Lactobacillus johnsonii Generates Cyclo(pro-trp) and Promotes Intestinal Ca²⁺ Absorption to Alleviate CKD-SHPT

Patients with chronic kidney disease (CKD) are at a high risk of developing secondary hyperparathyroidism (SHPT), which may cause organ dysfunction and increase patient mortality. The main clinical interventions for CKD-SHPT involve calcium supplements to boost absorption, but ineffective for some patients, and the reasons remain unclear. Here, CKD mice are divided into high and low groups based on intact parathyroid hormone (iPTH) levels. The high group exhibits significant changes in gut microbes, including a decrease in Lactobacillus, an increase in parathyroid hyperplasia, and a decrease in intestinal calcium. Fecal microbiota transplantation and L. johnsonii colonization indicate a link between gut microbes and CKD-SHPT. Clinically, higher L. johnsonii levels are correlated with milder hyperparathyroidism CKD-SHPT. The receiver operating characteristic (ROC) curve for L. johnsonii abundance and surgical risk is 0.81, with the calibration curve confirming predictive accuracy, and decision curve analysis revealing good clinical applicability. In vivo and in vitro experiments show that cyclo(pro-trp) enhance calcium inflow and lower iPTH levels in intestinal epithelial cells via a calcium-sensing receptor and transient receptor potential vanilloid 4 pathways. This study identified the crucial role of L. johnsonii in CKD-SHPT, unveiling a new mechanism for calcium imbalance and offering novel strategies for SHPT treatment and drug development.