But they’re not uncomfortable with the setting which I think is the salient point here. If someone is uncomfortable with fictional religions and gods, they should choose a different game.
In my experience, no one felt uncomfortable about a D&D setting. The discomfort is the core class whose rules require roleplaying worship of a D&D god.
Players who expessesd discomfort at my tables include American Orthodox Jew, Lebanese Muslim, American Baptist Christian, Indian Hindu, and Norwegian Secular.
The Jewish player comes from a halakhic tradition that forbids both the worship of other gods and the appearance of the worship of other gods. For the Muslim, it is similarly forbidden. For the Christian, there is clear distress. For the Hindu there is discomfort at how D&D portrays polytheism. For the Norwegian, there is frustration with how D&D culturally misrepresents Norse traditions.
None of them care that other people worship D&D gods. No one cares that Lolth is a demon who some creatures worship.
The problem is the Cleric class. It lacks reallife cultural sensitivity.
Meanwhile, all D&D settings refer to core rules. Not all D&D settings have gods. Even settings that do, such as Theros handle the concept differently and more sensitively than Forgotten Realms does, and is a choosable setting.
I feel Eberron has the most helpful approach for a roleplaying game by highlighting the cultural relativity of sacred traditions.
The Playtest Cleric helps by emphasizing the Divine magic comes from the Astral Plane itself, a mindscape, rather than from any worship. This plane keeps the flavor traditional D&D, and the mindscape is easy enough to accommodate in other settings. It is a realm of archetypal ideals.
Well, that level of energy. ;(
