In an important human study conducted by Sampath et al., it was revealed that mutations in the single immunoglobulin IL-1-related receptor (SIGIRR) gene, an important negative regulator in the TLR4 signaling pathway,237 are prevalent in a substantial number (10/17) of individuals with severe NEC.238 Richardson et al. demonstrated that nucleotide-binding oligomerization domain-containing 2 (NOD2),70 an intracellular pattern recognition receptor, can inhibit TLR4 activation in the gut, thereby preventing NEC. Here, TLR4 is linked to necrotizing enterocolitis.