Retinoic Acid, Leaky Gut, and Autoimmune Diseases

Abstract

A leaky gut has been observed in a number of autoimmune diseases including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Previous studies from our laboratory have shown that lupus mice also bear a leaky gut and that the intestinal barrier function can be enhanced by gut colonization of probiotics such as Lactobacillus spp. Retinoic acid (RA) can increase the relative abundance of Lactobacillus spp. in the gut. Interestingly, RA has also been shown to strengthen the barrier function of epithelial cells in vitro and in the absence of probiotic bacteria. These reports bring up an interesting question of whether RA exerts protective effects on the intestinal barrier directly or through regulating the microbiota colonization. In this review, we will discuss the roles of RA in immunomodulation, recent literature on the involvement of a leaky gut in different autoimmune diseases, and how RA shapes the outcomes of these diseases.

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

“…Similarly, it significantly reduced the transcript level of the barrier-forming tight junction protein Occludin (Figure 5D) and induced a moderate increase in the expression of the pore-forming tight junction protein transcript claudin-2 (Cldn2) ( Figure S5B) in the IECs as observed at 6 months post induction. These observations indicate that pristane was able to recapitulate a phenotype similar to a leaky gut described in genetically prone models of SLE (10,20), further supporting the leaky gut as a danger signal for autoimmunity even in the absence of genetic predisposition.…”

“…Notably, VA exerts its function through a predominant metabolite known as all-trans-retinoic acid (tRA) (9). The effects of tRA treatment in different autoimmune disorders, including type 1 diabetes, multiple sclerosis, and inflammatory bowel disease, were shown to be disease-specific (10). However, in the context of systemic immune dysregulation associated with SLE, VA exerts more complex roles.…”

The role of the retinoids in schizophrenia: genomic and clinical perspectives

“…This T reg subpopulation exerts an immunosuppressive effect via downregulation of effector T lymphocytes and, thus, prevents aberrant inflammation and autoimmunity [67]. Retinoids further act as regulators of the blood-gut barrier-a vital structure for preventing inflammation in response to the gut microbiome [68]. Aberrant permeability ('leakiness') in this barrier has been linked with several inflammatory conditions and may also have implications for adverse immune responses associated with schizophrenia [69,70].…”

Nanoparticles and danger signals: Oral delivery vehicles as potential disruptors of intestinal barrier homeostasis

“…Disruption or damage to any of these parts, especially the mucus and/or epithelial layers, not only influences tolerance, but also potentially induces exposure to autoantigens and self‐produced danger signals associated with aberrant cellular damage and death. Such danger signals can lead to disruption of the mucus and barrier function, life‐threatening gut dysbiosis, and the signals themselves can be a function of dysbiosis . This in turn can cause the polarization of intraepithelial and lamina propria lymphoid tissues toward specific phenotypes, such as Th1 and Th17, resulting in persistent autoimmune pathologies.…”