TY - JOUR
T1 - Tryptophol Acetate and Tyrosol Acetate, Small-Molecule Metabolites Identified in a Probiotic Mixture, Inhibit Hyperinflammation
AU - Malka, Orit
AU - Malishev, Ravit
AU - Bersudsky, Marina
AU - Rajendran, Manikandan
AU - Krishnamohan, Mathumathi
AU - Shaik, Jakeer
AU - Chamovitz, Daniel A.
AU - Tikhonov, Evgeni
AU - Sultan, Eliya
AU - Koren, Omry
AU - Apte, Ron N.
AU - Rosental, Benyamin
AU - Voronov, Elena
AU - Jelinek, Raz
N1 - Publisher Copyright:
© 2023 S. Karger AG. All rights reserved.
PY - 2023/2/21
Y1 - 2023/2/21
N2 - 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 proinflammatory 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 proinflammatory 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.
AB - 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 proinflammatory 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 proinflammatory 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.
KW - Anti-inflammation
KW - Catechol metabolites
KW - Fermented foods
KW - Hyperinflammation
KW - Probiotics
UR - http://www.scopus.com/inward/record.url?scp=85181179010&partnerID=8YFLogxK
U2 - 10.1159/000529782
DO - 10.1159/000529782
M3 - Article
C2 - 36809756
AN - SCOPUS:85181179010
SN - 1662-811X
VL - 15
SP - 531
EP - 547
JO - Journal of Innate Immunity
JF - Journal of Innate Immunity
IS - 1
ER -