Microbiota adapt to high-salt diet by downregulating phosphotransferase system (PTS)

Introduction: Previous studies have demonstrated that a high dietary salt intake imposes a high demand for ATP and dampens host energy. Since the host is a holobiont inhabited by trillions of microbiota, which also require energy for their sustenance, we reasoned that a high-salt diet-induced lower energy of the host will also similarly impose stress on the energy metabolism of gut microbiota. Microbiota use the phosphotransferase system as an energy-efficient sugar transport mechanism by using phosphoenopyruvate, which is a high-energy molecule. This allows bacteria to conserve ATP for other processes. Accordingly, we hypothesized that the phosphotransferase system of gut microbiota is jeopardized by a high salt diet. Methods: To test this hypothesis, six weeks old male S rats (n=8/group) were fed with either a high (2%) and low (0.3%) NaCl containing diet for 30 days. On day 31, all the animals were euthanized, and their fecal samples and sera were collected for gut microbiota profiling using 16S RNA sequencing and Gas Chromatography time-of-flight Mass spectrometry based untargeted metabolomic analysis, respectively. Ingenuity Pathway Analysis was used for pathway analysis of the metabolomic data. Results: A large-scale remodeling of gut microbiota was noted in the high salt fed rats. Specifically, Proteobacteria were depleted (45.54%) while Prevotella were repleted (18.39%) in the rats on a high salt diet compared to the low-salt group. Notably, metagenomic analysis of functional pathways revealed that the phosphotransferase system was the highest-ranking pathway significantly downregulated (2.3-fold) in the high-salt fed rats compared to the low-salt fed rats. Additionally, Ingenuity Pathway Analysis indicated metabolic disease pathway as one of the major pathways impacted by a high salt diet. Conclusion: This study is the first to reveal that a high-salt diet, which imposes a high demand for energy on the host, also triggers an adaptive response by gut microbiota. Specifically, in response to a high salt diet, microbiota succumbs by downregulating its phosphotransferase system for conserving bacterial energy. Funding from the NHLBI/NIH (R01HL171401-01) is gratefully acknowledged This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.