Antibiotics drive immunometabolic rewiring of human immune responses

Abstract

Antibiotics are routinely evaluated for their antimicrobial activity, potential host toxicity, and disruption of the microbiome. Certain antibiotics can also impact cell-intrinsic host processes, including evolutionarily conserved processes in the mitochondria. These raise the possibility that antibiotics can directly impact host immunity, which relies on mitochondrial function for their immunometabolic activation. However, the immunological consequences of most antibiotics in current use have not been systematically examined. Here, we performed a comprehensive analysis of the effects of clinically used antibiotics on activation of primary human immune cells. We uncovered an underappreciated antibiotic-specific modulation of immune function in healthy individuals and infectious disease patients. Focusing on the immunomodulatory antibiotic ciprofloxacin, we found altered mitochondrial gene expression across multiple immune populations, driving distinct, lineage-specific responses and heightened sensitivity of T-cells. Ciprofloxacin impaired primary human T-cell expansion and activation and altered mitochondrial function and metabolism. We further demonstrated immunomodulatory effects of selected antibiotics in response to inactivated bacteria and during live viral infection. Finally, to test the implications of our findings in vivo, we showed that immune activation is altered shortly after a single dose of antibiotic administration in mice. This work established a widespread impact of antibiotics on immune-cell function, and identified mitochondrial perturbation as one underlying mechanism, with implications for host-pathogen interactions and antimicrobial therapy.

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BibTeX RIS

BibTeX

@misc{henavivi2026antibiotics,
  title = {{Antibiotics drive immunometabolic rewiring of human immune responses}},
  author = {S. Hen-Avivi and N. Bossel Ben-Moshe and R. Avera and I. Adin and Y. Kitsberg and S. K. Lyskov and S. Navon and A. Zalmanovich and T. Yardeni and R. Ben-Ami and R. Avraham},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.03.763842},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763842v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Antibiotics drive immunometabolic rewiring of human immune responses
AU  - S. Hen-Avivi
AU  - N. Bossel Ben-Moshe
AU  - R. Avera
AU  - I. Adin
AU  - Y. Kitsberg
AU  - S. K. Lyskov
AU  - S. Navon
AU  - A. Zalmanovich
AU  - T. Yardeni
AU  - R. Ben-Ami
AU  - R. Avraham
PY  - 2026
DA  - 2026/11/03
PB  - bioRxiv
DO  - 10.64898/2026.11.03.763842
UR  - https://www.biorxiv.org/content/10.64898/2026.11.03.763842v1
AB  - Antibiotics are routinely evaluated for their antimicrobial activity, potential host toxicity, and disruption of the microbiome. Certain antibiotics can also impact cell-intrinsic host processes, including evolutionarily conserved processes in the mitochondria. These raise the possibility that antibiotics can directly impact host immunity, which relies on mitochondrial function for their immunometabolic activation. However, the immunological consequences of most antibiotics in current use have not been systematically examined. Here, we performed a comprehensive analysis of the effects of clinically used antibiotics on activation of primary human immune cells. We uncovered an underappreciated antibiotic-specific modulation of immune function in healthy individuals and infectious disease patients. Focusing on the immunomodulatory antibiotic ciprofloxacin, we found altered mitochondrial gene expression across multiple immune populations, driving distinct, lineage-specific responses and heightened sensitivity of T-cells. Ciprofloxacin impaired primary human T-cell expansion and activation and altered mitochondrial function and metabolism. We further demonstrated immunomodulatory effects of selected antibiotics in response to inactivated bacteria and during live viral infection. Finally, to test the implications of our findings in vivo, we showed that immune activation is altered shortly after a single dose of antibiotic administration in mice. This work established a widespread impact of antibiotics on immune-cell function, and identified mitochondrial perturbation as one underlying mechanism, with implications for host-pathogen interactions and antimicrobial therapy.
ER  -

Abstract

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