Cyclophosphamide induces the loss of taste bud innervation in mice

Many common chemotherapeutics produce disruptions in the sense of taste which can lead to loss of appetite, nutritional imbalance, and reduced quality of life, especially if taste loss persists after treatment ends. Cyclophosphamide (CYP), an alkylating chemotherapeutic agent, affects taste sensitivity through its cytotoxic effects on mature taster receptor cells (TRCs) and on taste progenitor cell populations, retarding the capacity to replace TRCs. Mechanistic studies have focused primarily on taste cells, however, taste signaling requires communication between TRCs and the gustatory nerve fibers which innervate them. Here, we evaluate the effect of CYP on the peripheral gustatory nerve fibers that innervate the taste bud. Following histological analysis of tongue tissues, we find that CYP reduces innervation within the fungiform and circumvallate taste buds within 4-8 days after administration. To better understand the dynamics of the denervation process, we used 2-photon intravital imaging to observe the peripheral gustatory neuron arbors within individual fungiform taste buds before and after CYP treatment. We find that gustatory fibers retract from the taste bud proper but are maintained within the central papilla core. These data indicate that, in addition to TRCs, gustatory nerve fibers are also affected by CYP treatment. Because the connectivity between TRCs and gustatory neurons must be re-established for proper function, gustatory fibers should continue to be included in future studies to understand the mechanisms leading to chemotherapy-induced persistent taste loss.