Lactoferrin Feeding Deficiency during Lactation Increases the Risk of Depression in Adult Mice by Affecting Microbiota-Gut-Brain Axis Development

Abstract Background Lactoferrin is an active protein in breast milk that plays an important role in the growth and development of infants and is implicated as a neuroprotective agent. The incidence of depression is currently increasing, and it is unclear whether the lack of lactoferrin during lactation affects the incidence of depression in adulthood. Objectives The purpose of our work was to investigate the effect of lactoferrin feeding deficiency during lactation on adult depression and related mechanisms. Methods Lactoferrin knockout mice provided lactoferrin-free milk to establish a lactoferrin feeding deficiency model during lactation. The chronic unpredictable mild stress (CUMS) depression model was established when the mice reached 9 weeks of age. Behavioural performance, serum indicators, and the microbiota, intestine, and hippocampus injury of the CUMS mice were investigated; RNA-seq of the small intestine and hippocampus, and gut microbiota compositions in 18-day-old lactoferrin-free mice were analysed; the development of the intestine and hippocampus and microbiota compositions in adult lactoferrin-free mice were also examined. Results Lack of lactoferrin feeding during lactation affected the barrier and innate immune functions of the intestine, disrupted the intestinal microflora, and led to neuroimmune dysfunction and neurodevelopmental delay in the hippocampus. 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 signalling pathway in hippocampus, increased abundance of depression-related bacteria, and decreased abundance of beneficial bacteria. Conclusions Overall, our findings reveal that feeding lactoferrin during lactation can reduce the risk of depression in adults. The mechanism is related to the regulatory effect of lactoferrin on the development of the "microbial–intestinal–brain" axis.