Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Department of Food Science, Nutrition and Technology, University of Nairobi, Nairobi, Kenya.
J Cachexia Sarcopenia Muscle. 2023 Dec;14(6):2676-2691. doi: 10.1002/jcsm.13342. Epub 2023 Sep 28.
Sarcopenia in liver cirrhosis is associated with low quality of life and high mortality risk. The pathogenesis has yet to be fully understood. We hypothesized that gut microbiome, bile acid (BA) composition and metabolites differ between cirrhotic patients with and without sarcopenia and contribute to pathogenesis.
Cirrhotic patients with (n = 78) and without (n = 38) sarcopenia and non-cirrhotic controls with (n = 39) and without (n = 20) sarcopenia were included in this study. Faecal microbiome composition was studied by 16S rDNA sequencing, serum and faecal BA composition by ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolite composition in serum, faeces and urine by nuclear magnetic resonance.
Bacteroides fragilis, Blautia marseille, Sutterella spp. and Veillonella parvula were associated with cirrhotic patients with sarcopenia, whereas Bacteroides ovatus was more abundant in cirrhotic patients without sarcopenia. We observed significantly elevated secondary BAs, deoxycholic acid (DCA; P = 0.01) and lithocholic acid (LCA; P = 0.02), and the ratios of deoxycholic acid to cholic acid (DCA:CA; P = 0.04), lithocholic acid to chenodeoxycholic acid (LCA:CDCA; P = 0.03) and 12 alpha-hydroxylated to non-12 alpha-hydroxylated BAs (12-α-OH:non-12-α-OH BAs; P = 0.04) in serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia, indicating an enhanced transformation of primary to secondary BAs by the gut microbiome. CA (P = 0.02) and the ratios of CA:CDCA (P = 0.03) and total ursodeoxycholic acid to total secondary BAs (T-UDCA:total-sec-BAs, P = 0.03) were significantly reduced in the stool of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia. Also, valine and acetate were significantly reduced in the serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia (P = 0.01 and P = 0.03, respectively). Multivariate logistic regression further confirmed the association of B. ovatus (P = 0.01, odds ratio [OR]: 12.8, 95% confidence interval [CI]: 168.1; 2.2), the ratios of 12-α-OH:non-12-α-OH BAs (P = 0.03, OR: 2.54, 95% CI: 0.99; 6.55) and T-UDCA:total-sec-BAs (P = 0.04, OR: 0.25, 95% CI: 0.06; 0.98) in serum and stool CA:CDCA (P = 0.04, OR: 0.79, 95% CI: 0.62; 0.99), and serum valine (P = 0.04, OR: 1.00, 95% CI: 1.02; 1.00) with sarcopenia in cirrhosis after correcting for the severity of liver disease and sex.
Our study suggests a potential functional gut microbiome-host interaction linking sarcopenia with the altered gut microbiomes, BA profiles and amino acids pointing towards a potential mechanistic interplay in understanding sarcopenia pathogenesis.
肝硬化伴发的肌肉减少症与生活质量降低和死亡风险增加有关。其发病机制尚未完全明确。我们推测，肝硬化伴发和不伴发肌肉减少症患者的肠道微生物组、胆汁酸（BA）组成和代谢物存在差异，并可能导致发病机制发生变化。
本研究纳入了 78 例肝硬化伴发肌肉减少症患者、38 例肝硬化不伴发肌肉减少症患者、39 例非肝硬化伴发肌肉减少症患者和 20 例非肝硬化不伴发肌肉减少症患者。采用 16S rDNA 测序研究粪便微生物组组成，采用超高效液相色谱-串联质谱法研究血清和粪便 BA 组成，采用核磁共振研究血清、粪便和尿液中的代谢物组成。
脆弱拟杆菌、马赛双歧杆菌、Sutterella 属和小韦荣球菌与肝硬化伴发肌肉减少症患者相关，而卵形拟杆菌在肝硬化不伴发肌肉减少症患者中更为丰富。我们观察到血清中次级 BA（脱氧胆酸（DCA）；P=0.01）和石胆酸（LCA）；P=0.02）以及 DCA:CA（P=0.04）、LCA:CDCA（P=0.03）和 12α-羟基化与非 12α-羟基化 BA（12α-OH:non-12α-OH BAs；P=0.04）的比值显著升高，提示肠道微生物组增强了初级 BA 向次级 BA 的转化。肝硬化伴发肌肉减少症患者粪便中 CA（P=0.02）和 CA:CDCA（P=0.03）以及总熊去氧胆酸与总次级 BA（T-UDCA:total-sec-BAs；P=0.03）的比值显著降低。肝硬化伴发肌肉减少症患者血清中缬氨酸和乙酸也显著减少（P=0.01 和 P=0.03）。多变量逻辑回归进一步证实了卵形拟杆菌（P=0.01，优势比[OR]：12.8，95%置信区间[CI]：168.1；2.2）、12α-OH:non-12α-OH BAs 的比值（P=0.03，OR：2.54，95%CI：0.99；6.55）和 T-UDCA:total-sec-BAs（P=0.04，OR：0.25，95%CI：0.06；0.98）与血清和粪便 CA:CDCA（P=0.04，OR：0.79，95%CI：0.62；0.99）以及血清缬氨酸（P=0.04，OR：1.00，95%CI：1.02；1.00）与肝硬化伴发肌肉减少症的相关性，校正了肝脏疾病严重程度和性别后。
我们的研究表明，肠道微生物组-宿主的潜在功能相互作用可能与肌肉减少症与改变的肠道微生物组、BA 谱和氨基酸有关，这可能为理解肌肉减少症发病机制提供潜在的机制联系。
