Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 01 December 2016 doi: 10.3389/fphar.2016.00459 Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer Arkadiusz Michalak †, Paula Mosinska´ † and Jakub Fichna * Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Polyunsaturated fatty acids (PUFAs) are bioactive lipids which modulate inflammation and immunity. They gained recognition in nutritional therapy and are recommended dietary supplements. There is a growing body of evidence suggesting the usefulness of PUFAs in active therapy of various gastrointestinal (GI) diseases. In this review we briefly cover the systematics of PUFAs and their metabolites, and elaborate on their possible use in Edited by: inflammatory bowel disease (IBD), functional gastrointestinal disorders (FGIDs) with focus Gabriella Aviello, University of Aberdeen, UK on irritable bowel syndrome (IBS), and colorectal cancer (CRC). Each section describes Reviewed by: the latest findings from in vitro and in vivo studies, with reports of clinical interventions Elisabetta Barocelli, when available. University of Parma, Italy Simona Pace, Keywords: n-3 PUFA, n-6 PUFA, eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid derivatives, University of Jena, Germany inflammatory bowel disease, irritable bowel syndrome, colorectal cancer *Correspondence: Jakub Fichna jakub.fi[email protected] INTRODUCTION † These authors have contributed Gastroenterology is a rapidly-evolving basic and clinical science that concerns organic and equally to this work. functional gastrointestinal (GI) disorders. The former include inflammatory, infectious and neoplastic diseases and the latter embrace conditions characterized by chronic symptoms and the Specialty section: This article was submitted to absence of recognized biochemical or structural explanations. Gastrointestinal and Hepatic Inflammatory bowel disease (IBD) has been constricted so far mainly to Europe and US, but Pharmacology, currently emerge also in newly industrialized countries in Asia, Middle East, and South America a section of the journal (Kaplan, 2015). North America and Europe also remain the leading regions of the occurrence Frontiers in Pharmacology of functional gastrointestinal disorders (FGIDs), especially irritable bowel syndrome (IBS) (Fox Received: 16 August 2016 and Muniraj, 2016). In turn, the incidence and mortality of colorectal cancer (CRC) are high in Accepted: 14 November 2016 developed countries and are rapidly rising in low-income and middle-income populations (Arnold Published: 01 December 2016 et al., 2016). Despite an ongoing progress in implementing structured screening in reducing the Citation: prevalence rate and developing new treatments, currently available options are not always effective Michalak A, Mosinska´ P and Fichna J and often prompt adverse effects (Favoriti et al., 2016). Hence, we still need new tools of prevention (2016) Polyunsaturated Fatty Acids and therapy. and Their Derivatives: Therapeutic The aim of this review is to explore the studies on polyunsaturated fatty acids (PUFAs), their Value for Inflammatory, Functional Gastrointestinal Disorders, and metabolites and derivatives, and relate the findings to the pressing problems of gastroenterology. Colorectal Cancer. The scientific bibliography included in this review was collected from the PubMed and Web of Front. Pharmacol. 7:459. Science databases. We searched for English language review articles or original research published doi: 10.3389/fphar.2016.00459 up to May 2016, using the following keywords alone or in combination: PUFA, arachidonic Frontiers in Pharmacology | www.frontiersin.org 1 December 2016 | Volume 7 | Article 459 Michalak et al. PUFA Derivatives in IBD, FGIDs, CRC acid, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, there is a growing awareness and support for regular PUFA fish oil, diet in irritable bowel syndrome, inflammatory bowel supplementation (González-Rodríguez et al., 2013; Sioen et al., disease, Crohn’s disease, ulcerative colitis, colorectal cancer, 2013; Kodentsova et al., 2014). functional gastrointestinal diseases. Clinical trials were searched Physiologically, PUFAs are built into lipid membranes. Once using ClinicalTrials.gov database. they are released by phospholipase A2 (PLA2), they undergo processing to many biologically active signaling molecules (Gomolka et al., 2011; Maskrey et al., 2013; Capra et al., 2015; SYSTEMATIC OVERVIEW OF PUFAs Powell and Rokach, 2015). The most important pathways of PUFAs metabolism include: A fatty acid (FA) comprises aliphatic hydrocarbon chain with methyl and carboxyl groups at opposite ends; PUFAs contain • cyclooxygenases (COXs)–act on both n-3 and n-6 more than one double bond in their structure. There are two PUFAs, yielding prostaglandins (PGs), prostacyclins and main groups of biologically important long chain PUFAs: n-6 thromboxanes (TXs); altogether branded prostanoids, PUFA with their first double bond at C6, counting from the • lipooxygenases (LOXs)–convert AA to lipoxins (LXs) and methyl C, and n-3 PUFAs with first unsaturated bond at C3. The leukotrienes (LTs). Together with COXs, LOXs also produce main representatives of these groups are: protectins, marensins, and resolvins (Rvs) from n-3 PUFAs, • cytochrome 450 (Cyp 450)–catalyzes the conversion of both • n-6 PUFAs: linoleic acid (LA, 18:2), arachidonic acid (AA, n-3 and n-6 PUFAs to epoxyeicosatrienoic acids (EETs). 20:4), Along with other enzymes, Cyp450 takes part in the • n-3 PUFAs: alpha-linolenic acid (ALA, 18:3), eicosapentaenoic synthesis of PUFA derivatives, producing biologically active acid (EPA, 19:5) and docosahexaenoic acid (DHA, 22:6). hydroxyeicosatetraenoic acids (HETEs). LA and ALA are referred to as essential FAs, because human body Polyunsaturated fatty acids (PUFAs) can also be processed by lacks the enzymes for their synthesis. Both LA and ALA are the non-enzymatic oxidation, creating isoprostanes, and isofurans precursors for AA, EPA and DHA, and are of primal biological which also display biological activity (Galano et al., 2015; Roy importance—both FAs must be thus additionally supplemented et al., 2016). in case of enzymatic defects or lack of dietary ALA or LA. Overall, there is a great variety of PUFAs metabolites which In humans, diet remains a primary source of DHA and EPA possess pro- and anti-apoptotic properties, play important roles because the efficacy of transforming ALA to longer n-3 PUFAs in inflammation, modulate the immune responses and probably is low and personally variable (Glaser et al., 2010). EPA and affect many yet unknown processes (Figure 1; Masoodi et al., DHA are mostly found in fish, especially salmon, whereas the 2015). most important source of ALA are seed oils derived from walnuts, chia, perilla, rapeseeds or soybeans. Currently, due to PUFAs in Inflammation the suboptimal total PUFAs consumption in most populations, So far, the role of PUFAs in inflammation has been mainly explained by the action of AA. One of its most important Abbreviations: 2-AG, 2-arachidonoylglycerol; 12-LO, 12-lipooxygenase; 5,6-EET, metabolites are PGs, a heterogenous group of molecules 5,6-epoxyeicosatrienoic acid; 5-LO, 5-lipooxygenase; AA, arachidonic acid; AEA, anandamide; ALA, alpha-linoleic acid; CB, cannabinoid; CD, Crohn‘s disease; produced by COX-1 and COX-2. Their common precursor CIC, chronic idiopathic constipation; CLA, conjugated linoleic acid; CNS, central is prostagandin H2 (PGH2) produced from AA and later nervous system; COX, cyclooxygenase; CRC, colorectal cancer; CSLC, cancer metabolized into downstream metabolites (Félétou et al., 2011). stem like cells; CVD, cardiovascular disease; Cyp450, cytochrome 450; DHA, The main pro-inflammatory one is prostaglandin E2 (PGE2), docosahexaenoic acid; DMPC, dimyristoylphosphatidylcholine; DP, prostaglandin produced in large quantities by macrophages and neutrophils in D2 receptor; DPA, docosapentaenoic acid; DSS, dextran sulfate sodium; EETs, epoxyeicosatrienoic acids; ENS, enteric nervous system; EPA, eicosapentaenoic response to inflammatory stimuli. PGE2 induces fever, increases acid; EPA-FFA, free fatty acid eicosapentaenoic acid; EPIC, European Prospective vascular permeability and vasodilation, and intensifies pain Investigation of Cancer; FA, fatty acid; FAAH, fatty acid amide hydrolase; FAD1, and oedema mediated by other inflammatory factors, such as fatty acid desaturase 1; FAP, familial adenomatous polyposis; FDA, Food and Drug histamine and bradykinin. It also enhances its own synthesis Administration; FGIDs, functional gastrointestinal disorders; GI, gastrointestinal; and induces production of IL-6 in macrophages. Moreover, GRAS, generally recognized as safe; HETEs, hydroxyeicosatetraenoic acids; HT- 29-EP4, HT-29 human CRC cells with EP4 overexpression; IBD, inflammatory PGE2 also plays a role in inducing immune tolerance in the bowel disease; IBS, irritable bowel syndrome; IBS-A, alternating IBS; IBS- intestine, not mediated by IL-10 or T regulatory cells (Stenson, C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; ICAM, 2014). Interestingly, prostaglandin D2 (PGD2), displays a strong, intracellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; LA, purely anti-inflammatory effect (Stenson, 2014) acting through linoleic acid; LOX, lipooxygenase;