Oral Supplementation with Non-Absorbable Antibiotics or Curcumin Attenuates Western Diet-Induced Atherosclerosis and Glucose Intolerance in LDLR−/− Mice – Role of Intestinal Permeability and Macrophage Activation

Abstract

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. Under physiological conditions, an intact intestinal barrier prevents this release of LPS underscoring the importance of examining and modulating the direct effects of Western diet on intestinal barrier function. In the present study we evaluated two strategies, namely selective gut decontamination and supplementation with oral curcumin, to modulate Western-diet (WD) induced changes in intestinal barrier function and subsequent development of glucose intolerance and atherosclerosis. LDLR−/− mice were fed WD for 16 weeks and either received non-absorbable antibiotics (Neomycin and polymyxin) in drinking water for selective gut decontamination or gavaged daily with curcumin. WD significantly increased intestinal permeability as assessed by in vivo translocation of FITC-dextran and plasma LPS levels. Selective gut decontamination and supplementation with curcumin significantly attenuated the WD-induced increase in plasma LPS levels (3.32 vs 1.90 or 1.51 EU/ml, respectively) and improved intestinal barrier function at multiple levels (restoring intestinal alkaline phosphatase activity and expression of tight junction proteins, ZO-1 and Claudin-1). Consequently, both these interventions significantly reduced WD-induced glucose intolerance and atherosclerosis in LDLR−/− mice. Activation of macrophages by low levels of LPS (50 ng/ml) and its exacerbation by fatty acids is likely the mechanism by which release of trace amounts of LPS into circulation due to disruption of intestinal barrier function induces the development of these diseases. These studies not only establish the important role of intestinal barrier function, but also identify oral supplementation with curcumin as a potential therapeutic strategy to improve intestinal barrier function and prevent the development of metabolic diseases.

The Western Diet–Microbiome-Host Interaction and Its Role in Metabolic Disease

“…A Western diet can lead to increased levels of endotoxin producing bacteria in the intestinal tract of both men and mice, resulting in metabolic endotoxemia [65,66]. Several studies investigating the effect of major dietary changes on microbiota in mice have utilized so-called high fat diets, and negative changes -including metabolic endotoxemia -are often attributed to the fat content [67].…”

“…When mice were fed a diet that induced metabolic endotoxemia, adding a prebiotic improved metabolic markers [69]. Correspondingly, dietary polyphenols have shown the ability to restore gut barrier integrity [66], attenuate a number of inflammatory effects of a so-called high fat diet and to induce a healthy microbiota profile in mice when fed together with the high fat diet [70]. Thus, the Western diet's contribution to inflammation in experimental settings could partly be explained by the low content of plant-derived nutrients like fibre and phytochemicals.…”

Nutrients, Nutraceuticals and Xenobiotics Affecting Renal Health

“…Among a variety of stimuli known to alter gut permeability and exposing gut-associated lymphoid tissue to mucosal antigens, intestinal lumen LPS is one of these. LPS, a component of Gram-bacterial wall, is able to promote the down-expression of tight junction proteins ZO-1 and claudin, that allow LPS to enter the bloodstream [101]. This results in a cascade of inflammatory events, including increased secretion of pro-inflammatory cytokines and chemokines, activation of macrophages and their infiltration within the renal tissues and the arterial walls, all predisposing to the development of CKD and atherosclerosis [102][103][104].…”

“…Intestinal Alkaline Phosphatase (IAP) has a very significant role in preserving mucosal barrier integrity. It is a membrane enzyme expressed by the intestinal epithelium, having the important role of detoxifying luminal LPS through the removal of one of the two phosphate groups from the lipid A [101,105,106]. The reduction of IAP (occurring in Western-style diets as well in CKD), results in increased active LPS in its turn causes the down-expression of ZO-1 and claudin.…”

Unraveling the environmental and genetic interactions in atherosclerosis: Central role of the gut microbiota

“…The diet not only affects the gut microbiome [73] but can also affect the structure of the gut mucosa. Increased intestinal permeability and inflammation has been reported in patients with heart failure [74] and mice fed “Western” diets [75]. Such changes in barrier function would likely promote systemic inflammation by increasing the release of bacterial products into the circulation [76].…”