Keywords

Autism, Propionic Acid, Astrocytes, Gliosis, Crohn's Disease, Mycobacterium avium paratuberculosis

Abstract

Short chain fatty acids (SCFAs), including propionic (PPA) and butyric (BA) acid, exert a variable and organ-specific effect on the body. They are by-products of human microbiota metabolism and are often used as a food preservative. Studies have shown that PPA and its producers are elevated in autism spectrum disorder (ASD) patients and their mothers. Our lab previously demonstrated that PPA alters neural stem cell differentiation in favor of glia. In this work, we utilized an in vivo mice model, in which dams and their offspring were fed a PPA-rich diet. In the brain, we observed a significant increase in Glial fibrillary acidic protein (GFAP; astrocytic marker), accompanied by an increase in pro-inflammatory cytokines (IL-6 and TNF-α) and a decrease in IL-10 (anti-inflammatory). We also observed an increase in GPR41 and p-Akt and a decrease in PTEN. In the intestine, GFAP was increased, however, the response was primarily anti-inflammatory, which suggested that immune cells, especially intestinal macrophages in M2 polarization, played a role. The anti-inflammatory properties of PPA could be harnessed in Crohn’s disease (CD), which is strongly associated with Mycobacterium avium paratuberculosis (MAP) infection and characterized by excessive inflammation and intestinal damage. We treated THP-1 macrophages with PPA or BA in the presence of MAP infection. We observed a significant decrease in TNF-a with SCFA treatment. Additionally, treatment of Caco-2 with SCFAs in conditioned media from THP-1 showed a decrease in oxidative stress (NOX1 and DHE) and restoration of tight junction integrity (decrease in Claudin-2). Finally, we observed several-fold decrease of MAP growth in MGIT culture supplemented with SCFAs. The data clearly demonstrated that SCFAs contain anti-inflammatory and antimicrobial properties with downstream beneficial effects on damaged intestinal epithelial cells, which suggest that they can be beneficial to non-pregnant CD patients as nutritional supplements.

Completion Date

2025

Semester

Fall

Committee Chair

Naser, Saleh

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Identifier

DP0029835

Document Type

Thesis

Campus Location

Orlando (Main) Campus

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