uremic dysbiosis.