Enterotoxigenic <i>Escherichia coli</i> (ETEC) infection causes the death of <i>Caenorhabditis elegans</i>, which can be prevented by certain <i>Lactobacillus</i> isolates. The host response of <i>C. elegans</i> to ETEC infection and its regulation by the isolates are, however, largely unclear. This study has revealed that, in agreement with the results of life-span assays, the expression of the genes encoding
p38 mitogen-activated protein kinase (MAPK) pathway (<i>
nsy-1,
sek-1</i>, and <i>
pmk-1</i>), insulin/insulin-like growth factor (DAF/IGF) pathway (<i>
daf-16</i>), or antimicrobial peptides (<i>
lys-7,
spp-1</i>, and <i>
abf-3</i>) and other defensing molecules (<i>
abf-2,
clec-85</i>) was upregulated significantly when the wild-type nematode (N2) was subjected to ETEC infection. This upregulation was further enhanced by the pretreatment with <i>Lactobacillus zeae</i> LB1, but not with <i>L. casei</i> CL11. Mutants defective in the cell signaling of <i>C. elegans</i> were either more susceptible (defective in NSY-1, SEK-1, PMK-1, or DAF16) or more resistant (defective in AGE-1, DBL-1, SKN-1, or SOD-3) to ETEC infection compared with the wild-type. Mutants defective in antimicrobial peptides (LYS-7, SPP1, or ABF-3) were also more susceptible. In addition, mutants that are defective in NSY-1, SEK-1, PMK-1, DAF16, ABF-3, LYS-7, or SPP1 showed no response to the protection from <i>L</i>. <i>zeae</i> LB1. The expression of the genes encoding antimicrobial peptides (<i>
lys-7,
spp-1</i>, and <i>
abf-3</i>) and other defensing molecules (<i>
abf-2,
clec-60</i>, and <i>
clec-85</i>) were almost all upregulated in AGE-1- or DBL-1-defective mutant compared with the wild-type, which was further enhanced by the pretreatment of <i>L. zeae</i> LB1. The expression of these genes was, however, mostly downregulated in NSY-1- or DAF-16-defective mutant. These results suggest that <i>L. zeae</i> LB1 regulates <i>C. elegans</i> signaling through the
p38 MAPK and DAF/IGF pathways to control the production of antimicrobial peptides and defensing molecules to combat ETEC infection.