Diet determines IgA induction and repertoire characteristics independently of the microbiota

A hallmark of the main secreted antibody immunoglobulinA is its mutational load that accumulates throughout life. This has been mainly interpreted in terms of continuing microbial induction, although once established in early life, the microbiome of humans and experimental mice is relatively stable and germinal center reactions in Peyers patches and mesenteric lymph nodes are also present in germ-free mice. Using germ-free and colonized mice fed different diets formulated with proprietary grain-based processing or from purified chemicals with different principal macronutrient calorie sources, we show that dietary composition during early life can promote IgA induction, its repertoire and mutational diversification independently of microbial exposure. Within the immense chemical diversity between the diets demonstrated by mass spectrometry, strain combination experiments showed that lipopolysaccharide contamination, signaling through Toll like receptor 4 and promotion of germinal center activity were sufficient to explain differences between mucosal immune responses under different dietary regimes in germ-free conditions. Effects of lipopolysaccharide on mucosal immune induction were phenocopied only when presented within colloidal liposomes rather than in dispersed solution. Dietary composition and its formulation can therefore be distinguished from the microbiota as a key factor leaving a durable impression on the resultant IgA repertoire.