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Low-Dose Colchicine Attenuates Sepsis-Induced Liver Injury: A Novel Method for Alleviating Systemic Inflammation

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Abstract

Sepsis is a significant public health challenge. The immune system underlies the pathogenesis of the disease. The liver is both an active player and a target organ in sepsis. Targeting the gut immune system using low-dose colchicine is an attractive method for alleviating systemic inflammation in sepsis without inducing immunosuppression. The present study aimed to determine the use of low-dose colchicine in LPS-induced sepsis in mice. C67B mice were injected intraperitoneal with LPS to induce sepsis. The treatment group received 0.02 mg/kg colchicine daily by gavage. Short and extended models were performed, lasting 3 and 5 days, respectively. We followed the mice for biochemical markers of end-organ injury, blood counts, cytokine levels, and liver pathology and conducted proteomic studies on liver samples. Targeting the gut immune system using low-dose colchicine improved mice’s well-being measured by the murine sepsis score. Treatment alleviated the liver injury in septic mice, manifested by a significant decrease in their liver enzyme levels, including ALT, AST, and LDH. Treatment exerted a trend to reduce creatinine levels. Low-dose colchicine improved liver pathology, reduced inflammation, and reduced the pro-inflammatory cytokine TNFα and IL1-β levels. A liver proteomic analysis revealed low-dose colchicine down-regulated sepsis-related proteins, alpha-1 antitrypsin, and serine dehydratase. Targeting the gut immune system using low-dose colchicine attenuated liver injury in LPS-induced sepsis, reducing the pro-inflammatory cytokine levels. Low-dose colchicine provides a safe method for immunomodulation for multiple inflammatory disorders.

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Data Availability

All data is available upon request.

Abbreviations

SOFA:

Sequential organ failure assessment score

TNFα:

Tumor necrosis factor α

LPS:

Lipopolysaccharide

MSS:

Murine sepsis score

CBC:

Complete blood count

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

IL:

Interleukin

IFNγ:

Interferon γ

ALT:

Alanine aminotransferase

LDH:

Lactate dehydrogenase

WBC:

White blood count

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Author notes

  1. Sarah Weksler-Zangen and Yaron Ilan contributed equally to this work.

Authors and Affiliations

  1. The Faculty of Medicine, The Hebrew University, Jerusalem, Israel

    Ariel Kenig, Tal Keidar-Haran, Henny Azmanov, Asa Kessler, Yotam Kolben & Yaron Ilan

  2. Department of Medicine, Hadassah Medical Center, POB 1200, IL91120, Jerusalem, Israel

    Ariel Kenig, Henny Azmanov, Asa Kessler, Yotam Kolben & Yaron Ilan

  3. Department of Pathology, Hadassah Medical Center, Jerusalem, Israel

    Tal Keidar-Haran

  4. Institute of Chemistry, The Hebrew University, Jerusalem, Israel

    Tamar Tayri-Wilk

  5. Center for Nanoscience and Nanotechnology, The Hebrew University, Jerusalem, Israel

    Tamar Tayri-Wilk

  6. Institute of Life Sciences, The Hebrew University, Jerusalem, Israel

    Nir Kalisman

  7. The Liver Research Laboratory, Hadassah Medical Center, Jerusalem, Israel

    Sarah Weksler-Zangen & Yaron Ilan

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  1. Ariel Kenig
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Contributions

Ariel Kenig, Tal Keidar-Haran, Henny Azmanov, Asa Kessler, Yotam Kolben, Tamar Tayri-Wilk, and Sarah Weksler-Zangen: conducted the experiments. Yaron Ilan and Nir Kalisman: conceptualized.

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Correspondence to Yaron Ilan.

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YI is the founder of Oberon Sciences. The other authors declare no competing interests.

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Kenig, A., Keidar-Haran, T., Azmanov, H. et al. Low-Dose Colchicine Attenuates Sepsis-Induced Liver Injury: A Novel Method for Alleviating Systemic Inflammation. Inflammation 46, 963–974 (2023). https://doi.org/10.1007/s10753-023-01783-9

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