Small molecule immunomodulins from cultures of the human microbiome member Lactobacillus plantarum

Lactobacillus plantarumstrains are noted for their presence in the human gastrointestinal tractand are distinguished for their immunomodulatory actions and therapeutic applications. Despite the uncertainty in the underlining molecular mechanisms, recent evidence suggests that L. plantarum secretes immunomodulatory agents that alter immunological signaling cascades. Elaboration of these metabolic products from L. plantarum strain WCFS1 was demonstrated previously to correlate with the mid-log-stationary transition, perhaps consistent with secondary metabolite expression. Here, we present the metabolomic shifts revealed by principal component analysis that correspond to the mid-log-stationary transition of L. plantarum, and identify pyroglutamic (pyro) dipeptides within this transition as correlative with the immunomodulatory actions. Four of these (pyro- phenylalanine, pyro-leucine, pyro- isoleucine, pyro-tryptophan) were characterized and the two dominant members, pyro- phenylalanineand pyro-tryptophan, were directly interrogated for immunomodulatory activity through in vivo administration using C57BL/6 mice. Administration of these compounds resulted in decreased production of pro-inflammatory cytokine interferon (IFN)-gamma, which is of noted importance in gastrointestinal immune homeostasis.