Identification and evaluation of Limosilactobacillus reuteri as an inducer of neonatal IgA and autoimmunity

Perturbing gut microbiota early in life can lead to the development of autoimmunity. We are just beginning to unravel how early immune programming by microbiota may have long-term effects on noncommunicable diseases. In this thesis, we lay groundwork for programming of the immune system by commensal bacteria early in life through our studies on the induction of early endogenous neonatal IgA, and we evaluate Limosilactobacillus reuteri's characteristics as an inducer. Garnering attention for use a probiotic, L. reuteri has many proven health promoting benefits, such as IgA induction, but emerging evidence also links specific strains to autoimmune disease. "Super-induction" of neonatal IgA can be achieved through cross-fostering immunocompetent pups on immunocompromised dams. We found that this phenomenon was categorically due to transferal of microbes from dam to offspring. By comparing strain CF48-3A to the non-gastric-related organism L. oris, we discovered that L. reuteri is a microorganism that can enhance early neonatal IgA induction. Further investigations revealed that the ability to induce neonatal IgA is not ubiquitous in all L. reuteri strains, as ATCC PTA 6475 did not significantly elevate IgA. We discovered that 6475 has the antigenic ability to stimulate B cell differentiation and IgA production, but it is suppressed by a mechanism related to differences in surface architecture of this strain. L. reuteri strains also vary in their potency of aryl hydrocarbon receptor (AhR) stimulation. In mice, activation of AhR during gestation by a potent prototypical ligand, TCDD, leads to development of autoimmunity offspring. We found that TCDD exacerbated autoimmunity in adult mice using a strain of mice with similar AhR affinity to humans. Further investigations can clarify whether differential AhR ligand expression between L. reuteri strains contributes to the relationship between L. reuteri and autoimmunity. Overall, we conclude that differences between strains of L. reuteri have profoundly different immunological consequences that contribute to our understanding of the linkage between strains and autoimmunity.