Abstract Objectives: Various studies provide evidence confirming that chronic diseases can derive from infections. Vice versa, chronic disorders impair immune responses and affect the incidence and severity of infections. Methods: We investigated the progress of Porphyromonas gingivalis (P. g) infection during chronic kidney disease (CKD) and the effects of P.g-overgrowth on CKD. Two infectious models: the alveolar bone-loss or chamber model were applied in CKD mice. We stimulated primary macrophages, B-lymphocytes as well as osteoclasts with P. g in the presence of uremic toxins to characterize immune responses. Results: We showed that CKD significantly increased survival and organ-distribution of P.g. We observed a decreased IgGs in sera of CKD mice infected with P.g, indicating an immune depression caused by uremia. Levels of pro-inflammatory factors indicated changes in inflammation and homeostasis. The bone-loss was significantly increased in the CKD group, indicating that uremia affects bone formation. In vitro results revealed that microbiome/pathogen-derived indoxyl sulfate significantly inhibited the formation of TRAP-positive multinucleated osteoclasts. These effects of indoxyl sulfate might be associated with a higher rate and severity of the gingival infections observed in the CKD group. Moreover, infected mice showed a significantly higher progression of CKD. Conclusion: This study represents a link between infection and chronic disease. It shows that controlling pathogens’ overgrowth might reduce the morbidity of preexisting chronic kidney disease. Moreover, the efficient removal of indoxyl sulfate by dialysis could be a therapeutic approach to restore local homeostasis and immune responses.