Iron regulatory protein 1 is required for the propagation of inflammation in inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation is known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution, and that this in turn perpetuates the inflammation. This study analyzed human biopsies, animal models, and cellular systems to decipher the role of iron homeostasis in IBD. We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP) 1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular coculture model was established, which replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

Reply to the Comment on "Revisiting the carrageenan controversy: do we really understand the digestive fate and safety of carrageenan in our foods?" by M. Weiner and J. McKim, Food Funct., 2019, 10: DOI: 10.1039/C8FO01282B.

This commentary re-emphasizes the aim of our recent review (David et al., 2018) and addresses some of the points raised in the adjacent commentary by M. Weiner and J. McKim, Food Funct., 2019, 10, DOI: 10.1039/C8FO01282B. In agreement with the commentary, the discussed review highlights the need to adequately understand the complex physicochemistry of the food additive carrageenan (CGN) and its fate in the alimentary canal. In fact, there is a realm of scientific findings that justify the continuation of an open discussion of CGN safety. This response emphasizes that there is sparse information on [i] the physicochemical properties of commercial CGN, [ii] human levels of exposure to CGN from foods, [iii] the role of CGN in gut microbiome dysbiosis and inflammation, and [iv] the effects of CGN on susceptible populations. As long as the determinants of the increased prevalence of chronic and autoimmune diseases are not identified, we must continue to explore the possible beneficial or deleterious effects that may arise from extrinsic factors, including food additives, and do so in meticulous independent studies.

Revisiting the carrageenan controversy: do we really understand the digestive fate and safety of carrageenan in our foods?

Carrageenan (CGN), a family of marine polysaccharides isolated from seaweeds, has been at the heart of considerable debate in recent years. To date, CGN is generally recognized as safe based on a history of safe use, various acute toxicology studies and some recent chronic toxicology tests. This review offers readers an overview of evidence on CGN characteristics and digestive fate that highlight various gaps in our understanding. Specifically, three unresolved gaps are identified. Firstly, little information can be found on the current levels of public exposure to CGN. Secondly, the link between CGN physicochemical properties, its impact on digestive proteolysis, the colon microbiome and inflammation are yet to be fully resolved. Thirdly, scant scientific evidence exists on the differential digestive fate of CGN in the gut of liable and predisposed populations, such as elderly people or IBD patients. Altogether, revisiting the scientific evidence indicates that more research is needed to elucidate the possibility that continued exposure to increasing levels of CGN in the human diet may compromise human health and well-being.

Digestive fate of dietary carrageenan: Evidence of interference with digestive proteolysis and disruption of gut epithelial function.

SCOPE: The objective of this study was to interrogate two mechanisms by which commercial Carrageenans (E407) (CGN) may adversely affect human health: (i) Through modification of gastric proteolysis and (ii) Through affecting gut epithelial structure and function. METHODS AND RESULTS: Three commercial CGN samples with distinct zeta-potentials (stable at the pH range of 3-7 and varied with physiological levels of CaCl2 ) were mixed with milk, soy or egg protein isolates, then subjected to a semi-dynamic in vitro digestion model and analyzed by SDS-PAGE. This revealed varying levels of interference with gastric digestive proteolysis and a significant decrease in pepsin activity. Further, a Caco-2 cell model was used to explore various effects of physiologically digested CGN (pdCGN) on various epithelial cell functions and characteristics. Samples of pdCGN (0.005-0.5 mg/mL) affected the epithelial barrier function, including redistribution of the tight-junction protein Zonula Occludens (Zo)-1, changes in cellular F-actin architecture and increased monolayer permeability to the transfer of macromolecules. Moreover, pdCGN induced elevation in the levels of the pro-inflammatory IL-8 receptor CXCR1. CONCLUSION: This work raises the possibility that CGN may reduce protein and peptide bioaccessibility, disrupt normal epithelial function, promote intestinal inflammation, and consequently compromise consumer health.

Corrigendum: Ferritin polarization and iron transport across monolayer epithelial barriers in mammals.

[This corrects the article on p. 194 in vol. 5, PMID: 25202274.].

Ferritin polarization and iron transport across monolayer epithelial barriers in mammals.

Epithelial barriers are found in many tissues such as the intestine, kidney and brain where they separate the external environment from the body or a specific compartment from its periphery. Due to the tight junctions that connect epithelial barrier-cells (EBCs), the transport of compounds takes place nearly exclusively across the apical or basolateral membrane, the cell-body and the opposite membrane of the polarized EBC, and is regulated on numerous levels including barrier-specific adapted trafficking-machineries. Iron is an essential element but toxic at excess. Therefore, all iron-requiring organisms tightly regulate iron concentrations on systemic and cellular levels. In contrast to most cell types that control just their own iron homeostasis, EBCs also regulate homeostasis of the compartment they enclose or the body as a whole. Iron is transported across EBCs by specialized transporters such as the transferrin receptor and ferroportin. Recently, the iron storage protein ferritin was also attributed a role in the regulation of systemic iron homeostasis and we gathered evidence from the literature and original data that ferritin is polarized in EBC, suggesting also a role for ferritin in iron trafficking across EBCs.