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To understand the mechanism underlying the protective effect of probiotics against infections through immune regulation, we examined protection against <jats:italic>Salmonella enterica<\/jats:italic> infection following exposure to nonpathogenic <jats:italic>Enterococcus faecium<\/jats:italic> in the nematode <jats:italic>Caenorhabditis elegans<\/jats:italic>. We found that the transcription factor HLH-26, a REF-1 family member of basic helix\u2013loop\u2013helix transcription factors, was required in the intestine for <jats:italic>E<\/jats:italic>. <jats:italic>faecium\u2013<\/jats:italic>mediated protection of <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic> against a lethal <jats:italic>S<\/jats:italic>. <jats:italic>enterica<\/jats:italic> infection. In addition, we uncovered that defense response genes controlled by the canonical Wnt\/BAR-1 pathway were activated upon exposure to <jats:italic>E<\/jats:italic>. <jats:italic>faecium<\/jats:italic> in an HLH-26\u2013dependent manner. 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