When exposed to external stimulation, adult lactoferrin feeding-deficient mice presented with worse depression-like symptoms; the mechanisms involved were activation of the LPS–TLR4 signalling pathway in the intestine and hippocampus, reduced BDNF-CREB signaling pathway in hippocampus, increased abundance of depression-related bacteria, and decreased abundance of beneficial bacteria. This evidence concerns the gene CREB1 and major depressive disorder.