Aging-Related Increase in Hepatic Microbiota and Glutamine Promotes M2 Polarization of Macrophage in the Aging Liver

In the aging liver, a distinct senescence-associated secretory phenotype (SASP) and a concomitant influx of inflammatory cells are observed. Traditionally considered an immune-privileged site, the etiology of pronounced immune cell infiltration into the liver during senescence remains inadequately understood. The potential contribution of microbial entities to this age-related hepatic inflammation is not well-characterized. Through the analysis of clinical liver specimens and aged murine models, we documented a notable augmentation in hepatic bacterial load that paralleled the progression of aging, concomitant with a marked decline in the diversity of the hepatic microbiome. With advancing senescence, we detected an upregulation of glutamine biosynthesis within the liver. Furthermore, our findings reveal that enhanced glutamine availability preferentially skews macrophage differentiation toward an anti-inflammatory M2 phenotype, rather than a pro-inflammatory M1 phenotype. Utilizing the glutaminase inhibitor BPTES, we demonstrated that attenuation of glutamine catabolism leads to a substantial reduction in both hepatic bacterial abundance and inflammatory cell infiltration, while simultaneously impeding the M2 macrophage polarization. Our study provides new insights into the dynamic relationship between shifts in hepatic microbial populations, glutamine metabolic pathways, and immune regulatory mechanisms throughout liver aging. These findings lay the groundwork for pioneering therapeutic approaches targeting the mitigation of liver pathologies associated with the aging process.