Intestinal mucosal barrier function is the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules while preserving the ability to absorb nutrients. The ...central element is the epithelial layer, which physically separates the lumen and the internal milieu and is in charge of vectorial transport of ions, nutrients, and other substances. The secretion of mucus-forming mucins, sIgA, and antimicrobial peptides reinforces the mucosal barrier on the extraepithelial side, while a variety of immune cells contributes to mucosal defense in the inner side. Thus, the mucosal barrier is of physical, biochemical, and immune nature. In addition, the microbiota may be viewed as part of this system because of the mutual influence occurring between the host and the luminal microorganisms. Alteration of the mucosal barrier function with accompanying increased permeability and/or bacterial translocation has been linked with a variety of conditions, including inflammatory bowel disease. Genetic and environmental factors may converge to evoke a defective function of the barrier, which in turn may lead to overt inflammation of the intestine as a result of an exacerbated immune reaction toward the microbiota. According to this hypothesis, inflammatory bowel disease may be both precipitated and treated by either stimulation or downregulation of the different elements of the mucosal barrier, with the outcome depending on timing, the cell type affected, and other factors. In this review, we cover briefly the elements of the barrier and their involvement in functional defects and the resulting phenotype.
Based on their composition, marine algae, and namely red seaweeds, are good potential functional foods. Intestinal mucosal barrier function refers to the capacity of the intestine to provide adequate ...containment of luminal microorganisms and molecules. Here, we will first outline the component of seaweeds and will summarize the effects of these on the regulation of mucosal barrier function. Special attention will be paid to unique components of red seaweeds: proteins and derived peptides (e.g., phycobiliproteins, glycoproteins that contain "cellulose binding domains", phycolectins and the related mycosporine-like amino acids) together with polysaccharides (e.g., floridean starch and sulfated galactans, such as carrageenans, agarans and "dl-hybrid") and minerals. These compounds have been shown to exert prebiotic effects, to regulate intestinal epithelial cell, macrophage and lymphocyte proliferation and differentiation and to modulate the immune response. Molecular mechanisms of action of peptides and polysaccharides are starting to be elucidated, and evidence indicating the involvement of epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), Toll-like receptors (TLR) and signal transduction pathways mediated by protein kinase B (PKB or AKT), nuclear factor-κB (NF-κB) and mitogen activated protein kinases (MAPK) will also be summarized. The need for further research is clear, but in vivo experiments point to an overall antiinflammatory effect of these algae, indicating that they can reinforce membrane barrier function.
Background and Aims:
Intestinal microbiota is required to maintain immune homeostasis and intestinal barrier function. At the same time, intraluminal bacteria are considered to be involved in ...inflammatory bowel disease and are required for colitis induction in animal models, with the possible exception of dextran sulphate sodium DSS colitis. This study was carried out to ascertain the mechanism underlying the induction of colitis by DSS in the absence of bacteria.
Methods:
Conventional and germ-free GF Naval Medical Research Institute NMRI mice were used, plus conventional mice treated with an antibiotic cocktail to deplete the intestinal microbiota ‘pseudo-GF’ or PGF mice. The differential response to DSS was assessed.
Results:
Conventional mice developed DSS-induced colitis normally, whereas GF mice showed only minimal inflammation no colonic thickening, lower myeloperoxidase activity, IL-6, IL-17, TNF-α, and IFN-γ secretion by splenocytes and mesenteric cell cultures, etc.. However, these mice suffered enhanced haemorrhage, epithelial injury and mortality as a consequence of a weakened intestinal barrier, as shown by lower occludin, claudin 4, TFF3, MUC3, and IL-22. In contrast, PGF mice had a relatively normal, albeit attenuated, inflammatory response, but were less prone to haemorrhage and epithelial injury than GF mice. This was correlated with an increased expression of IL-10 and Foxp3 and preservation barrier-related markers.
Conclusions:
We conclude that enteric bacteria are essential for the development of normal DSS-induced colitis. The absence of microbiota reduces DSS colonic inflammation dramatically but it also impairs barrier function, whereas subtotal microbiota depletion has intermediate effects at both levels.
A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to ...the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action.
Flavonoids possess several biological/pharmacological activities including anticancer, antimicrobial, antiviral, anti-inflammatory, immunomodulatory and antioxidant. The aim of this study was to ...evaluate the effect of flavonoids on macrophage physiology. For this purpose we selected some flavonoids belonging to the most common and abundant groups (flavonols—quercetin and kaempferol; flavones—diosmetin, apigenin, chrysin and luteolin; isoflavones—genistein and daidzein and flavanones—hesperetin). We decided to use primary bone marrow-derived macrophages (BMDM) as cellular model, since they represent a homogenous, non-transformed population of macrophages that can be stimulated
in vitro to proliferate by macrophage colony-stimulating factor (M-CSF) or activated by LPS. In this regard, we demonstrated that most of the flavonoids assayed reduce macrophage M-CSF-induced proliferation without affecting cellular viability. Moreover, some flavonoids also inhibit TNFα production as well as iNOS expression and NO production in LPS-activated macrophages, an effect that has been associated with the inhibition of the NF-κB pathway. We also found that luteolin and quercetin are able to stimulate the expression of the anti-inflammatory cytokine IL-10 at low concentrations (<50
μM). Analysis of the structure–activity relationship showed that four hydroxylations at positions 5, 7, 3′ and 4′, together with the double bond at C
2–C
3 and the position of the B ring at 2, seem to be necessary for the highest anti-inflammatory effect.
Glucocorticoids (GCs) are important hormones involved in the regulation of multiple physiologic functions. GCs are also widely used in anti‐inflammatory/immunosuppressant drugs. GCs are synthesized ...by the adrenal cortex as part of the hypothalamus‐pituitary‐adrenal axis and also by intestinal epithelial cells, among other peripheral sites. GCs are one of the main therapy choices for the exacerbations of inflammatory bowel disease, but they are not useful to prolong remission, and development of tolerance with secondary treatment failure is frequent. Thus, GC actions at the intestinal epithelial level are of great importance, both physiologically and pharmacologically. We generated a tamoxifen‐inducible nuclear receptor subfamily 3 group C member 1 (NR3C1)ΔIEC mouse model to study the effects of GCs on epithelial cells in vivo. Nr3c1 deletion in epithelial cells of the small intestine and colon was associated with limited colonic inflammation at 1 wk postdeletion, involving augmented epithelial proliferation and mucus production, plus local and systemic immune/inflammatory changes. This phenotype regressed substantially, but not completely, after 2 wk. The mechanism may involve augmented inflammatory signaling by epithelial cells or defective barrier function. We conclude that the epithelial GC receptor plays a significant role in colonic homeostasis in basal conditions, but its deficiency can be compensated in the short term. Future studies are required to assess the impact of Nr3c1 deletion in other conditions such as experimental colitis.—Aranda, C. J., Arredondo‐Amador, M., Ocón, B., Lavín, J. L., Aransay, A. M., Martínez‐Augustin, O., Sánchez de Medina, F. Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function. FASEB J. 33, 14067‐14082 (2019). www.fasebj.org
Abstract
Background
Fat mobilization in adipose tissue (AT) has a specific timing. However, circadian rhythms in the activity of the major enzyme responsible for fat mobilization, hormone-sensitive ...lipase (HSL), have not been demonstrated in humans.
Objective
To analyze in a cross-sectional study whether there is an endogenous circadian rhythm in HSL activity in human AT ex vivo and whether rhythm characteristics are related to food timing or fasting duration.
Methods
Abdominal AT biopsies were obtained from 18 severely obese participants (age: 46 ± 11 years; body mass index 42 ± 6 kg/m2) who underwent laparoscopic gastric bypass. Twenty-four-hour rhythms of HSL activity and LIPE (HSL transcript in humans) expression in subcutaneous AT were analyzed together with habitual food timing and night fasting duration.
Results
HSL activity exhibited a circadian rhythm (P = .023) and reached the maximum value at circadian time 16 (CT) that corresponded to around midnight (relative local clock time. Similarly, LIPE displayed a circadian rhythm with acrophase also at night (P = .0002). Participants with longer night fasting duration >11.20 hours displayed almost double the amplitude (1.91 times) in HSL activity rhythm than those with short duration (P = .013); while habitual early diners (before 21:52 hours) had 1.60 times higher amplitude than late diners (P = .035).
Conclusions
Our results demonstrate circadian rhythms in HSL activity and may lead to a better understanding of the intricate relationships between food timing, fasting duration and body fat regulation.
Glucocorticoids (GCs) are widely used drugs for their anti-inflammatory and immunosuppressant effects, but they are associated with multiple adverse effects. Despite their frequent oral ...administration, relatively little attention has been paid to the effects of GCs on intestinal barrier function. In this review, we present a summary of the published studies on this matter carried out in animal models and cultured cells. In cultured intestinal epithelial cells, GCs have variable effects in basal conditions and generally enhance barrier function in the presence of inflammatory cytokines such as tumor necrosis factor (TNF). In turn, in rodents and other animals, GCs have been shown to weaken barrier function, with increased permeability and lower production of IgA, which may account for some features observed in stress models. When given to animals with experimental colitis, barrier function may be debilitated or strengthened, despite a positive anti-inflammatory activity. In sepsis models, GCs have a barrier-enhancing effect. These effects are probably related to the inhibition of epithelial cell proliferation and wound healing, modulation of the microbiota and mucus production, and interference with the mucosal immune system. The available information on underlying mechanisms is described and discussed.
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The glucocorticoid receptor NR3C1 is expressed in multiple cell types in the gut and elsewhere. Intestinal epithelial cells both produce and respond to glucocorticoids in different physiological and ...pathological contexts. In experimental colitis, glucocorticoids have been shown to exert a dual role, dampening inflammation while producing a deterioration in animal status, including death. Mice with tamoxifen-inducible, intestinal epithelial-specific deletion of NR3C1 (NR3C1
mice) are protected against experimental colitis, suggesting glucocorticoid epithelial actions are deleterious. Since glucocorticoids modulate epithelial proliferation, it follows that they may affect the development of colon cancer. In this study, we set out to test this hypothesis using the dextran sulfate sodium-azoxymethane model of colitis-associated cancer. Knockout (KO) mice were found to exhibit a twofold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend close to the submucosal layer (36% vs. 0%) in NR3C1
mice, and overexpressed
,
, and
, consistent with distinct expression of proliferative/stemness markers
and
were upregulated specifically in tumors of NR3C1
mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial glucocorticoid (GC) receptor. We conclude that endogenous GC epithelial signaling is involved in colitis-associated cancer.
Mice carrying a tamoxifen-inducible deletion of the glucocorticoid receptor in intestinal epithelial cells (NR3C1
mice) and their corresponding controls were subjected to the azoxymethane-dextran sulfate sodium model of colitis-associated cancer. KO mice exhibit a twofold higher tumor load, with a higher trend to extend close to the submucosal layer (36% vs. 0%), but with similar incidence and tumor size. Colonic tumors in NR3C1
mice showed signs of increased neoplastic transformation and tumor-associated inflammation.
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