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Tryptophol acetate and tyrosol acetate, small molecule metabolites identified in a probiotic mixture, inhibit hyperinflammation

Orit Malka, Ravit Malishev, Marina Bersudsky, Manikandan Rajendran, Mathumathi Krishnamohan, Jakeer Shaik, Daniel A. Chamovitz, Evgeni Tikhonov, Eliya Sultan, Omry Koren, Ron N. Apte, Benyamin Rosental, Elena Voronov, View ORCID ProfileRaz Jelinek
doi: https://doi.org/10.1101/2021.12.16.472991
Orit Malka
1Department of Chemistry, Ben-Gurion University of the Negev, 84105 Be’er Sheva, Israel
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Ravit Malishev
1Department of Chemistry, Ben-Gurion University of the Negev, 84105 Be’er Sheva, Israel
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Marina Bersudsky
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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Manikandan Rajendran
1Department of Chemistry, Ben-Gurion University of the Negev, 84105 Be’er Sheva, Israel
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Mathumathi Krishnamohan
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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Jakeer Shaik
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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Daniel A. Chamovitz
1Department of Chemistry, Ben-Gurion University of the Negev, 84105 Be’er Sheva, Israel
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Evgeni Tikhonov
3The Azrieli Faculty of Medicine, Bar Ilan University, 1311502 Safed, Israel
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Eliya Sultan
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
4Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev
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Omry Koren
3The Azrieli Faculty of Medicine, Bar Ilan University, 1311502 Safed, Israel
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Ron N. Apte
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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Benyamin Rosental
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
4Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev
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Elena Voronov
2Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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  • For correspondence: elena@bgu.ac.il razj@bgu.ac.il
Raz Jelinek
1Department of Chemistry, Ben-Gurion University of the Negev, 84105 Be’er Sheva, Israel
5Ilse Katz Institute for Nanoscale Science & Technology Ben Gurion University of the Negev, Be’er Sheva 84105, Israel
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  • ORCID record for Raz Jelinek
  • For correspondence: elena@bgu.ac.il razj@bgu.ac.il
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Abstract

Probiotic fermented foods are perceived as contributing to human health, however solid evidence for their presumptive therapeutic systemic benefits is generally lacking. Here we report that tryptophol acetate and tyrosol acetate, small molecule metabolites secreted by the probiotic milk-fermented yeast Kluyveromyces marxianus inhibit hyperinflammation (e.g., “cytokine storm”). Comprehensive in vivo and in vitro analyses, employing LPS-induced hyperinflammation models, reveal dramatic effects of the molecules, added in tandem, on mice morbidity, laboratory parameters, and mortality. Specifically, we observed attenuated levels of the pro-inflammatory cytokines IL-6, IL-1α, IL-1β and TNF-α, and reduced reactive oxygen species. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress pro-inflammatory cytokine generation, rather brought their concentrations back to baseline levels thus maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, leading to NF-kB inhibition. Overall, this work illuminates phenomenological and molecular details underscoring anti-inflammatory properties of small molecules identified in a probiotic mixture, pointing to potential therapeutic avenues against severe inflammation.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted October 29, 2022.
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Tryptophol acetate and tyrosol acetate, small molecule metabolites identified in a probiotic mixture, inhibit hyperinflammation
Orit Malka, Ravit Malishev, Marina Bersudsky, Manikandan Rajendran, Mathumathi Krishnamohan, Jakeer Shaik, Daniel A. Chamovitz, Evgeni Tikhonov, Eliya Sultan, Omry Koren, Ron N. Apte, Benyamin Rosental, Elena Voronov, Raz Jelinek
bioRxiv 2021.12.16.472991; doi: https://doi.org/10.1101/2021.12.16.472991
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Tryptophol acetate and tyrosol acetate, small molecule metabolites identified in a probiotic mixture, inhibit hyperinflammation
Orit Malka, Ravit Malishev, Marina Bersudsky, Manikandan Rajendran, Mathumathi Krishnamohan, Jakeer Shaik, Daniel A. Chamovitz, Evgeni Tikhonov, Eliya Sultan, Omry Koren, Ron N. Apte, Benyamin Rosental, Elena Voronov, Raz Jelinek
bioRxiv 2021.12.16.472991; doi: https://doi.org/10.1101/2021.12.16.472991

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