Curcumin as a potential therapeutic option for NAFLD and other metabolic diseases: need for establishing the underlying mechanism(s) of action
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The natural polyphenol, curcumin, the most widely studied component of the Asian spice Turmeric, is shown to have potent anti-oxidant, anti-inflammatory, anti-bacterial and anti-neoplastic activities [1, 2, 3, 4]. These varied beneficial effects have been largely examined using cell culture-based assays in vitro where curcumin is in direct contact with the target cells. However, limited oral bioavailability of curcumin and levels of curcumin or its metabolites in systemic circulation below the detection limits of most analytical methods hinder the establishment of a cause–effect relationship between orally administered curcumin and the observed beneficial effects in vivo . Furthermore, results from several small-scale clinical studies/trials have not been entirely consistent complicating an already difficult problem. Nonetheless, ever increasing published data and widespread recognition of curcumin as a dietary supplement warrant a systematic review of existing literature, preferably in the context of a specific disease process.
Will enhancing the bioavailability of curcumin increase the magnitude of its beneficial effects? In recent years, multiple formulations of curcumin have been developed to increase its absorption and bioavailability. However, no clinical trials or studies have been conducted examining the effects of curcumin or these modified versions in parallel with unmodified curcumin precluding the direct comparative efficacy. For example, addition of piperine is thought to increase curcumin bioavailability , but while RCT examining the effects of this combination was placebo controlled, it did not include a curcumin alone group to facilitate the evaluation of the effects of piperine addition and resulting curcumin bioavailability on changes in the metabolic parameters examined . Furthermore, circulating levels of curcumin or curcumin metabolites are seldom quantified in any clinical study or trial precluding the direct examination of any changes in bioavailability and observed metabolic effects. More appropriately designed studies are required to establish a causative link between changes in bioavailability of curcumin and its observed beneficial effects. In this regard, it would be critical to focus on one disease at a time and collect data on all parameters relevant to the likely cause(s) of the disease and correlate them with plasma levels of curcumin and/or its metabolites to firmly establish the much needed cause–effect relationship to move the use of curcumin to therapeutic arena.
Are the beneficial systemic/metabolic effects of orally administered curcumin not directly related to the amount of Curcumin absorbed but rather due to action of curcumin in the gastrointestinal (GI) tract? It is noteworthy that clinical use of curcumin is most advanced in the treatment of inflammatory bowel disease, ulcerative colitis and other GI tract-related diseases . In addition, data from several pre-clinical studies provide strong evidence for the direct effects of curcumin on the GI tract. Zou et al.  reported that curcumin acts as a potent anti-atherogenic agent by inhibiting cholesterol absorption in mice. Feng et al.  demonstrated that curcumin dramatically shifted the overall structure of the high fat diet-disrupted gut microbiota toward that of lean rats fed a normal diet and attributed these changes as the likely mechanism for the observed attenuation of hepatic steatosis. Curcumin-mediated improvement of metaflammation-related diseases such as diabetes, atherosclerosis or chronic kidney disease is also likely due to the effects of curcumin in improving intestinal barrier function  and limiting the release of bacterial endotoxin  and other bacterial products into systemic circulation . Similar attenuation of systemic inflammation by oral curcumin might also underlie the beneficial effects on other inflammatory diseases such as arthritis. While studies with animal models of metaflammation-related diseases provide additional evidence for the GI tract-focused effects of curcumin, it is critical to monitor similar parameters (e.g., intestinal permeability, plasma levels of intestinal bacteria-derived products, gut microbiome analyses) in clinical studies/trials to advance our current understanding of the mechanism of action of curcumin.
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Conflict of interest
Shobha Ghosh declares no conflict of interest.
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