Activation of the Nrf2 Cell Defense Pathway by Ancient Foods: Disease Prevention by Important Molecules and Microbes Lost from the Modern Western Diet

PLoS One. 2016 Feb 17;11(2):e0148042. doi: 10.1371/journal.pone.0148042. eCollection 2016.


The Nrf2 (NFE2L2) cell defense pathway protects against oxidative stress and disorders including cancer and neurodegeneration. Although activated modestly by oxidative stress alone, robust activation of the Nrf2 defense mechanism requires the additional presence of co-factors that facilitate electron exchange. Various molecules exhibit this co-factor function, including sulforaphane from cruciferous vegetables. However, natural co-factors that are potent and widely available from dietary sources have not been identified previously. The objectives of this study were to investigate support of the Nrf2 cell defense pathway by the alkyl catechols: 4-methylcatechol, 4-vinylcatechol, and 4-ethylcatechol. These small electrochemicals are naturally available from numerous sources but have not received attention. Findings reported here illustrate that these compounds are indeed potent co-factors for activation of the Nrf2 pathway both in vitro and in vivo. Each strongly supports expression of Nrf2 target genes in a variety of human cell types; and, in addition, 4-ethylcatechol is orally active in mice. Furthermore, findings reported here identify important and previously unrecognized sources of these compounds, arising from biotransformation of common plant compounds by lactobacilli that express phenolic acid decarboxylase. Thus, for example, Lactobacillus plantarum, Lactobacillus brevis, and Lactobacillus collinoides, which are consumed from a diet rich in traditionally fermented foods and beverages, convert common phenolic acids found in fruits and vegetables to 4-vinylcatechol and/or 4-ethylcatechol. In addition, all of the alkyl catechols are found in wood smoke that was used widely for food preservation. Thus, the potentially numerous sources of alkyl catechols in traditional foods suggest that these co-factors were common in ancient diets. However, with radical changes in food preservation, alkyl catechols have been lost from modern foods. The absence of alkyl catechols from the modern Western diet suggests serious negative consequences for Nrf2 cell defense, resulting in reduced protection against multiple chronic diseases associated with oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacteria / metabolism*
  • Biotransformation / drug effects
  • Blotting, Western
  • Caffeic Acids / pharmacology
  • Carboxy-Lyases / metabolism
  • Catechols / chemistry
  • Catechols / pharmacology*
  • Cells, Cultured
  • Chlorogenic Acid / pharmacology
  • Diet, Western*
  • Food*
  • Gene Expression Regulation / drug effects
  • Heme Oxygenase-1 / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hydroxybenzoates / metabolism
  • Immunohistochemistry
  • Isothiocyanates / chemistry
  • Isothiocyanates / pharmacology
  • Male
  • Mice, Inbred BALB C
  • Models, Biological
  • NF-E2-Related Factor 2 / metabolism*
  • Oxygen / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Sulfoxides


  • Caffeic Acids
  • Catechols
  • Hydroxybenzoates
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • RNA, Messenger
  • RNA, Small Interfering
  • Sulfoxides
  • Chlorogenic Acid
  • protocatechuic acid
  • Heme Oxygenase-1
  • Carboxy-Lyases
  • phenolic acid decarboxylase
  • sulforaphane
  • Oxygen
  • caffeic acid