Harnessing the microbiome to regulate myeloid TREM2 expression and innate immune responses

Abstract The composition of the gastrointestinal microbiome is correlated with numerous immune-mediated systemic diseases, but underlying mechanisms remain unclear. In murine studies, we recently identified microbiome Bacteroidota-derived bacterial molecules, serine-glycine lipodipeptides (S/G lipids), as mediators of microbiome-systemic innate immune system crosstalk. By altering microbiome production of S/G lipids, we documented that proinflammatory responses of splenic monocytes could be regulated. Transcriptomic analysis revealed that this regulation occurred by modulating the mRNA levels of inhibitors of the TLR/NF-κB pathways such as Trem2. The present murine study had 2 goals: (1) to determine if our approach allows for modulation of activated innate immune cells, that is, macrophages rather than splenic monocytes, in a site of inflammation and (2) to document that our approach regulates cellular expression of the disease-relevant TLR/NF-κB pathway inhibitor, TREM2, at the protein level. We now report that decreasing microbiome-derived S/G lipid levels enhances proinflammatory responses and decreases expression of TREM2 in activated peritoneal macrophages (PMs). Furthermore, after lowering microbiome S/G lipid production, administering S/G lipids normalizes both PM proinflammatory responses and TREM2 expression. The harnessing of the microbiome and S/G lipids to modulate proinflammatory responses and TREM2 expression in activated innate immune cells suggests the therapeutic potential of this approach in inflammatory diseases such as Alzheimer’s disease, atherosclerosis, autoimmunity and liver disease.