Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic debilitating conditions with an increasing incidence and prevalence globally [1,2]. There are many factors thought to lead to the development of colitis, including persistent intestinal inflammation (related to age, gender, and genetics factors), diet, alterations in the function of gut microbiota and immune system homeostasis, all of which are interlinked [3]. Whilst the aetiology and pathogenesis are not yet fully known [4], it seems that persistent intestinal inflammation may result from a dysregulated immune response to mucosal antigens involving a variety of cells with pathogenic and regulatory properties [5]. Among them, T helper (Th) cells (mainly Th1 and Th17) and regulatory T (Treg) cells play a crucial role in the perpetuation and maintenance of self-tolerance in IBD, respectively [6].

Despite the lack of specific dietary advice in IBD, more than 70% of sufferers note that inadequate nutrition significantly affects the course of the disease and increases the frequency and severity of symptoms [7]. Consequently, patients with UC often seek nutritional guidance to help improve their quality of life and contribute to symptom relief [7,8]. Unfortunately, studies to date do not provide a solid basis for creating strong evidence-based dietary recommendations [9]. Whether dietary supplements and/or nutraceuticals are effective against colonic inflammation and immune dysregulation remains an open area of active investigation [10]. Recently, a growing body of studies has indicated that phytochemicals derived from natural products are potent regulators of Th17/Treg repertoire and exert preferable protective benefits against colonic inflammation [11]. This “immunological hypothesis” has attracted increasing scientific evidence, and it may represent the “turning key” for IBD-related dietary recommendations and the rationale for the specific use of herbal-based preparation/formulation in disease onset and/or progression [12,13].

Recent research has demonstrated the relevance of Mangifera indica L. extract (here referred as MIE, and commonly known as mango) polyphenols (mainly the glucosylxanthone mangiferin) in the prevention of chronic inflammatory diseases, including IBD [14,15]. Mangiferin possesses prominent anti-inflammatory and immunomodulatory properties thanks to its capacity to decrease CD4+IL-17+ cells (Th17 phenotype) maturation [16] and to promote the development of CD3+CD25− T cells into CD4+FOXP3+ cells (Treg phenotype) by suppressing the mTOR activation pathway [17]. In parallel, studies on DSS- and TNBS-induced experimental colitis in mice revealed that an oral supplement with Mangifera indica L. and/or its active component(s) effectively ameliorates colonic inflammation through nuclear factor-kappa B (NF-κB) and MAPK signalling inhibition [18] and by the restoration of altered Th17/Treg cells physiological ratio [16,19]. In other disease settings, such as gouty arthritis, we have also shown the ability of MIE to ameliorate inflammation related to clinical and biochemical parameters [20].

The current relevant literature demonstrates a protective role for mangiferin or Mangifera indica L. extract in experimental IBD, but these studies are limited to the observation of an association between mangiferin-induced modulations in gut immunoinflammatory state and the disease outcome. Notably, no single animal model completely recapitulates the clinical and histopathological characteristics of human IBD, considering that chronic gut inflammation, largely mediated by T lymphocytes and the presence of commensal enteric bacteria, are detrimental to the initiation and perpetuation of intestinal and/or colonic inflammation. These features are required to mimic the human disease [21]. Thus, conclusive evidence is lacking to connect the mechanism of action of mangiferin in clinically relevant models of IBD (in both preclinical and clinical assessments) and a full understanding of its anti-inflammatory and immunomodulatory properties.

With this rationale, we explored the therapeutic potential of a Mangifera indica L. extract (MIE; at 90% purity of mangiferin) by taking a reverse translational approach, initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Our investigation demonstrates the potent action of MIE in ameliorating inflammatory mediator release from lipopolysaccharides (LPS)-stimulated blood taken from CD, Irritable Bowel Syndrome (IBS) and UC patients and, preclinically, to reverse disease severity and intestinal inflammation. Mechanistically, we show MIE regulates the trafficking of the inflammatory infiltrate through the cyclooxygenase-2 (COX-2)-prostaglandin D2 receptor (DP)2 signalling pathway in vitro and in vivo. Collectively, these data highlight Mangifera indica L. extract and its main active constituent mangiferin as a natural therapeutic agent [22] with the potential to treat a broad range of immune-mediated inflammatory diseases (IMIDs).