Dataset Information

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia.

ABSTRACT: Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells (Treg), which suppress inhibitory antibody formation directed at hemophilia proteins induced by intravenous replacement therapy in hemophilia A and B mice. Further analyses of Treg CD4⁺ lymphocyte sub-populations in hemophilia B mice reveal a marked increase in the frequency of CD4⁺CD25^-FoxP3^-LAP⁺ T cells (but not of CD4⁺CD25⁺FoxP3⁺ T cells) in the lamina propria of the small but not large intestine. The adoptive transfer of very small numbers of CD4⁺CD25^-LAP⁺ Treg isolated from the spleen of tolerized mice was superior in suppression of antibodies directed against FIX when compared to CD4⁺CD25⁺ T cells. Thus, tolerance induction by oral delivery of antigens bioencapsulated in plant cells occurs via the unique immune system of the small intestine, and suppression of antibody formation is primarily carried out by induced latency-associated peptide (LAP) expressing Treg that likely migrate to the spleen. Tolerogenic antigen presentation in the small intestine requires partial enzymatic degradation of plant cell wall by commensal bacteria in order to release the antigen. Microbiome analysis of hemophilia B mice showed marked differences between small and large intestine. Remarkably, bacterial species known to produce a broad spectrum of enzymes involved in degradation of plant cell wall components were found in the small intestine, in particular in the duodenum. These were highly distinct from populations of cell wall degrading bacteria found in the large intestine. Therefore, FIX antigen presentation and Treg induction by the immune system of the small intestine relies on activity of a distinct microbiome that can potentially be augmented to further enhance this approach.

SUBMITTER: Kumar SRP

PROVIDER: S-EPMC7251037 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia.

Kumar Sandeep R P SRP Wang Xiaomei X Avuthu Nagavardhini N Bertolini Thais B TB Terhorst Cox C Guda Chittibabu C Daniell Henry H Herzog Roland W RW

Frontiers in immunology 20200520

Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells (Treg), which suppress inhibitory antibody formation directed at hemophilia proteins induced by intravenous replacement therapy in hemophilia A and B mice. Further analyses of Treg CD4<sup>+</sup> ly ...[more]

PMID: 32508814

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Project description:BackgroundHealthy plant-based diet index (hPDI) is associated with a lower risk of cardiometabolic conditions, but its association as well as interactions with microbiome have not been elucidated.ObjectivesWe aimed to investigate the interrelations between hPDI, gut microbiome, and cardiometabolic risk markers.MethodshPDI was derived from dietary assessments by a validated FFQ and was examined in relation to metagenomic profiles of 911 fecal samples collected from 303 men aged 71 ± 4 y with an average BMI (in kg/m2) of 25.2 ± 3.6 in the Men's Lifestyle Validation Study. Principal coordinate (PCo) analysis based on Bray-Curtis dissimilarity was conducted, and interactions between hPDI and PCo were examined by using a metabolic risk score composed of blood lipids, BMI, and glycated hemoglobin.ResultsAfter multivariable adjustment, hPDI was significantly associated with the relative abundance of 7 species and 9 pathways. In particular, higher hPDI was significantly associated with a higher relative abundance of Bacteroides cellulosilyticus and Eubacterium eligens, amino acid biosynthesis pathways (l-isoleucine biosynthesis I and III and l-valine biosynthesis), and the pathway of pyruvate fermentation to isobutanol. A favorable association between hPDI and the metabolic risk score was more pronounced among men with a higher PCo characterized by higher abundance of Bacteroides uniformis and lower abundance of Prevotella copri. At the individual species level, a similar interaction was also observed between hPDI and P. copri, as well as with Clostridium clostridioforme or Blautia hydrogenotrophica (all P-interaction < 0.01).ConclusionA greater adherence to a healthy plant-based diet by older men was associated with a microbial profile characterized by a higher abundance of multiple species, including B. cellulosilyticus and E. eligens, as well as pathways in amino acid metabolism and pyruvate fermentation. In addition, inverse associations between healthy plant-based diet and human metabolic risk may partially depend on microbial compositions.

Dataset Information

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia.

Publications

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia.

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