Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance

Abstract

Graphical AbstractHighlights d Deficiency of KDM5 demethylase causes gut dysbiosis and abnormal social behavior in flies d Lactobacillus plantarum administration improves social behavior in kdm5-deficient animals d KDM5 maintains proper immune activity in a transcriptional and microbiota-mediated manner d KDM5 demethylase affects social behavior through the gutmicrobiome-brain axis SUMMARY Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients. Here, we use the model organism Drosophila melanogaster to delineate how KDM5 contributes to ID and ASD. We show that reducing KDM5 causes intestinal barrier dysfunction and changes in social behavior that correlates with compositional changes in the gut microbiota. Therapeutic alteration of the dysbiotic microbiota through antibiotic administration or feeding with a probiotic Lactobacillus strain partially rescues the behavioral, lifespan, and cellular phenotypes observed in kdm5-deficient flies. Mechanistically, KDM5 was found to transcriptionally regulate component genes of the immune deficiency (IMD) signaling pathway and subsequent maintenance of host-commensal bacteria homeostasis in a demethylase-dependent manner. Together, our study uses a genetic approach to dissect the role of KDM5 in the gut-microbiome-brain axis and suggests that modifying the gut microbiome may provide therapeutic benefits for ID and ASD patients.

The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

“…Ethics statement. All zebrafish experiments were approved by the University of Oregon Institutional Animal Care and Use Committee (protocols 18-08 and [18][19][20][21][22][23][24][25][26][27][28][29].…”

“…For example, the Drosophila melanogaster microbiota promotes social preference through serotonergic signaling. 23 GF zebrafish have abnormal anxiety-related and locomotor behaviors, which can be attenuated by probiotic administration that also influences shoaling behavior via brain-derived neurotrophic factor (BDNF) and serotonin signaling. [24][25][26] However, these Lactobacillus strains were applied as a probiotic to adult zebrafish and do not normally populate the zebrafish intestine, so it is unclear whether microbial modulation occurs by this mechanism during normal neurodevelopment of circuits that regulate social behavior.…”

Effect of fecal microbiota transplantation on neurological restoration in a spinal cord injury mouse model: involvement of brain-gut axis

“…The commensal microbiome affects intestinal physiology, and modulates functions of the immune and endocrine systems of host [3][4][5][6]. Emerging evidence indicates that the composition and metabolites of microbiome not only regulate normal development in the central nervous system (CNS) such as formation of blood brain barrier, myelination, neurogenesis and microglia maturation [7][8][9], but also contribute to the onset and/or progression of neurological diseases including Alzheimer's disease, Parkinson's Disease, stroke, depression, anxiety, and autism [10][11][12][13][14][15].…”

The histone demethylase KDM5 controls developmental timing inDrosophilaby promoting prothoracic gland endocycles

“…Whole-exome sequencing of individuals with intellectual disability has identified loss of function mutations in KDM5A, KDM5B and KDM5C (Collins et al, 2019;Kim et al, 2017;Vallianatos and Iwase, 2015). Efforts to understand the link between KDM5 and intellectual disability using mice, flies and worms have revealed that KDM5 can regulate many genes that impact neuronal development or function (Chen et al, 2019;Iwase et al, 2016;Mariani et al, 2016;Zamurrad et al, 2018). However, the extent to which any of these pathways contribute to the cognitive impairments observed in patients remains unknown.…”