Since narrowbody aircraft are used on the vast majority of domestic flights, and even the vast majority of domestic flights over 1500 miles (American Airlines uses Airbus A321s for its ‘premium’ cross country flights between New York and San Francisco, Los Angeles and Orange County) it’s a major challenge.
And it means that non-stop flights are generally off the table for a subset of passengers unable to use modern narrowbody bathrooms. They have to connect using flights no longer than they’re able to ‘hold it’.