Background: Butyrate is a microbiota-derived short-chain fatty acid with established roles in maintaining intestinal barrier integrity and regulating immune responses. Although its effects have been extensively investigated in immunocompetent models, systemic immune homeostasis in severely immunodeficient hosts remains incompletely understood. This exploratory study evaluated the impact of sodium butyrate (NaB) supplementation on tissue-associated microbial antigen detection and immune marker distribution along different organs in athymic nude mice. Methods: Female NU/J athymic mice were administered either regular drinking water (H₂O, n = 10) or NaB-supplemented water (150 mM, n = 5) for six weeks. Intestinal, liver, lung, and kidney tissues were collected for histopathological and immunohistochemical analyses. Expression of microbial antigens, including lipopolysaccharide (LPS) and lipoteichoic acid (LTA), as well as immune-associated markers (CD3, CD8a, CD68, CD278, and transglutaminase-2 [TGM2]), was assessed using a semiquantitative scoring system. Results: NaB supplementation did not significantly affect organ morphology but was associated with better weight gain. Histological examination revealed preserved tissue architecture in all organs, with only mild condensation of small intestinal crypts in NaB-treated mice. Immunohistochemical analysis showed consistently lower LPS expression in NaB-treated animals compared with controls in the small intestine, liver, and kidney, with a borderline reduction in the lungs. Reduced LPS detection was accompanied by significantly lower expression of the macrophage marker CD68 in the kidney. Conclusions: Oral NaB supplementation was associated with lower detection of bacterial antigens in tissues and reduced innate immune expression across multiple organs. These findings support a potential role for butyrate in limiting microbial expression and systemic inflammatory signaling in athymic mice.