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. / Doctor of Philosophy / Differences in microbes transferred to infants through maternal routes shapes the early
development of the immune system. In general, transferred microbes are healthy for the
infant, and studies suggest that disruption of healthy microbes in the infant gut is linked
to long-term health consequences, like autoimmune diseases. We found that a particular
difference in maternally transferred microbes increases the early appearance of
immunoglobulin A (IgA, a gut-related antibody) in neonatal mice, which is an antibody
important for protecting against gut-related infections. We were able to link this early
IgA production to a probiotic species Limosilactobacillus reuteri. Within the species
classification as L. reuteri, several genetically different strains are health-promoting and
broadly marketed over-the-counter for use in probiotic supplements for infants, children,
and pregnant and nursing mothers. Emerging scientific evidence also points to a potential
connection between other L. reuteri strains and autoimmune disease. Secreted products of
genetically different L. reuteri strains have been discovered to activate aryl hydrocarbon
receptor (AhR) with various potency. We used a prototypical AhR ligand and found
exacerbation of autoimmune disease in adult mice. Thus, we have concluded that
different strains of L. reuteri have broadly different effects on immune system
development, and strain variability may explain the different effects on autoimmunity
that have been observed.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/112896 |
| Date | 22 June 2021 |
| Creators | Swartwout, Brianna Kendall |
| Contributors | Graduate School, Luo, Xin, Leeth, Caroline M., Reilly, Christopher Michael, Li, Liwu |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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