Which physiological issue is most directly affected by changes in cabin pressure during flight?

The most directly affected physiological issue by changes in cabin pressure during flight is indeed associated with the auditory system. As an aircraft ascends or descends, the changes in cabin pressure can create a difference between the pressure inside the middle ear and the external environment. This pressure differential can lead to discomfort or pain in the ears, commonly referred to as ear barotrauma.

The Eustachian tube, responsible for equalizing pressure in the middle ear, may not react quickly enough to changes in external pressure, resulting in temporary hearing issues or sensations of fullness. In extreme cases, it can lead to a rupture of the eardrum or other auditory complications.

While other systems (respiratory, circulatory, and digestive) can also be affected by cabin pressure changes, they are not as directly impacted in terms of immediate physiological response and discomfort experienced by passengers as the auditory system. For instance, while the respiratory system does require a certain level of pressure for optimal gas exchange, modern aircraft are designed to maintain sufficient cabin pressure to mitigate significant issues during flight. This makes the auditory system the primary focus when considering direct effects from changes in cabin pressure.