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

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-1 alpha, IL-1 beta and TNF-alpha, 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.

Automated summary

Probiotic fermented yeast produces small molecules, tryptophol acetate and tyrosol acetate, which can inhibit hyperinflammation. These molecules were found to reduce pro-inflammatory cytokines and reactive oxygen species, while maintaining core immune functions. The anti-inflammatory effects were mediated through the downregulation of signaling pathways and NF-kB inhibition. This study highlights the potential therapeutic avenues for severe inflammation.