A Maternal and Postnatal Ad Libitum Propionic Acid-Rich Diet in Mice Alters Intestinal Glia Proliferation and Inflammatory Response: Contrary to Effect in the Brain

We previously demonstrated that propionic acid (PPA), a common food preservative and a metabolic byproduct of bacteria in dysbiosis (as seen in individuals affected with autism spectrum disorder, ASD), can lead to increased brain astrocyte proliferation and neuroinflammation in mice. We also showed that in vitro treatment of human neural stem cells with PPA increased glial cell vs. neuron differentiation and yielded a marked increase in pro-inflammatory cytokines. In this study, a group of mice (FVB/N-Tg(GFAPGFP)14Mes/J) was exposed in utero through the maternal diet and postnatally ad libitum to a PPA-rich diet, while the control group was fed a normal diet. Intestinal tissue from offspring mice at 1 month (1 M) and 5 months (5 M) were then studied for neurodifferentiation and gastrointestinal (GI) inflammation. There was a significant increase in <i>GFAP</i> (Glial fibrillary acidic protein) expression (1.5427-fold and 1.6097-fold in 1 M and 5 M, respectively) and GFAP protein levels (1.5616-fold and 1.6701-fold in 1 M and 5 M, respectively) in the PPA group mice. It is worth mentioning that the expression level of intestinal astrocyte markers in the PPA group was significantly and multi-fold lower than that in the brain tissue. Contrary to data from brain tissue, the expression of pro-inflammatory cytokines in the PPA group decreased in intestinal tissue at 5 M (<i>IL-6</i>: 0.4403-fold; <i>TNF-α</i>: 0.4007-fold), while IL-10 expression and protein levels increased (1.9360-fold and 1.3428-fold, respectively). The data demonstrates that although there was a significant increase in GFAP in the intestine suggesting gliosis, there was an overall anti-inflammatory cytokine profile. The effect of PPA on intestinal cytokines is most likely in part due to the lower expression of GFAP in the enteric nervous system than the central nervous system (and the lower number of intestinal glia than astrocytes in the brain) and the dominance of intestinal macrophages and other immune cells compared to that in the brain. The overall finding strongly suggests that the PPA-rich diet affects the enteric glia state as shown by an increase in GFAP; however, it maintains the overall anti-inflammatory cytokine profile, possibly due to M2 macrophage polarization.