Central to the understanding of the relationships between diet, gut microbiota, and vitamins D and A in multiple sclerosis is low-grade inflammation, which is involved in all chronic inflammatory diseases and is influenced by each of the above effectors. We show that food components have either proinflammatory or anti-inflammatory effects and influence both the human metabolism (the “metabolome”) and the composition of gut microbiota. Hypercaloric, high-animal-fat Western diets favor anabolism and change gut microbiota composition towards dysbiosis. Subsequent intestinal inflammation leads to leakage of the gut barrier, disruption of the blood-brain barrier, and neuroinflammation. Conversely, a vegetarian diet, rich in fiber, is coherent with gut eubiosis and a healthy condition. Vitamin D levels, mainly insufficient in a persistent low-grade inflammatory status, can be restored to optimal values only by administration of high amounts of cholecalciferol. At its optimal values (>30 ng/ml), vitamin D requires vitamin A for the binding to the vitamin D receptor and exert its anti-inflammatory action. Both vitamins must be supplied to the subjects lacking vitamin D. We conclude that nutrients, including the nondigestible dietary fibers, have a leading role in tackling the low-grade inflammation associated with chronic inflammatory diseases. Their action is mediated by gut microbiota and any microbial change induced by diet modifies host-microbe interactions in a consequent way, to improve the disease or worsen it.