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<p>While the impact of non-antibiotic drugs on gut bacteria is well-known, their mechanisms of action remain poorly characterized, and effective mitigation strategies for drug-induced dysbiosis are still limited. Here, we screened bacteria-derived drug-target protein homologs (BDTPHs) mapped to 63 target proteins and 107 associated drugs to quantify “drug–BDTPH–bacterium” interactions. These interactions were validated by co-culture experiments using 10 drugs and 25 strains, enzyme assays, and genetic perturbations in <i>Escherichia coli</i>. Ex vivo and in vivo testing with six drugs showed that over 50% of affected genera exhibited high affinity, indicating microbiota alterations through the “drug–BDTPH–bacterium” axis. Leveraging this quantitative interaction framework, we identified a strain of <i>Bifidobacterium animalis</i> that can competitively bind methotrexate through high-affinity BDTPH, thereby effectively alleviating gut microbiota dysbiosis in vivo. Our findings elucidate a mechanism by which non-antibiotic drug effects on bacterial growth, and suggest a universal homology-based competition strategy to restore drug-disrupted microbiota.</p>

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Probiotics mitigate non-antibiotic drug-induced dysbiosis via protein homology-driven competitive binding

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Shuo Feng,
  • Shu-xin Zhou,
  • Zi-lin Si,
  • Yu-min Cai,
  • Yi-fan Huangfu,
  • Yi-jia Hou,
  • Zi-tong Wang,
  • Qi Liu,
  • Hong-xi Liu,
  • Li-juan Zhai,
  • Tao He,
  • Mao Gu,
  • Gong-hui Tan,
  • Ao-bo Zhang,
  • Jun-ling Zhao,
  • Tao Xu,
  • Yan Ling,
  • Ying-jian Hou,
  • Xiao Zheng,
  • Jing Li,
  • Xing-zhen Lao

摘要

While the impact of non-antibiotic drugs on gut bacteria is well-known, their mechanisms of action remain poorly characterized, and effective mitigation strategies for drug-induced dysbiosis are still limited. Here, we screened bacteria-derived drug-target protein homologs (BDTPHs) mapped to 63 target proteins and 107 associated drugs to quantify “drug–BDTPH–bacterium” interactions. These interactions were validated by co-culture experiments using 10 drugs and 25 strains, enzyme assays, and genetic perturbations in Escherichia coli. Ex vivo and in vivo testing with six drugs showed that over 50% of affected genera exhibited high affinity, indicating microbiota alterations through the “drug–BDTPH–bacterium” axis. Leveraging this quantitative interaction framework, we identified a strain of Bifidobacterium animalis that can competitively bind methotrexate through high-affinity BDTPH, thereby effectively alleviating gut microbiota dysbiosis in vivo. Our findings elucidate a mechanism by which non-antibiotic drug effects on bacterial growth, and suggest a universal homology-based competition strategy to restore drug-disrupted microbiota.