Antibiotic exposure exacerbates acute-on-chronic liver failure via gut microbiota imbalance and secondary liver lesion

<b>Introduction.</b> The correlation between antibiotic exposure and adverse outcomes in patients with acute-on-chronic liver failure (ACLF) remains controversial, and the underlying mechanism is unclear.<b>Hypothesis/Gap Statement.</b> This study hypothesizes that antibiotic exposure in ACLF patients alters gut microbiota, which affects the outcome of ACLF.<b>Aim.</b> To explore the effect of antibiotic exposure on gut microbiota that affects the outcome of ACLF.<b>Methodology.</b> A retrospective matched study of ACLF patients and the ACLF rat model was used to assess adverse outcomes associated with antibiotic exposure. The gut microbiota of the ACLF patients and the ACLF rat model were sequenced using the Illumina MiSeq platform.<b>Results.</b> Twenty-three ACLF patients who were exposed to antibiotics and 46 matched controls who were not exposed to antibiotics were enrolled. The survival rates at 4, 12 and 24 weeks were significantly lower in the exposure group than in the non-exposure group. In the ACLF rat model, hepatitis in the antibiotic-exposure group became more severe, and the alanine transaminase levels were higher than those of the non-exposure group. The gut microbiota diversity was decreased in the ACLF patients with antibiotic exposure, and the proportions of <i>Enterococcaceae</i> and <i>Peptostreptococcaceae</i> were increased, while those of <i>Lachnospiraceae</i>, <i>Bifidobacteriaceae</i> and <i>Bacteroidaceae</i> were decreased. In the rat model, antibiotic exposure induced Gram-positive and Gram-negative bacterial eradication, and <i>Klebsiella</i> became the dominant micro-organism.<b>Conclusion.</b> Antibiotic exposure aggravated hepatitis and had no survival benefit for ACLF. The underlying mechanism may be related to dysbiosis in the gut microbiota.