Curcumin improves intestinal barrier function: modulation of intracellular signaling, and organization of tight junctions

Abstract

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as type 2 diabetes and atherosclerosis) has shifted the focus from high-fat high-cholesterol containing Western-type diet (WD)-induced changes in gut microbiota per se to release of gut bacteria-derived products (e.g., LPS) into circulation due to intestinal barrier dysfunction as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. We demonstrated earlier that oral supplementation with curcumin attenuates WD-induced development of type 2 diabetes and atherosclerosis. Poor bioavailability of curcumin has precluded the establishment of a causal relationship between oral supplementation and it is in vivo effects. We hypothesized that curcumin attenuates WD-induced chronic inflammation and associated metabolic diseases by modulating the function of intestinal epithelial cells (IECs) and the intestinal barrier function. The objective of the present study was to delineate the underlying mechanisms. The human IEC lines Caco-2 and HT-29 were used for these studies and modulation of direct as well as indirect effects of LPS on intracellular signaling as well as tight junctions were examined. Pretreatment with curcumin significantly attenuated LPS-induced secretion of master cytokine IL-1β from IECs and macrophages. Furthermore, curcumin also reduced IL-1β-induced activation of p38 MAPK in IECs and subsequent increase in expression of myosin light chain kinase involved in the phosphorylation of tight junction proteins and ensuing disruption of their normal arrangement. The major site of action of curcumin is, therefore, likely the IECs and the intestinal barrier, and by reducing intestinal barrier dysfunction, curcumin modulates chronic inflammatory diseases despite poor bioavailability.

Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis

“…Furthermore, the increased concentrations of pro-inflammatory cytokines such as TNF-α, IL.-1β and IL-6 in C. jejuni infected co-cultures were down-regulated after curcumin treatment [99]. These results indicate that curcumin in competition to TLR-4 binding antagonized local and systemic inflammatory responses triggered by bacterial LPS/LOS [99,100]. Moreover, it has been reported that the competition between curcumin and LPS/LOS to bind TLR-4 inhibited the MyD88-dependent pathway [101].…”

Microbiota, Inflammation, and Gut Barrier Dysfunction in HCC

“…Similarly in NAFLD mice model, treatment with resveratrol enhances barrier function by increasing mRNA expression of TJ proteins ZO-1, occludin, and claudin-1 in the intestinal mucosa [144]. Curcumin also modulates intestinal barrier integrity and attenuates paracellular permeability and organization of TJs [145]. Thus, targeting TJ proteins, which maintain intact intestinal epithelia, is another area of therapeutic approach for the control of intestinal permeability in cirrhosis and HCC.…”

The Role of Glycosaminoglycans in Protection from Neonatal Necrotizing Enterocolitis: A Narrative Review

“…The innate immune system in the small intestine is comprised of both a physical barrier of intestinal epithelial cells (IECs) and their biochemical products, and an underlying and complementary immunological barrier [49]. The physical barrier is often considered to include intestinal alkaline phosphatase, a loose layer of mucus [50], tight junctions linking IECs, and antimicrobial proteins (AMPs) released by a specialized lineage of IECs, Paneth cells [51].…”