Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice
Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen
Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen
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Research Article Hepatology Metabolism Microbiology

Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice

Abstract

Acute-on-chronic liver failure (ACLF) is a leading cause of global liver-related mortality. Bacterial infection, especially in patients with decompensated cirrhosis, commonly triggers ACLF and is difficult to treat with antibiotics. Therefore, finding alternative strategies for preventing and managing bacterial infection is an urgent priority. Here, we observed that patients with bacterial infection and decompensated cirrhosis, as well as ACLF mice, exhibited lower fecal panose levels than uninfected controls. Megamonas funiformis, with 4α-glucanosyltransferase (4αGT) as a key enzyme for panose production, was identified as a potential panose producer. Animal experiments demonstrated that panose efficiently reduced liver injury and extended survival in ACLF mice by mitigating bacterial infection. Further results revealed that panose enhanced resistance to bacterial infection by inhibiting oxidative stress–induced gut barrier disruption, thereby limiting bacterial dissemination. Mechanistically, panose interacted with the solute carrier family 7 member 11 (SLC7A11, also known as xCT) protein to boost antioxidant glutathione levels in intestinal epithelial cells. These findings highlight panose’s potential in preventing bacterial infection, offering a valuable insight into mitigating ACLF progression.

Authors

Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen

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Figure 7

Panose reduces intestinal oxidative stress by interacting with the xCT protein.

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Panose reduces intestinal oxidative stress by interacting with the xCT p...
(A–G) Mode-K cells were exposed to H2O2-induced oxidative stress for 12 hours before sample collection and analysis. (A) Intracellular cysteine levels (n = 6/group). (B) FITC-cystine uptake was measured by flow cytometry and quantified using MFI (n = 3–4/group). (C) Cystine uptake was analyzed using a fluorescent enzyme labeler at 490/535 nm (n = 3/group). (D) Glutamate efflux levels in the media (n = 8/group). (E–G) Mode-K cells transfected with si-NC or si-xCT were analyzed as follows: (E) Intracellular ROS levels were assessed using DCFH-DA staining, measured by flow cytometry, and quantified with MFI (n = 8/group). (F) MDA and GSH levels (n = 6/group). (G) Western blot analysis and quantification of ZO-1 and occludin protein expression (n = 4–5/group). (H) Schematic depiction of molecular docking between panose and the extracellular structural domain of the xCT protein (PDB: 7EPZ, B chain), with a docking affinity of –6.4 kcal/mol. (I) The DARTS experiment was conducted to assess the panose-xCT protein interaction (n = 6/group). (J) The CETSA experiment was conducted to assess the panose-xCT protein interaction (n = 9/group). Data are presented as mean ± SEM. Statistical significance was determined by 1-way ANOVA with Bonferroni’s post hoc test (A–G, and I) and 2-tailed Student’s t test (J). *P < 0.05. NS, nonsignificant. xCT (known as SLC7A11), solute carrier family 7 member 11; si-NC, negative control siRNA; si-xCT, xCT-specific siRNA; DARTS, drug affinity responsive target stability; CETSA, cellular thermal shift assays.