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

Abstract

Gut immune system homeostasis involves diverse structural interactions among resident microbiota, the protective mucus layer, and a variety of cells (intestinal epithelial, lymphoid, and myeloid). Due to the substantial surface area in direct contact with an "external" environment and the diversity of xenobiotic, abiotic, and self-interactions coordinating to maintain gut homeostasis, there is enhanced potential for the generation of endogenous danger signals when this balance is lost. Here, we focus on the potential generation and reception of damage in the gut resulting from exposure to nanoparticles (NPs), common food and drug additives. Specifically, we describe recent evidence in the literature showing that certain NPs are potential generators of damage-associated molecular patterns, as well as potential immune-stimulating molecular patterns themselves. K E Y W O R D SATP, DAMP, mtDNA, NAMP, Nanoparticles, NLRP3Over the past decade, the commercial use of NPs by the food and biomedical industries has seen immense growth. The small, nanoscale size of NPs confers unique physicochemical properties that allow them to be effective oral delivery mechanisms for pharmaceuticals, food flavors, nutrient additives, and more. The accepted size range of NPs is not straightforward, varying across different biomedical and engineering disciplines and government agencies. 10,11 Although certain sources indicate that a typical NP is 1-100 nm in three dimensions, other sources consider accepted dimensions (one or more) for NPs to include <200 nm, 12 <500 nm, 13 or as large as <1000 nm. 14,15 The ASTM International definition provides for either two or three dimensions at the nanoscale, 16 whereas the ISO definition indicates nanoscale in three dimensions. 17 In an officially issued

Environmental factors in epithelial barrier dysfunction

“…125 After oral intake, NPs accumulate on the surfaces of intestinal epithelial cells, M cells, and Peyer patches. 126 They are translocated through the intestinal epithelial barrier either via endocytosis by M cells (TiO 2 ) or by increasing the cell leakage secondary to disruption of the cell membrane integrity (SiO 2 , TiO 2 , and ZnO) or by phagocytosis by macrophages. 126 Furthermore, paracellular permeability of the intestinal barrier has been shown to increase after the administration of TiO 2 -NPs.…”

“…126 They are translocated through the intestinal epithelial barrier either via endocytosis by M cells (TiO 2 ) or by increasing the cell leakage secondary to disruption of the cell membrane integrity (SiO 2 , TiO 2 , and ZnO) or by phagocytosis by macrophages. 126 Furthermore, paracellular permeability of the intestinal barrier has been shown to increase after the administration of TiO 2 -NPs. Both in vitro and in vivo studies have demonstrated that NPs induce ROS following internalization.…”

“…127 It has been suggested that danger signals and chronic inflammation secondary to NPs may lead to the development of autoimmune diseases. 126…”

The origins of allergy from a systems approach

“…Currently, there are substantial data reporting that pollutants such as cigarette smoke, particulate matter, diesel exhaust, ozone, nanoparticles, microplastic, detergents, and cleaning agents and chemicals in household substances damage the epithelial barrier. 37,38,[66][67][68][69][70][71][72][73][74][75] After the opening of the barrier, a local inflammation starts, and the tissue may become more vulnerable to inflammatory and tissue destructive effects of pollution. Most of these pollutants indicate synergistic effects, and the area is fully open for future research.…”

How to Address the Adjuvant Effects of Nanoparticles on the Immune System

“…The "danger signals" would act on DCs, in aseptic conditions, in a similar manner to the microbial molecular patterns. Therefore, the question to be addressed is whether engineered NP could act as danger signals, as previously suggested for ultrafine or diesel exhaust particles [14] and could be considered as NAMPs (nanoparticle-associated molecular patterns) [15][16][17].…”