The gut microbiota of the malaria vector mosquito Anopheles coluzzii are understood to have wide reaching influence on mosquito physiology and basal immunity. Here, it is shown that the microbiota proliferation that is associated with a mosquito blood meal causes a reduction in mosquito life span and fecundity, both of which translate to reduced mosquito vectorial capacity. A transcriptional analysis is employed to explore the responses of the mosquito midgut to the dynamic changes in microbial load occurring over the blood feeding and egg laying cycle, leading to the identification and characterisation of a key mosquito resistance response that reduces the load of specific bacterial families within the gut, abrogates the stimulation of epithelial immunity and prevents the gut microbiota from seeding a systemic infection. Finally, the role of the variable transmembrane receptor PGRPLC in microbota-dependent immune stimulation is characterised. Altogether, these data contribute to our understanding of mosquito gut homeostasis, supporting the potential of exploiting microbiota-immune interactions for novel transmission blocking applications.