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Polyunsaturated fatty acids and inflammatory bowel disease
Abstract
The rationale for supplementation with n-3 fatty acids to promote the health of the gastrointestinal tract lies in the antiinflammatory effects of these lipid compounds. The first evidence of the importance of dietary intake of n-3 polyunsaturated fatty acids was derived from epidemiologic observations of the low incidence of inflammatory bowel disease in Eskimos. The aim of this paper was to briefly review the literature on the use of n-3 fatty acids in inflammatory bowel disease (ulcerative colitis and Crohn disease), the results of which are controversial. The discrepancies between studies may reside in the different study designs used as well as in the various formulations and dosages used, some of which may lead to a high incidence of side effects. Choosing a formulation that lowers the incidence of side effects, selecting patients carefully, and paying strict attention to experimental design are critical when investigating further the therapeutic potential of these lipids in inflammatory bowel disease.
... The advantage of polyunsaturated fatty acids (PUFAs) intake in IBD was elucidated by epidemiologic studies in Eskimos [137] and by lower levels of PUFAs in patients' sera [138] . Although, data are conflicting, most of the studies support the efficiency of PUFAs in IBD [137] . ...
... The advantage of polyunsaturated fatty acids (PUFAs) intake in IBD was elucidated by epidemiologic studies in Eskimos [137] and by lower levels of PUFAs in patients' sera [138] . Although, data are conflicting, most of the studies support the efficiency of PUFAs in IBD [137] . PUFAs are able to attenuate inflammation, as in IBD, by altering the production of eicosanoids and COX-2, and by modulating PPAR-γ and NF-κB [139][140][141][142][143] . ...
Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.
... [8] Omega-3 fatty acids in Fish oil are one of the most important polyunsaturated fatty acids (PUFA) that have an anti-inflammatory and an antioxidant activity. [10,11] The dietary intake of Omega-3 (PUFA) could be useful in prevention of diabetes; as it reduced the activity of the pro-inflammatory processes which stimulated the body to attack its own insulin-producing cells. [12,13] Dietary intake of long chain omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protects against heart disease. ...
... In spite of that, some other myofibrils were similar to the control, contained regular pattern of Z line. Mitochondria, were of variable sizes and shapes, even some of them were hugely enlarged formed what is called megamitochondria, some mitochondria were swollen, mitochondrial cristae could not be seen, these mitochondria were arranged in an irregular manner fig (11,12). ...
ABSTRACT
Introduction: Cardiovascular disease is responsible for about 80% of deaths among diabetic patients. Scientific
evidence revealed that a diet rich in long chain omega -3 fatty acids help in the development of healthy brain, heart
and immune system. Aim of work: The current study was designed to investigate the biochemical, histological and
ultrastructural changes occurring in the diabetic heart of albino rats induced by streptozotocin (STZ) and the
possible protective role of the omega-3 fatty acids. Materials and Methods: Forty five adult male albino rats were
used in this study. The animals were divided into four groups, each group including 10 male rats except the group I
was 15 rats. Group I (control group), Group II (Omega-3 group): was given daily oral dose of 54mg/ rat omega
-3 fatty acids dissolved in corn oil. Group III (Diabetic group): this group was given single intraperitoneal
injection of streptozotocin (STZ), the dose was 60mg/kg. Group IV (Diabetic and Omega-3 group): in this group
the rats were given both omega-3 fatty acids and STZ. The experiment continued for 6 weeks, then blood samples
were collected for blood glucose level, creatine kinase-MB (CK-MB) and troponin-I estimation and statistical
study was also done. Heart specimens were processed for light and electron microscopic study. Result: Light
microscopic results of Group I and II showed the usual histological architecture of the myocardium. Group III
showed discontinuous, widely spaced cardiomyocytes, vascular congestion and mononuclear cellular infiltration.
Ultrastructural results showed discontinuous broken myofibril, mitochondria swollen of variable shapes and sizes.
The blood glucose, CK-MB and troponin-I were significantly increased. Administration of omega-3 fatty acids to
the diabetic rats (group IV) ameliorates the previous changes. Conclusion: Omega-3 fatty acids administration can
protect the heart in cases of diabetic cardiomyopathy.
KEYWORDS: cardiomyopathy, STZ, omega -3 fatty acids, diabetes.
... Currently the health-promoting effects of -3 PUFAs are controversial, which is a major barrier to implement -3 PUFAs for disease prevention. For example, in terms of colon inflammation and colon cancer, substantial epidemiological and pre-clinical studies support that -3 PUFAs reduce the risks of colon inflammation [1][2][3] and colon cancer [4][5][6][7][8][9]. However, there are inconsistent results from animal and human studies, which showed that -3 PUFAs had no effect [10,11] or detrimental effects [12,13]. ...
... Substantial epidemiological and pre-clinical studies support that -3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA, 20:5-3) and docosahexaenoic acid (DHA, 22:6-3), have beneficial effects in many human diseases. For example, many studies have shown that increased dietary intake of -3 PUFAs is correlated with reduced risks of colon inflammation [1][2][3] and colon cancer [4][5][6][7][8][9]. On the other hand, there are inconsistent results which showed that -3 PUFAs have no effect [10,11] or even detrimental effects [12,13]. ...
The ω-3 polyunsaturated fatty acids (PUFAs) are among the most popular dietary supplements in the US, but they are chemically unstable and highly prone to lipid peroxidation. Many studies performed in different countries demonstrate that the majority of ω-3 PUFA products on the market are oxidized, suggesting that the resulting ω-3 PUFA peroxidation-derived compounds could be widely consumed by the general public. Therefore, it is of practical importance to understand the effects of these oxidized lipid compounds on human health. In this review, we summarize and discuss the chemical structures and biological activities of ω-3 PUFA peroxidation-derived compounds, and emphasize the importance to better understand the role of lipid peroxidation in biological activities of ω-3 PUFAs.
... NF-kB is a pro-inflammatory transcription factor produced under altered epithelial permeability barrier conditions, including IBD [60]. Thus, v3-PUFAs can inhibit IL-1b and TNF-a production [61], and act as free radical scavengers [62,63]. ...
... In the case of PGE 2 , its biosynthesis is inhibited by v3-PUFAs as they avoid the conversion of arachidonic acid (an v6-PUFA) toward pro-inflammatory PGs and LTs. EPA and DHA can replace arachidonic acid and inhibit pro-inflammatory mediators production, including that of LTB 4 and thromboxanes (TX), which are elevated in the inflamed intestinal mucosa [62]. TXA 2 may be especially important since it modulates platelet aggregation, and gastrointestinal infarctions have been suggested as one of the first pathogenic steps in CD [64]. ...
Inflammatory bowel diseases (ulcerative colitis; Crohn's disease) are debilitating relapsing inflammatory disorders affecting the gastrointestinal tract, with deleterious effect on quality of life, and increasing incidence and prevalence. Mucosal inflammation, due to altered microbiota, increased intestinal permeability and immune system dysfunction underlies the symptoms and may be caused in susceptible individuals by different factors (or a combination of them), including dietary habits and components. In this review we describe the influence of the Western diet, obesity, and different nutraceuticals/functional foods (bioactive peptides, phytochemicals, omega 3-polyunsaturated fatty acids, vitamin D, probiotics and prebiotics) on the course of IBD, and provide some hints that could be useful for nutritional guidance. Hopefully, research will soon offer enough reliable data to slow down the spread of the disease and to make diet a cornerstone in IBD therapy.
... The typical Western-style diet has a high n-6/n-3 ratio of approximately 10-15:1 [114]. The increase in dietary n-6/n-3 PUFAs was positively correlated with the increased incidence of IBD [115] (Figure 2). John et al. [116] suggested that increasing the consumption of n-3 PUFAs may help prevent UC. ...
The interactions among diet, intestinal immunity, and microbiota are complex and play contradictory roles in inflammatory bowel disease (IBD). An increasing number of studies has shed light on this field. The intestinal immune balance is disrupted by a high-fat diet (HFD) in several ways, such as impairing the intestinal barrier, influencing immune cells, and altering the gut microbiota. In contrast, a rational diet is thought to maintain intestinal immunity by regulating gut microbiota. In this review, we emphasize the crucial contributions made by an HFD to the gut immune system and microbiota.
... Nevertheless, clinical trials evaluating the impact of supplementation and n-3-rich diets on the development of IBD are still quite controversial and conflicting, especially in Crohn's disease (CD), due to the lack of standardization of cohorts, choice of placebos, and therapies (dosages and duration) adopted. In general, they show a discreet beneficial association between the use of n-3 PUFAs and the development of IBD, with reduced disease activity and improvement of quality of life[73, [81][82][83]. ...
The resolution of inflammation is an active process, guided by specialized pro-resolution lipid mediators (SPMs). These mediators originate from polyunsaturated fatty acids, such as omega-3. Sufficient evidence suggests that the beneficial effects attributed to omega-3 are, at least in part, the result of the immunomodulatory action of the SPMs, which act systemically by overcoming inflammation and repairing tissue damage, without suppressing the immune response. Recent studies suggest that an imbalance in the synthesis and/or activity of these compounds may be associated with the pathogenesis of several inflammatory conditions, such as inflammatory bowel disease (IBD). Thus, this review highlights the advances made in recent years with regard to the endo-genous synthesis and the biological role of lipoxins, resolvins, protectins, and maresins, as well as their precursors, in the regulation of inflammation; and provides an update on the participation of these mediators in the development and evolution of IBD and the therapeutic approaches that these immunomodulating substances are involved in this context.
... The first evidence of the possible therapeutic value of ω−3 PUFA dietary intake came from epidemiological observations reporting a low incidence of IBD in Eskimos, which was explained based on the more balanced ratio of ω−6:ω−3 PUFA of 3-4:1 compared to the 15-20:1 ratio typical of some Western diets (Belluzzi et al., 2000). Experimentally, inflammation in the colonic mucosa is attenuated by fish oil or ω−3 PUFA supplementation (Bosco et al., 2013;Cho, Chi, & Chun, 2011;Whiting, Bland, & Tarlton, 2005;Zhao et al., 2017) via several molecular mechanisms including inhibition of proinflammatory mediators such as eicosanoids and cytokines, downregulation of iNOS and COX-2, and inhibition of NF-kB (Gil, 2002;Hudert et al., 2006;Yates et al., 2014;Zhao et al., 2015). ...
Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.
... Specific IBD diets may be helpful to defined groups of patients, however, given this disease's heterogeneity and the risk of weight loss and malnutrition, there is no one-size-fits-all diet for these patients. Supplementation with unsaturated fatty acids to decrease inflammation in gastrointestinal diseases has been based on epidemiologic observations, mainly in IBD [48]. Dietary nutrients are the most common luminal antigens in the bowel and may influence intestinal inflammation. ...
Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder characterized by chronic intestinal inflammation. The etiology of IBD is still unclear, although genetic, environmental and host factors have been associated to the disease. Extra-virgin olive oil (EVO) is a central component of the Mediterranean diet and it decreases chronic inflammation by interfering with arachidonic acid and NF-κB signaling pathways. Specifically, the different components of EVO are able to confer advantages in terms of health in their site of action. For instance, oleic acid displays a protective effect in liver dysfunction and gut inflammation, whereas phenolic compounds protect colon cells against oxidative damage and improve the symptoms of chronic inflammation in IBD. Given the biological properties of EVO, we investigated whether its administration is able to confer protection in a mouse model of dextrane sodium sulfate (DSS)-induced colitis. Four EVO cultivars from the Apulian Region of Italy, namely Ogliarola (Cima di Bitonto), Coratina, Peranzana and Cima di Mola, respectively, were used. Administration of EVO resulted in reduced body weight loss in our colitis model. Furthermore, mice treated with Ogliarola, Coratina and Cima di Mola EVO displayed a reduction of rectal bleeding and IL-1β, TGFβ, IL-6 gene expression levels. Furthermore, Ogliarola, Coratina and Peranzana EVO administration ameliorated intestinal permeability and histopathological features of inflammation. Our data further validate the well-known positive effects of EVO supplementation in promoting human health and suggest the bona fide contribution of EVO in preventing onset and reducing progression of intestinal inflammation.
... Most genes have the same regulatory relationship in UC and CD, but a small number of genes have different expressions. This also verifies that these two (Yanai et al., 1999) hsa00190 Oxidative phosphorylation (Soderholm et al., 2000;Söderholm et al., 2002) hsa00531 Glycosaminoglycan degradation (Lee et al., 2008b) hsa00730 Thiamine metabolism (Mehanna et al., 2008) hsa00860 Porphyrin and chlorophyll metabolism (Jansson et al., 2009) hsa04012 ErbB signaling pathway (Ando et al., 2013) hsa04340 Hedgehog signaling pathway (Ghorpade et al., 2013) hsa04920 Adipocytokine signaling pathway (Karmiris et al., 2006) hsa00062 Fatty acid elongation (Belluzzi et al., 2000) hsa00020 Citrate cycle (TCA cycle) (Schicho et al., 2012) types of diseases are very similar, but there are differences between them. Furthermore, we have visualized samples using the two principal components of our PASS features and overlaid the classification results from PASS model (Figure 4). ...
Since similar complex diseases are much alike in clinical symptoms, patients are easily misdiagnosed and mistreated. It is crucial to accurately predict the disease status and identify markers with high sensitivity and specificity for classifying similar complex diseases. Many approaches incorporating network information have been put forward to predict outcomes, but they are not robust because of their low reproducibility. Several pathway-based methods are robust and functionally interpretable. However, few methods characterize the disease-specific states of single samples from the perspective of pathways. In this study, we propose a novel framework, Pathway Activation for Single Sample (PASS), which utilizes the pathway information in a single sample way to better recognize the differences between two similar complex diseases. PASS can mainly be divided into two parts: for each pathway, the extent of perturbation of edges and the statistic difference of genes caused by a single disease sample are quantified; then, a novel method, named as an AUCpath, is applied to evaluate the pathway activation for single samples from the perspective of genes and their interactions. We have applied PASS to two main types of inflammatory bowel disease (IBD) and widely verified the characteristics of PASS. For a new patient, PASS features can be used as the indicators or potential pathway biomarkers to precisely diagnose complex diseases, discover significant features with interpretability and explore changes in the biological mechanisms of diseases.
... Our group has previously reported that eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid (PUFA) mainly found in fish oil, was able to attenuate the inhibitory effects of pathologic levels of TNF-α on skeletal muscle cell differentiation [3]. EPA has been found to reduce symptoms in chronic inflammatory diseases, for example, rheumatoid arthritis [4] and inflammatory bowel disease [5], and has reported health benefits for chronic diseases such as cardiovascular disease, cancer and insulin resistance [6], where there is significant elevation of proinflammatory cytokines. It has been suggested that blocking the actions or production of proinflammatory mediators is one beneficial effect of ω-3 PUFAs [7]. ...
... [17][18][19][20][21][22][23] Omega-3 fatty acids (x-3) are a family of polyunsaturated fatty acids, with the three most important ones being alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). [24] In particular, x-3 from fish oil have been investigated in clinical and preclinical studies, with results showing that they may modulate inflammatory and immune functions [25] thus, contribute to reducing the inflammatory pain associated with rheumatoid arthritis, [26] neuromuscular pain, [27] inflammatory bowel disease, [28] dysmenorrhoea. [29] and through modulation of central µ-opioid receptors in diabetic neuropathy. ...
Objective
The aim of this work was to assess the preventive effect of an eicosapentaenoic acid/docosahexaenoic acid‐concentrate fish oil on neuropathic pain development and regenerative features of sciatic nerve in rats.
Methods
In the present study, rats with chronic constriction injury (CCI) of the sciatic nerve and sham‐operated ones received fish oil enriched in omega‐3 fatty acids (0.36 or 0.72 g/kg per day, oral) or saline solution for 21 days, with thermal hyperalgesia and mechanical allodynia being assessed before and 3, 7, 14 and 21 days after injury.
Key findings
Fish oil enriched in omega‐3 fatty acids (0.72 g/kg) reversed thermal hyperalgesia and significantly reduced mechanical allodynia. In addition, ω‐3 treatment (0.72 g/kg) promoted the recovery of the Sciatic Functional Index as well as restored axonal density and morphology, without the formation of neuroma in the injured sciatic nerves after 21 days.
Conclusion
We conclude that the fish oil enriched in omega‐3 fatty acids administration relieves thermal hyperalgesia and mechanical allodynia effectively and also enhances the recovery process in rats with CCI of the sciatic nerve. These findings might contribute to new therapeutic approaches including omega‐3 fatty acids in neuropathic pain treatment.
... Fish oil supplementation has been reported to be generally beneficial in autoimmune, inflammatory and cardiovascular disorders (Guo et al., 2018;. A growing number of dietary supplementation studies using healthy human subjects as well as animal disease models have clearly shown that long chain n-3 polyunsaturated fatty acids (PUFA) found in fish oil, are capable of modulating critical determinants which link infectious disease, inflammation and neurodegenerative disease (Che, Li, et al., 2018;Che, Zhou, et al., 2018a, 2018b, especially, EPA (20: 5) and docosahexaenoic acid (DHA; 22: 6) (Belluzzi, Boschi, Brignola, & Miglio, 2000;Bouwens et al., 2009;Davidson et al., 2004;Hudert et al., 2006;Prescott & Stenson, 2005). N-3 PUFA are also known to be beneficial in the treatment of several types of diseases, including cancers of mammary, lung and colonic and Parkinson's disease (Biondo, Brindley, Sawyer, & Field, 2008;Schley, Jijon, Robinson, & Field, 2005;Wang et al., 2018). ...
Eicosapentaenoic acid (EPA) has been known to induce human ovarian cancer cells apoptosis in vitro. However, the anti-tumor mechanisms of EPA in vivo have been rarely reported. In this study, the effect of EPA on the ovarian cancer rat model and its related mechanism were investigated. The results showed after EPA treatment, the index of spleens and thymus was significantly increased, and the proliferation of spleen cells, the natural killer (NK) cell activity and phagocytosis activity of macrophages were prompted. Besides, EPA could reverse the decrease of CD4+ and CD8+ T lymphocytes induced by ovarian cancer. It was found that EPA could inhibit the phosphorylation status of PI3K (phosphatidylinositol 3-hydroxy kinase)/Akt (serine-threonine kinase), ERK1/2 (extracellular signal-regulated kinase 1/2) and NF-κB p65, and prompt the expression of cytochrome C and caspase-3. These results suggested that EPA has a remarkable anti-tumor activity by improving the immunomodulatory on the ovarian cancer rat model.
... Meta-analyses revealed a low incidence of IBD in eskimos, whose diet is particularly rich in n-3 PUFAs [134]. Starting from these clinical evidences, the impact of dietary n-3 PUFAs has been evaluated in different models of colitis. ...
Studies over several decades have documented the beneficial actions of n-3 polyunsaturated fatty acids (PUFAs), which are plentiful in fish oil, in different disease states. Mechanisms responsible for the efficacy of n-3 PUFAs include: (1) Reduction of triglyceride levels; (2) anti-arrhythmic and antithrombotic effects, and (3) resolution of inflammatory processes. The human microbiota project and subsequent studies using next-generation sequencing technology have highlighted that thousands of different microbial species are present in the human gut, and that there has been a significant variability of taxa in the microbiota composition among people. Several factors (gestational age, mode of delivery, diet, sanitation and antibiotic treatment) influence the bacterial community in the human gastrointestinal tract, and among these diet habits play a crucial role. The disturbances in the gut microbiota composition, i.e., gut dysbiosis, have been associated with diseases ranging from localized gastrointestinal disorders to neurologic, respiratory, metabolic, ocular, and cardiovascular illnesses. Many studies have been published about the effects of probiotics and prebiotics on the gut microbiota/microbioma. On the contrary, PUFAs in the gut microbiota have been less well defined. However, experimental studies suggested that gut microbiota, n-3 PUFAs, and host immune cells work together to ensure the intestinal wall integrity. This review discussed current evidence concerning the links among gut microbiota, n-3 PUFAs intake, and human inflammatory disease.
... The functional relationship between PUFAs and pain has been the subject of many studies (8). Both basic and clinical studies have revealed that a dietary intake of n-3 series PUFAs results in a reduction in pain associated with rheumatoid arthritis (9,10), dysmenorrhea (11), inflammatory bowel disease (12), and neuropathy (13), whereas n-6 series PUFAs are high in abundance in patients with chronic pain, including patients with IBS (4,14,15). The n-3 PUFA metabolites, such as resolvins (Rvs), are analgesic in multiple pain models, an effect attributed to inhibition of certain transient receptor potential (TRP) channels (16). ...
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca ²⁺ imaging of dorsal root ganglion (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)–positive DRG neurons through a phospholipase C (PLC)– and pertussis toxin–dependent mechanism, suggesting that the effect was mediated by a G protein–coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C.
... [17][18][19][20][21][22][23] Omega-3 fatty acids (x-3) are a family of polyunsaturated fatty acids, with the three most important ones being alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). [24] In particular, x-3 from fish oil have been investigated in clinical and preclinical studies, with results showing that they may modulate inflammatory and immune functions [25] thus, contribute to reducing the inflammatory pain associated with rheumatoid arthritis, [26] neuromuscular pain, [27] inflammatory bowel disease, [28] dysmenorrhoea. [29] and through modulation of central µ-opioid receptors in diabetic neuropathy. ...
Neuropathic pain is associated with injury to the central or peripheral nervous system, and is con-sidered to be particularly difficult to treat because of its diverse etiology and the underlying patho-physiological mechanism. In the clinical practice, in less than 50% of the cases the pain relief issatisfactorily achieved using the indicated treatment. The aim of the present work was to study thepotential analgesic effect of fatty acids in neuropathic pain, by evaluating this treatment in an animalmodel of sciatic nerve ligation (SNL) in rats and describing the histopathological findings.The male Wistar rats (200-250 g) used in this study were obtained from UNLaR. For the SNL model,four ligatures of 4.0 chromic cat-gut were loosely tied around the sciatic nerve (SN). The animalswere randomized and placed in two groups (6 rats/group) with sciatic nerve injury; they receivedoral saline solution (control group) or omega-3 fatty acids (DHA and EPA) (720 mg/kg/day) (ome-ga-3 group) for 21 days. The hot plate test was used as the animal model of pain, and the level ofpain was assessed on days 3 and 5 pre-surgery and on days 3, 7, 14 and 21 post-surgery. After 21days postoperatively, the animals were sacrificed using a carbon dioxide chamber. SN dissectionwas performed using cross section cuts for histopathologic analysis. For statistical analysis, theanalysis of variance, ANOVA, and post-hoc comparisons using Fisher test were used.The time course analysis of the pre- and post-surgical pain in the Hot Plate Test showed that oraladministration of omega-3 produced a significantly higher analgesic effect than the control group7 days after surgery. Histopathological changes such as disorder, compression and clustering ofSchwann cells, a slightly thickened perineurium, and infiltrated inflammatory mononuclear and multi-nucleated giant cells were observed, which may have been related to the phenomenon of cell repair.Analgesic effect and histopathological changes were observed after treatment with omega-3 fattyacids for this model of neuropathic pain, which may constitute a new pharmacological tool for dea-ling with this type of pain.
... Many studies support that ω-3 PUFAs reduce the risks of colon inflammation [29][30][31] and colon cancer [2][3][4][5][6][7]. However, there are inconsistent results from animal and human studies, which showed that ω-3 PUFAs had no effect [32,33] or detrimental effects [34,35], making it difficult to implement ω-3 PUFAs for disease prevention. ...
Many studies have shown that dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) reduces the risks of colorectal cancer, however the underlying mechanisms are not well understood. Here we used a LC-MS/MS-based lipidomics to explore the roles of eicosanoid signaling in the anti-colorectal cancer effects of ω-3 PUFAs. Our results showed that dietary feeding of ω-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor, and modulated profiles of fatty acids and eicosanoid metabolites in C57BL/6 mice. Notably, we found that dietary feeding of ω-3 PUFAs significantly increased levels of epoxydocosapentaenoic acids (EDPs, metabolites of ω-3 PUFA produced by cytochrome P450 enzymes) in plasma and tumor tissue of the treated mice. We further showed that systematic treatment with EDPs (dose = 0.5 mg/kg/day) suppressed MC38 tumor growth in mice, with reduced expressions of pro-oncogenic genes such as c-myc, Axin2, and C-jun in tumor tissues. Together, these results support that
formation of EDPs might contribute to the anti-colorectal cancer effects of ω-3 PUFAs.
... Several experimental and clinical studies have demonstrated that ALA reduces total cholesterol [15], coronary heart diseases [16] and colon cancer [17]. The lignan constituents of flaxseed (but not its oil) possesses in vitro antioxidant and possible estrogen receptor agonist/antagonist properties, prompting hypotheses on its utility in the treatment of breast cancer [18], prostate cancer [19], inflammatory bowel disease [20], lupus nephritis [21], and type 2 diabetes [22]. ...
The anti-ulcer activity of the oil and mucilage obtained from flaxseed (Linum usitatissimum) was evaluated in a rat model of ethanol-induced gastric ulcer. Our results show that pretreatment of rats with flaxseed oil and flaxseed mucilage significantly reduced the number and length of gastric ulcers induced by ethanol. Flaxseed oil was more effective than flaxseed mucilage in reducing the number of ulcers. The reduction in ulcer severity (cumulative length in mm) provided by an oral dose of flaxseed oil (5 ml/kg) was more prominent than that obtained by ranitidine (50 mg/kg). This study indicates that both flaxseed oil and flaxseed mucilage can provide a cytoprotective effect against ethanol-induced gastric ulcers in rats.
... Eikosanoat adalah zat/agen biologis yang dapat mengontrol seluruh sistem hormon di dalam tubuh dan juga mengontrol seluruh fungsi fisiologis yang vital seperti sistem kardiovaskuler, sistem imun, sistem syaraf pusat, sistem reproduksi, dan lainnya. Kelebihan atau kekurangan asam eikosanoat akan berdampak pada peradangan di dalam tubuh dan semua fungsi sel tubuh (Belluzzi et al., 2000;Anon., 2010b). Oleh sebab itu, keseimbangan antara asam lemak -3 dan asam lemak -6 sangat penting untuk pengontrolan aktivitas yang bertentangan tersebut. ...
Lepidocybium flavobrunneumis a pelagic fish with high economical value. Its high price isdue to its nutritional contents that comprise of high unsaturated and low saturated fatty acids. It isreported that the total contents of Saturated Fatty Acids (SFA) in Lepidocybium flavobrunneumisonly 2.9%, while the amount of Unsaturated Fatty Acids are 97.06% that consist of 8.32% ofpolyunsaturated (PUFA) and 88.74% of Monounsaturated Fatty Acids (MUFA). Approximately,0.05% of linolenic acids -3 (C18:3), 0.51% of eicosatrienoic acids -3 (C20:3) and 1.98% ofdocosahexanoic acids -3 (C22:6) comprise the PUFAs; whereas the MUFAs is composed by84.71% of oleic acids -9 (C18:1) and 0.27% of nervonoic acids -9 (C24:1). -6in Lepidocybiumflavobrunneum contains 0.46% of linoleic acids -6 (C18:2), 0.72% of arachidonic acids -6(C20:4) and 0.01% of lauric acids (C20:0).
... The mechanism by which fatty acids influence IBD is not fully understood, but it has been suggested that n-6 PUFA promote pro-inflammatory cytokines via metabolism of AA [19,20]. In addition, n-3 PUFA have anti-inflammatory properties including displacement of AA from the cell membrane with resultant decreased derivatives, altered cell membrane fluidity and protein binding capability, and inhibition of NF-κB and its nuclear targets [21]. ...
Background and aims:
Ulcerative colitis (UC) is associated with increased dietary intake of fat and n-6 polyunsaturated fatty acids (PUFA). Modification of fat metabolism may alter inflammation and disease severity. Our aim was to assess differences in dietary and serum fatty acid levels between control and UC subjects and associations with disease activity and inflammatory cytokines.
Methods:
Dietary histories, serum, and colonic tissue samples were prospectively collected from 137 UC subjects and 38 controls. Both histologic injury and the Mayo Disease Activity Index were assessed. Serum and tissue cytokines were measured by Luminex assay. Serum fatty acids were obtained by gas chromatography.
Results:
UC subjects had increased total fat and oleic acid (OA) intake, but decreased arachidonic acid (AA) intake vs controls. In serum, there was less percent saturated fatty acid (SFA) and AA, with higher monounsaturated fatty acids (MUFA), linoleic acid, OA, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA) in UC. Tissue cytokine levels were directly correlated with SFA and inversely correlated with PUFA, EPA, and DPA in UC subjects, but not controls. 5-aminosalicylic acid therapy blunted these associations.
Conclusions:
In summary, we found differences in serum fatty acids in UC subjects that correlated with pro-inflammatory tissue cytokines. We propose that fatty acids may affect cytokine production and thus be immunomodulatory in UC.
... Although reviews of trials of fish oil in inflammatory bowel diseases have frequently concluded that there is some benefit from fish oil in inflammatory bowel diseases [134][135][136][137][138], meta-analyses do not reach this conclusion. A meta-analysis identified 13 studies of fish oil supplementation in inflammatory bowel diseases (i.e., both ulcerative colitis and Crohn's disease) reporting outcomes related to clinical score, sigmoidoscope score, gut mucosal histology score, induced remission, and relapse, but concluded that that there were sufficient data to perform meta-analysis only for relapse and only for ulcerative colitis [139]. ...
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn’s disease, is a chronic relapsing intestinal inflammatory disorder of the gastrointestinal tract. IBD is occurring with increasing frequency among Western populations and is emerging in countries that have traditionally had a low prevalence of the component diseases. IBD is a multifactorial, heterogeneous disease that occurs in genetically susceptible individuals in response to environmental and immunological factors associated with a dysregulated intestinal mucosal immunological response. The increase in incidence of IBD parallels the increase in dietary intake of omega-6 (n-6) polyunsaturated fatty acids and the change in balance of intake of n-6 to n-3 fatty acids. Experimental data suggest that high intake of n-6 fatty acids may contribute to the development and severity of IBD through increased synthesis and membrane incorporation of arachidonic acid (ARA) with the accompanying production of pro-inflammatory mediators, and increased oxidative stress in n-6 fatty acid rich membranes. Conversely, the n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid (DHA) partly replace ARA in cell membranes and are metabolized to weaker pro-inflammatory eicosanoids and to strong pro-resolving mediators with roles in inflammation cessation. Consequently, high dietary n-6 fatty acid intake and high n-6–n-3 fatty acid ratios may be an important environmental modifier that contributes to the development of IBD in genetically susceptible individuals, while increased intake of n-3 fatty acids may lower risk of IBD and could be therapeutic.
... Tem como principal função produzir eicosanoides, leucotrienos e tromboxanos, que promovem diminuição da ação dos leucócitos e das citocinas inflamatórias TNF-α e interleucina-1, com ação antioxidante e anti-inflamatória. 63 No artigo de revisão de Belluzzi et al. 64 , observou-se que o w-3 estava associado com a diminuição de leucotrieno e de tromboxano, além da inibição de IL-1b, TNF-α e radicais livres, evitando a recidiva inflamatória na DC e na RCUI. Porém, os autores alertam que são necessários novos estudos devido às diferenças encontradas nos desenhos dos trabalhos avaliados, nas formulações do w-3, nas doses administradas e nos efeitos colaterais. ...
... Der therapeutische Einsatz von PUFA wird auch bei entzündlichen Darmerkrankungen wie Colitis ulcerosa und Morbus Crohn diskutiert [37]. In einer kleinen Doppelblindstudie mit Colitis-Patienten (n=42) bewirkte Nachtkerzenöl einen Anstieg der erythrozytären Dihomogamma-Linolensäure (DGLA) und eine Besserung der Stuhlkonsistenz, nicht aber der anderen klinischen, endoskopischen oder histologischen Kriterien. ...
Background: Polyunsaturated fatty acids (PUFAs) are an important component of practically all lipids and are therefore components of cellular fat stores and the structural building blocks of the cell membrane. Objective: To draw up a position paper for PUFA. Methods: Systematic analysis and rating of human studies (prospective double-blind studies, epidemiologic and retrospective studies, short period biochemical/haematological studies ("surrogate markers") of the last 10 years from major data bases, coupled to information in standard works and published monographs. Results and Conclusions: Two polyunsaturated fatty acids, linoleic acid and alpha-linolenic acid, are essential for man. The various PUFAs are contained in various oils, particularly fish oils. n-3 PUFAs from fish oils must be combined with antioxidants, to stabilise them and to maintain their activity. The probability of inadequate PUFA supply is greatest in people with raised requirements, for example, during infections, chronic disease or in phases of growth. German, Austrian and Swiss nutritional societies have expressed the opinion that the ratio of alpha-linolenic acid (n-3) to linoleic acid (n-6) should be raised to at least 1:5, to optimise preventive activity. PUFAs have favourable effects on various organs systems and in different diseases: skin diseases, coronary heart disease, obstructive lung disease and recurrent infection, and they reduce postoperative morbidity due to infection. Alpha-linolenic acid offers practical advantages in comparison with fish oil preparations. Unpleasant belching is reduced and only low levels of stabilisers (antioxidants) are needed in the formulation.
... In einer anderen Studie zeigte sich unter einer DHA/EPA-Therapie eine klinische Besserung bei Patienten mit distaler Proktokolitis [23]. Eine Zusammenfassung verschiedener Studien bei chronisch entzündlichen Darmerkrankungen zeigt Tabelle 2, Abbildung 3) [24,25]. ...
Background: Docosahexaenoic acid (DHA) is an end product formed from the omega-3 fatty acids derived from alpha-linolenic acid. DHA has various important functions in the organism. Objective: To conduct a systematic review of the clinical significance of long chain omega-3 fatty acids for inflammatory and other diseases. Methods: Systematic analysis and evaluation of human studies - including prospective double blind studies, epidemiological and retrospective studies, short term biochemical and haematological studies with surrogate markers - performed in the last 10 years and found in the major electronic databases, coupled to information in standard works and published monographs. Results and Conclusions: Relatively high doses of DHA or long chain omega-3 fatty acids (more than 3g daily) administered as adjuvant to patients with rheumatoid arthritis can reduce the incidence of painful joints and morning stiffness. With the exception of possible maintenance of cognitive function or protection against Alzheimer's disease, there have been no convincing studies on neuropsychiatric indications. In vitro and animal studies indicate that omega-3 fatty acids can probably inhibit tumour growth. If an adequate supply of DHA and long chain omega-3 fatty acids in food is not guaranteed, supplements can be used. Diabetics and patients on anticoagulants should only take supplements of omega-3 fatty acids with the agreement of their doctors.
... As for the use of nutrients for disease treatment, it was observed that zinc (Zn) supplements (in the form of 110 mg Zn sulfate three times per day for 8 weeks) could ameliorate the alteration of small intestine permeability in 12 patients with quiescent Crohn's disease (Sturniolo et al., 2001). Supplementation with omega-3 PUFA may be also useful due to their anti-inflammatory effects, as shown with supplements of 3 g d -1 EPA plus 5 g d -1 DHA (Belluzzi et al., 2000). Other authors have suggested a role for probiotics in the intestinal microbiota balance in Crohn's disease, although more studies are required (see "Further Reading"). ...
... Omega-3 FA are a form of essential polyunsaturated fat, the most nutritionally notable being alpha-linolenic acid (C18:3 cis-9, cis-12, cis-15; ALA) in milk and cheese products. Biomedical studies with animal models have evidenced several profitable properties (anticarcinogenic, antiatherogenic, antioxidant, antiobesity, antidiabetic, etc) attributed to CLA [4,5], omega-3 [6,7], and other FA, which have been related to human health because of their unsaturated nature [8,9]. In addition, the relationship among FA in the final product is also important. ...
A total of 30 Zamorano-type cheeses were manufactured in order to study the effects of milk conjugated linoleic acid (CLA) content, ripening time, and interactions between both effects on fatty acid (FA) profile. Cheeses elaborated from milk with a high CLA content showed higher contents of vaccenic, oleic, alpha-linolenic (ALA), CLA, monounsaturated (MUFA) and polyunsaturated (PUFA) FA, and lower contents of capric, lauric, myristic, palmitic, estearic, linoleic, and saturated (SFA) FA than cheese from milk with a low CLA content. Content of unsaturated C18 FA along with MUFA and PUFA groups increased throughout the ripening, while SFA content decreased. The interactions between milk CLA content and ripening time were significant for palmitic, linoleic, CLA, SFA, and omega-6/omega-3 ratio in Zamorano-type cheese. Decreases in cheese omega-6/omega-3 ratio were obtained from milk with a high CLA content; this ratio worsened over ripening in cheeses from low-CLA milk. In conclusion, these results emphasize the importance of the initial CLA content in milk with regard to improve the lipid profile in cheese for consumption.
Inflammation is an essential component of the host defense system, but uncontrolled chronic low-grade inflammation is believed to play a central role in many chronic pathologies including auto-immune diseases (e.g., rheumatoid arthritis), inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), and neurodegenerative diseases (e.g., Alzheimer's disease). Dietary essential fatty acids are precursors of inflammatory mediators, with n-6 and marine n-3 polyunsaturated fatty acids (PUFAs) possessing pro-inflammatory and antiinflammatory properties, respectively. Marine n-3 PUFAs (e.g., DHA and EPA), especially EPA, competitively inhibit the production of prostaglandins and leukotrienes from AA by competing for the same enzymatic pathway and also act as precursors of less potent pro-inflammatory mediators. Additionally, antiinflammatory activity of marine n-3 PUFAs includes reduction in the production of cytokines such as IL-1β, IL-6 and TNF-α, reduction in the expression of adhesion molecules on immune cells, reduction in T-cell proliferation and resolving inflammation through metabolites acting as specialized pro-resolving mediators. Therefore, marine n-3 PUFAs are believed to be potentially therapeutic candidates targeting resolution of inflammation for preventing and treating a variety of chronic inflammatory diseases, including rheumatoid arthritis, inflammatory bowel diseases, and Alzheimer's disease. Although in vitro and animal experiments consistently demonstrated promising effects of marine n-3 PUFAs on inflammation resolution and alleviation of inflammation related diseases, clinical trials of n-3 PUFAs in inflammatory bowel diseases and Alzheimer's disease did not provide enough robust evidence yet to support the therapeutic use of marine n-3 PUFAs.
Scope: The proliferation and differentiation of intestinal stem cells (ISCs) are the basis of intestinal renewal and regeneration, and gut microbiota plays an important role in it. Dietary nutrition has the effect of regulating the activity of ISCs, however, the regulation effect of α-linolenic acid (ALA) has seldom been reported.
Methods and results: After intervening mice with different doses of ALA for 30 days, we found that ALA (0.5 g/kg) promoted small intestinal and villus growth by activating the Wnt/β-catenin signaling pathway to stimulate the proliferation of ISCs. Furthermore, ALA administration increased the abundance of the Ruminococcaceae and Prevotellaceae, and promoted the produce of short-chain fatty acids (SCFAs). Subsequent fecal transplantation and antibiotic experiments demonstrated that ALA on the proliferation of ISCs are gut microbiota dependent, among them the functional microorganism may be derived from Ruminococcaceae. Administration of isobutyrate showed a similar effect to ALA in terms of promoting ISCs proliferation. Furthermore, ALA mitigated 5-fluorouracil-induced intestinal mucosal damage by promoting ISCs proliferation.
Conclusion: These results indicate that SCFAs produced by Ruminococcaceae mediates ALA promote ISCs proliferation by activating Wnt/β-catenin signaling pathway, and suggest the possibility of ALA as a prebiotic agent for the prevention and treatment of intestinal mucositis.
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Nutrition is one of the main determinants of human health. Functional foods can help reduce the risk of disease. The development of new types of functional food concentrates, which will be competitive both in the domestic and foreign markets, should be based on consumer preferences. The article presents a marketing research of consumer preferences for functional food concentrates. The research was carried out in the form of a sociological survey. The target audience was determined, the issues of «healthy nutrition» and the reasons for refusing to use food concentrates for functional purposes were considered. The most significant criteria for choosing functional products were established: «usefulness» — 18.33 %, «safety» — 16.72 %, «taste» — 15.56 %. Taking into account the results obtained, a line of food concentrates enriched with linseed fiber, which is a source of omega-3 PUFA, has been developed.
The naturally occurring bioactive compounds that bridge the gap between food products and drugs are called nutraceuticals. Nutraceutical products may provide health and medicinal benefits, including the prevention and treatment of diseases in addition to the basic nutritional value of the natural source. The term was coined by Stephen L. DeFelice, founder and chairman of the Foundation of Innovation Medicine. Although it is a hybrid of the words “nutrition” and “pharmaceutical,” it is different from pharmaceuticals and applied to products ranging from dietary supplements (minerals, vitamins, and antioxidant supplements), herbal products, probiotics, processed foods, and essential oils. Although in the modern era use of traditional medicine has been surpassed by pharmaceutical products, the renewed interest in the general population for alternative medicine is apparent from the fact that the world market reached $250 billion by 2018, having stood at $35 billion in 2010.
This chapter reviews the characteristics of inflammatory bowel disease, the nature of the inflammatory process, and the potential role for nutrition interactions Also, nutrition and short bowel syndrome, one of the potential complications of Crohn's disease and other gastrointestinal maladies, are addresses in the chapter.The two primary forms of idiopathic inflammatory bowel disease, Crohn's disease and ulcerative colitis, are characterized as chronic, inflammatory diseases of varying severity. The cause is unknown but the disease appears to involve significant interaction of the intestinal wall with intestinal microbes, ingested foods and beverages, gastrointestinal secretions, local and systemic immune components, and genetic factors. The disease may result in malabsorption of nutrients, obstruction of the gastrointestinal tract, decreased oral intake, increased nutrient requirements, and adverse response to ingested foods. Malnutrition is common. Medications and other therapies employed in treating inflammatory bowel disease can further compromise nutritional status. Specific dietary factors may enhance or attenuate the underlying inflammatory processes involved in the disease, and certain dietary habits can worsen or reduce the severity of symptoms of inflammatory bowel disease. Surgery is common in the life of patients with inflammatory bowel disease and, in some cases, may significantly affect the ability of the patient to maintain adequate nutritional status without specialized nutrition care. Consequently, dietary interventions have a significant role in the management of inflammatory bowel disease, its symptoms, and its consequences.are reviewed.
In the era of post genomics, identification of a potential miRNA to regulate gene and transcription factors by applying a computational approach is a challenging task to execute. The challenge was addressed by identifying the associated transcription factors (TFs) and genes from Mogrify along with micro RNAs from miRTarBase. On the basis of association between Genes-miRNAS-TFs a network of transcription factor based miRNA was constructed. Finally, on the basis of statistical studies and miRNA based compatibility the network was analyzed to identify a potential miRNA to be utilized as a biomarker to treat psoriasis.
A highly stressed and busy life schedule demands a balanced diet with all nutritive components. Thus, among all other nutrition, intake of essential fatty acids (EFAs) is highly recommended due to the inability of the human body to synthesize these essential fats. Fishes, algae, oilseed crops, aquatic foods and vertebrates are the key sources of polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, demand for these nutraceuticals is burgeoning at a tremendous rate which has led to enormous pressure on the current market. So, there should be constant efforts to advance the current production potential by upgrading the technologies in obtaining these nutraceuticals from aquatic and agricultural sources. The current chapter mainly explores the prospective of fish and food crops for n‐3 and n‐6 PUFA production and also discusses the variation in fatty acid profiles in interspecific and intraspecific association of species. Furthermore, this article also describes the variation of lipid profile with different factors like geographical locations, season, temperature, salinity, farmed or wild fish.
This study examines the effects of vitamin D and omega-3 fatty acid co-supplementation on inflammation and nutritional status in colorectal cancer patients. Patients were randomly assigned into four groups: (1) controls, receiving placebos; (2) omega-3 fatty acid arm, receiving two 330 mg omega-3 fatty acid capsules daily and placebo (for vitamin D3) weekly; (3) vitamin D arm, receiving a 50,000 IU vitamin D3 soft gel weekly and two placebos (for omega-3 fatty acids) daily; and (4) co-supplementation arm, receiving a 50,000 IU vitamin D3 soft gel weekly and two 330 mg omega-3 fatty acids capsules daily for 8 weeks. As outcomes, we measure height; weight; fat-free mass (FFM); serum levels of 25(OH)D, TNF-α, and IL-6; C-CRP; and albumin, before and after the intervention. The presented results show that vitamin D3 plus omega-3 fatty acid co-supplementation in colorectal cancer patients has beneficial impacts on inflammation and nutritional status.
Substantial studies have shown that ω-3 polyunsaturated fatty acids (PUFAs) have various health-promoting effects, however, there are inconsistent results from animal studies which showed that ω-3 PUFAs have no effects or even detrimental effects. Emerging research suggests that oxidized ω-3 PUFAs have different effects compared with un-oxidized ω-3 PUFA, therefore, lipid oxidation of dietary ω-3 PUFAs could contribute to the mixed results of ω-3 PUFAs in animal studies. Here we prepared an AIN-93G-based, semi-purified, powder diet, which is one of the most commonly used rodent diets in animal studies, to study the oxidative stability of fortified ω-3 PUFAs in animal feed. We found that lowering the storage temperature or addition of a certain antioxidant, notably tert-butylhydroquinone (TBHQ), helps to stabilize ω-3 PUFAs and suppress ω-3 oxidation in the animal diet while reducing the level of oxygen in storage atmosphere is not very effective. Addition of 50 ppm TBHQ in the diet inhibited 99.5 ± 0.1 % formation of primary oxidation products and inhibited 96.1 ± 0.7 % formation of secondary oxidation products, after 10-day storage of the prepared diet at a typical animal-feeding-experiment condition. Overall, our results highlight that ω-3 PUFAs are highly prone to lipid oxidation in a typical animal feeding experiment, emphasizing the critical importance to stabilize ω-3 PUFAs in animal studies.
about this Special Issue This special issue is highly related to Microbiology and Bioinformatics application for pharmacology and its usage in medical and health care systems towards providing leads for molecular development and an initiative in Basic science to perform advanced research in areas like the virtual patient and CRISPER Human. Also, it focuses on the integration of machine learning algorithms to mankind. In addition to the basic science involved in Microbiology, Bioinformatics and Pharmacology, the advancements in the current stage of applying the schemas of artificial intelligence (AI) in basic sciences are also focused in this issue. Artificial intelligence in the diagnosis of health care is the requirement for the current era of Digital Genomics. This special issue focuses on both basic science and advanced developments in the current era of Digital Genomics. The articles published in this special issue will certainly bring a positive effect for the development of health care systems and scientific leads to develop molecules with the available resources enhance the maximum utilization of scientific knowledge to potentiate diagnosis and therapy in health care. CONTENT
This special issue is highly related to Microbiology and Bioinformatics application for pharmacology and its usage in medical and health care systems towards providing leads for molecular development and an initiative in Basic science to perform advanced research in areas like the virtual patient and CRISPER Human. Also, it focuses on the integration of machine learning algorithms to mankind. In addition to the basic science involved in Microbiology, Bioinformatics and Pharmacology, the advancements in the current stage of applying the schemas of artificial intelligence (AI) in basic sciences are also focused in this issue. Artificial intelligence in the diagnosis of health care is the requirement for the current era of Digital Genomics. This special issue focuses on both basic science and advanced developments in the current era of Digital Genomics. The articles published in this special issue will certainly bring a positive effect for the development of health care systems and scientific leads to develop molecules with the available resources enhance the maximum utilization of scientific knowledge to potentiate diagnosis and therapy in health care.
Objectives: This study aimed to investigate the effects of vitamin D and omega-3 fatty acids co-supplementation on inflammatory factors and tumor marker CEA in colorectal cancer patients undergoing chemotherapy.
Methods: In this study, 81 patients with stage ӀӀ or ӀӀӀ colorectal cancer were randomly assigned into four groups: (1) control: receiving a vitamin D placebo, weekly + two omega-3 fatty acid placebo capsules, daily; (2) omega-3 fatty acid, receiving two omega-3 fatty acid capsules (each capsule containing 330 mg of omega-3 fatty acids), daily + a vitamin D placebo, weekly; (3) vitamin D, receiving a 50,000 IU vitamin D soft gel, weekly + two omega-3 fatty acid placebo capsules, daily; (4) co-supplementation, receiving a 50,000 IU vitamin D soft gel, weekly + two omega-3 fatty acids capsules, for 8 weeks. Before and after the intervention, serum levels of 25(OH)D, TNF-α, IL-1β, IL-6, IL-8, NF-kB activity, and tumor marker CEA, were measured.
Results: After 8 weeks of intervention, patients who received combined vitamin D and omega-3 fatty acids supplements compared with omega-3, vitamin D, and placebo had significantly decreased TNF-α, and IL-1β (P < .05). In addition, serum levels of TNF-α, IL-1β, IL-6, IL-8, and tumor marker CEA were decreased significantly in omega-3, vitamin D, and co-supplementation of them, compared with baseline. NF-kB activity was decreased significantly in vitamin D and co-supplementation groups, compared with baseline. Regarding CEA, there was no significant difference between the four groups at the end of intervention (P > .05).
Conclusion: Results show that co-supplementation of vitamin D and omega-3 fatty acids co-supplementation, in colorectal cancer patients have beneficial impacts on inflammation and tumor marker CEA.
This study aimed to evaluate the effects of vitamin D3 and omega-3 fatty acids cosupplementation on inflammation and nutritional status in colorectal cancer patients. In this clinical trial, 81 colorectal cancer patients were randomly assigned into four groups: (1) control group: receiving a vitamin D3 placebo weekly + omega-3 fatty acid placebo capsules daily; (2) omega-3 fatty acid group: receiving 2 omega-3 fatty acid capsules (each capsule containing 330 mg of omega-3 fatty acids) daily + a vitamin D3 placebo weekly; (3) vitamin D group: receiving a 50,000 IU vitamin D3 soft gel weekly + 2 omega-3 fatty acid placebo capsules daily; (4) cosupplementation group: receiving a 50,000 IU vitamin D3 soft gel weekly + 2 omega-3 fatty acids capsules daily for 8 weeks. Before and after the intervention, height, weight, fat-free mass (FFM), serum levels of 25(OH)D, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), C-reactive protein (CRP), and albumin, were measured. After 8 weeks of intervention, patients who received combined vitamin D3 and omega-3 fatty acids supplements compared with omega-3, vitamin D3, and placebo groups had significantly decreased CRP and TNF-α. In addition, serum level of IL-6 was decreased significantly in omega-3, vitamin D3, and cosupplementation groups compared with baseline. Regarding nutritional status, weight, BMI, and FFM% were increased significantly in vitamin D3, omega-3, and cosupplementation groups at the end of the intervention. Vitamin D3 plus omega-3 fatty acids cosupplementation in colorectal cancer patients has beneficial impacts on inflammation and nutritional status.
Background:
Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics.
Methods:
We tested diabetic neuropathic wild-type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu-opioid receptor antagonist.
Results:
The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids.
Conclusions:
The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions.
Significance:
EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects.
Dietary factors have been considered as a possible risk factor for ulcerative colitis (UC). Red meat, high fat intake and high protein intake are associated with development and relapse in UC. On the other hand, probiotics, fish oil and dietary fiber have shown good efficacy in the treatment of UC. This paper reviews the updated data on the role of dietary factors in the pathogenesis and treatment of UC.
During the last 30 years there has been an increasing interest in marine omega-3 polyunsaturated fatty acids (PUFAs) for nutritional applications due to their health beneficial effects, which will be briefly summarised. There are different sources of omega-3 PUFAs, but the major source is fish oils. Due to their polyunsaturated nature omega-3 PUFAs are highly susceptible to lipid oxidation, which will lead to formation of undesirable fishy and rancid off-flavours. Such off-flavours can lead to consumer rejection of omega-3 enriched foods. This chapter will summarise our current knowledge about the most important factors affecting lipid oxidation in a range of different omega-3 enriched foods and means to reduce lipid oxidation will also be discussed.
The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentaenoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore--stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.
Background:
Several lines of evidence suggest that supplementation of diet with omega-3 polyunsaturated fatty acids (ω-3) PUFA), commonly referred to as fish oils, may reduce blood pressure (BP). However, most clinical trials of ω-3 PUFA supplementation have been of insufficient size to detect relevant BP changes.
Methods:
We conducted a meta-analysis of 17 controlled clinical trials of ω-3 PUFA supplementation. To estimate an overall effect of ω-3 PUFA supplementation on BP, we calculated the net BP change in each trial (BP A in ω-3 PUFA group minus BP A in control group), which was then weighted according to the inverse of the variance.
Results:
In the 11 trials that enrolled normotensive individuals (n=728), ω-3 PUFA supplementation led to significant reductions of systolic BP (SBP) and diastolic BP (DBP) in two and one trials, respectively. In the six studies that enrolled untreated hypertensives (n=291), significant reductions of SBP and DBP were present in two and four trials, respectively. Weighted, pooled estimates of SBP and DBP change (mm Hg) with 95% confidence intervals were —1.0 (—2.0 to 0.0) and —0.5 (—1.2 to +0.2) in the trials of normotensives, and —5.5 (—8.1 to —2.9) and —3.5 (—5.0 to —2.1) in the trials of untreated hypertensives. In 13 of 17 studies, trial duration was less than 3 months. Doses of ω-3 PUFA tended to be high (average dose >3 g/d in 11 trials). The magnitude of BP reduction was greatest at high BP but was not significantly associated with dose of ω-3 PUFA. Side effects, most commonly eructation and a fishy taste, occurred more frequently in ω-3 PUFA participants than in control participants (28% vs 13%, P<.001).
Conclusions:
Our analyses indicate that diet supplementation with a relatively high dose of ω-3 PUFA, generally more than 3 g/d, can lead to clinically relevant BP reductions in individuals with untreated hypertension. However, use of ω-3 PUFA as antihypertensive therapy will require demonstration of long-term efficacy and patient acceptability of lower doses.(Arch Intern Med. 1993;153:1429-1438)
We evaluated the efficacy of fish oil n-3-[omega]-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. An open trial of 10 patients with mild to moderate ulcerative colitis who had either failed (n = 9) or refused (n = 1) conventional therapy was performed. Patients received 15 MAX-EPA capsules containing a total of 2.7 g of eicosapentanoic acid in three divided doses daily for 8 weeks. The activity of ulcerative colitis and response to therapy was based upon daily stool diaries, sigmoidoscopy, and symptomatic response. All patients tolerated the fish oil and showed no alteration in routine blood studies. Seven patients had moderate to marked improvement; steroid dose could be reduced in four of the five patients on prednisone. Three patients had little or no improvement. No patient worsened. These results of our open study appear to justify a double-blind trial of this dietary supplement in ambulatory patients with ulcerative colitis.
Background: There is no established therapy for maintaining remission in patients with Crohn's disease. Following different suggestions from the literature, two potential interventions for maintaining remission were tested against placebo, using either 5 g/day of a highly concentrated omega-3 fatty acid compound or a carbohydrate-reduced diet (84 g/day). Methods: A total of 204 patients were recruited after they had had an acute relapse. After remission (CDAI ≤ 150) was attained with steroid therapy, patients were randomized to receive either omega-3 fatty acids (n = 70), placebo (n = 65), or diet (n = 69). Low-dose prednisolone was given to all patients for the first 8 weeks of intervention. CDAI and an acute-phase protein (CRP) were used as criteria for a relapse. Results: The proportion of patients without relapse within a year were similar in the placebo and active treatment group (intention-to-treat analysis: placebo, 30%; active treatment, 30%; protocol-adhering patients, 29% versus 28%). Patients did gain benefit (53%; p = 0.023) for as long as they maintained the diet. However, intention-to-treat analysis (diet group, 40%) did not show a noticeable difference when compared with placebo. Conclusions: Omega-3 fatty acids did not show an effect on extending the remission in Crohn's disease. For the diet patients the question remains whether the noncompliant patients dropped out early because they sensed a relapse approaching or whether their condition deteriorated because they failed to comply with the diet.
Background: Steroids are highly effective in active Crohn's disease; clinical relapse following steroid withdrawal, however, is frequent. We used two steroid regimens of different duration in order to compare their efficacy in inducing and maintaining clinical remission. Methods: Seventy patients with active Crohn's disease were treated with methylprednisolone 40 mg/day i.m. for 3 weeks and then with two different regimens of tapering dosage: one for a further 4 weeks and another for a further 12 weeks.
Results: Steroid therapy induced remission within 3 weeks in 91 % of the whole group of patients: at the end of each protocol remission rates were 85% of patients in the group treated for the shorter period and 87% of those treated for the longer period (difference 2%. CI = - 14 to 18, P = NS); remission rates within 6 months after stopping steroids were 53% and 37% respectively (difference 16%, CI = -9 to 41, P = NS). Conclusions: No significant differences were found between the two regimens. Multiple courses of steroid treatment in the previous 3 years and a short time interval following previous steroid treatment seem to be risk factors for relapse.
This study was designed to investigate the in vitro effects of phenolic compounds extracted from olive oil and from olive derived fractions. More specifically, we investigated the effects on platelets of 2-(3,4-di-hydroxyphenyl)-ethanol (DHPE), a phenol component of extra-virgin olive oil with potent antioxidant properties. The following variables were studied: aggregation of platelet rich plasma (PRP) induced by ADP or collagen, and thromboxane B2 production by collagen or thrombin-stimulated PRP. In addition, thromboxane B2 and 12-hydroxyeicosatetraenoic acid (12-HETE) produced during blood clotting were measured in serum. Preincubation of PRP with DHPE for at least 10 min resulted in maximal inhibition of the various measured variables. The IC50s (concentration resulting in 50% inhibition) of DHPE for ADP- or collagen-induced PRP aggregations were 23 and 67 μM, respectively. At 400 μM DHPE, a concentration which completely inhibited collagen-induced PRP aggregation, TxB2 production by collagen- or thrombin-stimulated PRP was inhibited by over 80 percent. At the same DHPE concentration, the accumulation of TxB2 and 12-HETE in serum was reduced by over 90 and 50 percent, respectively. We also tested the effects on PRP aggregation of oleuropein, another typical olive oil phenol, and of selected flavonoids (luteolin, apigenin, quercetin) and found them to be much less active. On the other hand a partially characterized phenol-enriched extract obtained from aqueous waste from olive oil showed rather potent activities. Our results are the first evidence that components of the phenolic fraction of olive oil can inhibit platelet function and eicosanoid formation in vitro, and that other, partially characterized, olive derivatives share these biological activities.
Polymorphonuclear leukocytes (PMNLs) are an important contributor to inflammation and are thus a part of the pathophysiology of many human diseases. We assessed the effect of fish oil on PMNL inflammatory potential by measuring chemiluminescence and superoxide production before and after six weeks of daily cod liver oil ingestion by healthy volunteers. Phagocytosing PMNLs demonstrated a 27% decrease in chemiluminescence (P less than 0.05) and a 64% decrease in superoxide production (P less than 0.01), following the cod liver oil supplementation. Analysis of PMNL and platelet fatty acids revealed the appearance of eicosapentaenoic acid and a significant decrease in arachidonic acid in both types of cells.
To determine the efficacy of fish oil supplementation in patients with active ulcerative colitis.
Multicenter, randomized, double-blind, placebo-controlled, crossover trail with 4-month treatment periods (fish oil and placebo) separated by a 1-month washout.
Four gastroenterology divisions.
Twenty-four patients with active ulcerative colitis entered the study. Five dropped out, and one was noncompliant. Eighteen patients completed the study. All patients had active disease as manifested by diarrhea and rectal inflammation.
Treatment with prednisone and sulfasalazine was continued. Fish oil supplementation consisted of 18 Max-EPA (eicosapentaenoic acid) capsules daily (eicosapentaenoic acid, 3.24 g; and docosahexaenoic acid, 2.16 g). Placebo supplementation consisted of 18 identical capsules containing isocaloric amounts of vegetable oil.
Patients were evaluated at study entry and after each diet period. Evaluations included a review of symptoms, flexible sigmoidoscopy, rectal biopsy, and rectal dialysis to measure prostaglandin E2 and leukotriene B4 levels.
Fish oil supplementation resulted in a significant decrease in rectal dialysate levels of leukotriene B4 from 71.0 to 27.7 pg/mL (average change, -43.3 pg/mL; 95% CI, -83 to -3.6). Significant improvements were seen in acute histology index (average change, -8.5 units from a baseline of 10.5 units; CI, -12.9 to -4.2) and total histology index (average change, -8.5 units from a baseline of 14.80; CI, -13.2 to -3.8) as well as significant weight gain (average weight gain, 1.74 kg, CI, 0.94 to 2.54). No significant changes occurred in any variable during the placebo period. Seven patients received concurrent treatment with prednisone. During the fish oil supplementation period, the mean prednisone dose decreased from 12.9 mg/d to 6.1 mg/d and rose from 10.4 mg/d to 12.9 mg/d during the placebo diet period (P greater than 0.20).
Four months of diet supplementation with fish oil in patients with inflammatory bowel disease resulted in reductions in rectal dialysate leukotriene B4 levels, improvements in histologic findings, and weight gain.
The efficacy of fish oil in decreasing restenosis following percutaneous transluminal coronary angioplasty (PTCA) remains controversial despite seven published reports of randomized trials involving 951 patients. We performed a meta-analysis to determine whether these trials, viewed in aggregate, demonstrate a significant benefit. We evaluated rates of restenosis two to 12 months after PTCA and calculated an estimate of the overall effect and 95% confidence interval (CI). The typical odds ratio (treatment versus control) was 0.71 (95% CI 0.54, 0.94), P = 0.016 (two-tailed). The data show a strong and highly significant (P less than .0001) relationship between daily fish oil dose and gastrointestinal side effects. While compatible with a small to moderate benefit of fish oil on rates of restenosis, these results require confirmation in a randomized clinical trial large enough to distinguish reliably between a clinically meaningful benefit and a null result.
Arachidonic acid metabolites formed by both the cyclooxygenase and lipoxygenase pathways may contribute to the clinical diarrhea and colitis of inflammatory bowel disease. Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa, and these levels tend to correlate with severity of the disease. In this study, we evaluated the efficacy of ingestion of fish oil n-3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. Eleven patients with ulcerative colitis of mild to moderate severity were studied in a 8-month, double-blind, placebo-controlled, crossover trial of dietary supplementation with fish oil, which provided about 4.2 g of omega-3- fatty acids per day. A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mucosal leukotriene B4 production was measured by radioimmunoassay. Mean disease activity index declined 56% for patients receiving fish oil and 4% for patients on placebo (p less than 0.05). There were no statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels. All patients tolerated fish oil ingestion and showed no alteration in routine blood studies. No patient worsened; anti-inflammatory drugs could be reduced or eliminated in eight patients (72%) while receiving fish oil. We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis but is not associated with significant reduction in mucosal leukotriene B4 production, compared with placebo therapy. Further studies are needed to elucidate the mechanism of action and optimal dose and duration of fish oil supplementation in ulcerative colitis.
We evaluated the efficacy of fish oil n--3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. An open trial of 10 patients with mild to moderate ulcerative colitis who had either failed (n = 9) or refused (n = 1) conventional therapy was performed. Patients received 15 MAX-EPA capsules containing a total of 2.7 g of eicosapentanoic acid in three divided doses daily for 8 weeks. The activity of ulcerative colitis and response to therapy was based upon daily stool diaries, sigmoidoscopy, and symptomatic response. All patients tolerated the fish oil and showed no alteration in routine blood studies. Seven patients had moderate to marked improvement; steroid dose could be reduced in four of the five patients on prednisone. Three patients had little or no improvement. No patient worsened. These results of our open study appear to justify a double-blind trial of this dietary supplement in ambulatory patients with ulcerative colitis.
Unlabelled:
In this open study involving 3,958 hyperlipemic patients of both sexes, the effect of a standardised omega-3 fatty acid preparation (omega-3-FA) obtained from fish oil (Eicosapen, Hormon-Chemie München GmbH) on lipid metabolism and blood pressure, together with its tolerance, was investigated under day-to-day conditions. The patients, on a lipid-lowering diet, received no lipid-lowering medication during the 3 months prior to the study, daily consumed an average of 11 +/- 2 capsules of the omega-3-FA preparation with 1.8-2.5 g omega-3-FA.
Results:
3,590 patients (90.7%) were evaluated. The serum lipid levels decreased on average by 34% for triglycerides, 17% for total cholesterol and 16% for LDL cholesterol, and increased by 12% for HDL cholesterol. In the case of hypertensives, the blood pressure (diastolic) normalized in 55%, while in the case of normotensives, only slight changes were observed. In 471 cases (11.9%), side effects--usually gastrointestinal--were reported, leading to abortion of the study in 71 patients (1.8%). All in all, tolerance was judged positively in more than 80%, and effectiveness in more than 90% of the cases.
In a pilot study six patients with active ulcerative colitis and six healthy controls were given fish oil (MaxEPA) containing 3-4 g of eicosapentaenoic acid daily for a period of 12 weeks. There was a significant improvement in the patients' symptoms and histological appearance of the rectal mucosa by the end of the treatment period. There was significant fall in neutrophil chemiluminescence during treatment in patients, whereas no change was observed in the control group. Neutrophil leukotriene B4 levels fell significantly during treatment. Serum from patients receiving fish oil was significantly less chemotactic for neutrophils compared with control serum. Eicosapentaenoic acid inhibited neutrophil chemotaxis and chemiluminescence in vitro. The omega-3 fatty acids, which occur naturally in fish oils, may exert a beneficial effect by decreasing the production of inflammatory mediators.
In a prospective study, specimens of resected small and large intestine from fifteen patients with Crohn's disease were prepared by heparin-saline vascular perfusion, followed by either resin casting of the mesenteric vascular supply and tissue maceration or glutaraldehyde perfusion-fixation, resin casting, and tissue clearance. The specimens were examined by macrophotography, histopathology, and either scanning or transmission electronmicroscopy. A pathogenetic sequence of events in Crohn's disease was seen--vascular injury, focal arteritis, fibrin deposition, arterial occlusion mainly at the level of the muscularis propria, followed by tissue infarction or neovascularisation. These features were confined to segments of intestine affected by Crohn's disease and did not occur in normal bowel. The findings suggest that Crohn's disease is mediated by multifocal gastrointestinal infarction. This pathogenetic process is compatible with many of the clinical features of Crohn's disease, and its recognition has important implications for the identification of the primary cause of the illness and advances in clinical management.
Thirty-nine patients with chronic inflammatory bowel disease were studied in a 7-month, double-blind, placebo controlled cross-over trial of dietary supplementation with fish oil, which provided about 3.2 g n-3 fatty acids per day. At control, biopsies from inflamed mucosa contained higher levels of arachidonic acid than uninvolved mucosa. Dietary n-3 fatty acids were well tolerated and incorporated into plasma and enteric mucosa phospholipids at the expense of n-6 fatty acids. The arachidonic acid-derived prostanoid generation was reduced by fish oil and the extension and severity of macroscopic bowel involvement was moderately improved. In patients with Crohn's disease, clinical activity was unchanged by fish-oil supplementation. In patients with ulcerative colitis, clinical disease activity fell during fish oil supplementation and thereafter; this was not significant however. Despite a moderate reduction in inflammatory lipid mediators by dietary n-3 fatty acids and limited morphological improvement in chronic inflammatory bowel disease, the clinical benefit seems to be confined to patients with ulcerative colitis.
We examined whether the synthesis of interleukin-1 or tumor necrosis factor, two cytokines with potent inflammatory activities, is influenced by dietary supplementation with n-3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concentrate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1 beta and IL-1 alpha) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1 beta was suppressed from 7.4 +/- 0.9 ng per milliliter at base line to 4.2 +/- 0.5 ng per milliliter after six weeks of supplementation (43 percent decrease; P = 0.048). Ten weeks after the end of n-3 supplementation, we observed a further decrease to 2.9 +/- 0.5 ng per milliliter (61 percent decrease; P = 0.005). The production of IL-1 alpha and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1 beta, IL-1 alpha, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids. The reported antiinflammatory effect of these n-3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor.
The effects of dietary fish-oil fatty acids on the function of the 5-lipoxygenase pathway of peripheral-blood polymorphonuclear leukocytes and monocytes were determined in seven normal subjects who supplemented their usual diet for six weeks with daily doses of triglycerides containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid. The diet increased the eicosapentaenoic acid content in neutrophils and monocytes more than sevenfold, without changing the quantities of arachidonic acid and docosahexaenoic acid. When the neutrophils were activated, the release of [3H]arachidonic acid and its labeled metabolites was reduced by a mean of 37 per cent, and the maximum generation of three products of the 5-lipoxygenase pathway was reduced by more than 48 per cent. The ionophore-induced release of [3H]arachidonic acid and its labeled metabolites from monocytes in monolayers was reduced by a mean of 39 per cent, and the generation of leukotriene B4 by 58 per cent. The adherence of neutrophils to bovine endothelial-cell monolayers pretreated with leukotriene B4 was inhibited completely, and their average chemotactic response to leukotriene B4 was inhibited by 70 per cent, as compared with values determined before the diet was begun and six weeks after its discontinuation. We conclude that diets enriched with fish-oil-derived fatty acids may have antiinflammatory effects by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4-mediated functions of neutrophils.
Leukotriene B4, an arachidonic acid metabolite, is a potent chemotactic agent, and is thought to be an important mediator of inflammation. To investigate the role of this compound as a mediator of inflammation in inflammatory bowel disease, arachidonic acid was incubated with ionophore and colonic mucosa from patients with inflammatory bowel disease and from normal subjects. Mucosa from patients with inflammatory bowel disease converted 2.17% of exogenous arachidonate to leukotriene B4; mucosa from normal subjects converted 0.37%. The production of leukotriene was blocked by sulfasalazine. To determine if inflammatory bowel mucosa contained endogenous leukotriene B4, lipid extracts were analyzed by high pressure liquid chromatography. Mucosa from patients with inflammatory bowel disease contained 254 ng of leukotriene B4 per gram and mucosa from normal subjects contained less than 5 ng of leukotriene B4 per gram. The presence of significant amounts of leukotriene B4 in colonic mucosa in patients with inflammatory bowel disease, combined with the known biologic effects of leukotriene B4, suggests that it may be an important mediator of inflammation in inflammatory bowel disease.
Fish oil has been recently proposed as a possible effective treatment in inflammatory bowel disease (IBD); however, a lot of annoying side effects (ie, belching, halitosis, diarrhea, etc) affect patient compliance. We carried out a study of patient tolerance in a group of Crohn's disease (CD) patients with a new fish oil derivative consisting of 500-mg capsules of eicosapentaenoic-docosahexaenoic (EPA 40%-DHA 20%), a free fatty acid mixture (Purepa), and we also evaluated its incorporation into phospholipids, both in plasma and in red cell membranes. Five groups of 10 CD patients in remission received nine Purepa capsules daily in four different preparations (A: uncoated, B: coated, pH 5.5; C: coated, pH 5.5, 60 min time release; D: coated, pH 6.9) and 12 x 1-g capsules daily of a triglyceride preparation (Max-EPA, EPA 18%-DHA 10%), respectively. We coated three of the four Purepa preparations in order to delay the release of contents in an attempt to minimize the side effects. After six weeks of treatment, the group taking Purepa capsules, coated, pH 5.5, 60 min time release (group C) showed the best incorporation of EPA and DHA in red blood cell phospholipid membranes (EPA from 0.2 to 4.4%, DHA from 3.7 to 6.3%), and no side effects were registered, whereas in all other groups side effects were experienced in 50% or more of subjects. This new preparation will make it possible to treat patients for long periods.
Several lines of evidence suggest that supplementation of diet with omega-3 polyunsaturated fatty acids (omega-3 PUFA), commonly referred to as fish oils, may reduce blood pressure (BP). However, most clinical trials of omega-3 PUFA supplementation have been of insufficient size to detect relevant BP changes.
We conducted a meta-analysis of 17 controlled clinical trials of omega-3 PUFA supplementation. To estimate an overall effect of omega-3 PUFA supplementation on BP, we calculated the net BP change in each trial (BP delta in omega-3 PUFA group minus BP delta in control group), which was then weighted according to the inverse of the variance.
In the 11 trials that enrolled normotensive individuals (n = 728), omega-3 PUFA supplementation led to significant reductions of systolic BP (SBP) and diastolic BP (DBP) in two and one trials, respectively. In the six studies that enrolled untreated hypertensives (n = 291), significant reductions of SBP and DBP were present in two and four trials, respectively. Weighted, pooled estimates of SBP and DBP change (mm Hg) with 95% confidence intervals were -1.0 (-2.0 to 0.0) and -0.5 (-1.2 to +0.2) in the trials of normotensives, and -5.5 (-8.1 to -2.9) and -3.5 (-5.0 to -2.1) in the trials of untreated hypertensives. In 13 of 17 studies, trial duration was less than 3 months. Doses of omega-3 PUFA tended to be high (average dose > 3 g/d in 11 trials). The magnitude of BP reduction was greatest at high BP but was not significantly associated with dose of omega-3 PUFA. Side effects, most commonly eructation and a fishy taste, occurred more frequently in omega-3 PUFA participants than in control participants (28% vs 13%, P < .001).
Our analyses indicate that diet supplementation with a relatively high dose of omega-3 PUFA, generally more than 3 g/d, can lead to clinically relevant BP reductions in individuals with untreated hypertension. However, use of omega-3 PUFA as antihypertensive therapy will require demonstration of long-term efficacy and patient acceptability of lower doses.
To assess the clinical efficacy and side effects of gammalinolenic acid, a plant-seed-derived essential fatty acid that suppresses inflammation and joint tissue injury in animal models.
A randomized, double-blind, placebo-controlled, 24-week trial.
Rheumatology clinic of a university hospital.
Thirty-seven patients with rheumatoid arthritis and active synovitis.
Treatment with 1.4 g/d gammalinolenic acid in borage seed oil or cotton seed oil (placebo).
Physicians' and patients' global assessment of disease activity; joint tenderness, joint swelling, morning stiffness, grip strength, and ability to do daily activities.
Treatment with gammalinolenic acid resulted in clinically important reduction in the signs and symptoms of disease activity in patients with rheumatoid arthritis (P < 0.05). In contrast, patients given a placebo showed no change or showed worsening of disease. Gammalinolenic acid reduced the number of tender joints by 36%, the tender joint score by 45%, swollen joint count by 28%, and the swollen joint score by 41%, whereas the placebo group did not show significant improvement in any measure. Overall clinical responses (significant change in four measures) were also better in the treatment group (P < 0.05). No patients withdrew from gammalinolenic acid treatment because of adverse reactions.
Gammalinolenic acid in doses used in this study is a well-tolerated and effective treatment for active rheumatoid arthritis. Gammalinolenic acid is available worldwide as a component of evening primrose and borage seed oils. It is usually taken in far lower doses than used in this trial. It is not approved in the United States for the treatment of any condition and should not be viewed as therapy for any disease. Further controlled studies of its use in rheumatoid arthritis are warranted.
Recent work suggests that thromboxanes may play a major pathogenic role in inflammatory bowel disease. Thromboxanes are produced in excess not only in inflamed mucosa but also in Crohn's disease, by uninflamed bowel and by isolated intestinal and peripheral blood mononuclear cells. Their cellular source is likely to include platelets, neutrophils, endothelial and epithelial cells as well as mononuclear cells, possible stimuli to their overproduction being chemotactic peptides, lipopolysaccharide, leukotrienes, platelet activating factor, interleukin-1, bradykinin and angiotensin II. The pro-inflammatory effects of thromboxanes are both direct (diapedesis and activation of neutrophils, mucosal ulceration, reduction of suppressor T-cell activity) and indirect (vasoconstriction, platelet activation). Although corticosteroids and aminosalicylates inhibit thromboxane synthesis, this action does not necessarily explain their therapeutic effect in inflammatory bowel disease. Selective thromboxane synthesis inhibitors and receptor antagonists, however, ameliorate experimental colitis in animals. Picotamide and ridogrel are dual thromboxane pathway blockers already used in man. Drugs of this type could prove useful not only for the prevention of systemic thrombo-embolism but also for suppressing intestinal mucosal inflammation in patients with inflammatory bowel disease.
Patients with inflammatory bowel disease are susceptible to thromboembolism and recently small vessel thrombosis has been implicated as an aetiological factor in Crohn's disease. This study therefore investigated platelet function in 104 patients with inflammatory bowel disease of whom eight had previous thromboembolism. Thirty five patients had reproducible spontaneous platelet aggregation of more than 30% (0 in controls) (p < 0.0001). A further 20 patients showed hypersensitivity of platelets to low concentrations of aggregating agents (p < 0.001). Plasma thromboxane B2 and beta thromboglobulin levels were significantly higher than controls (p < 0.001 and p < 0.001), but platelet lifespan studies were normal. There was no correlation with disease activity. Patients with inflammatory bowel disease have abnormal platelet activity, which may contribute to the inflammatory process.
In a placebo-controlled study, 43 patients with stable ulcerative colitis were randomized to receive either MaxEPA (n = 16), super evening primrose oil (n = 19), or olive oil as placebo (n = 8) for 6 months, in addition to their usual treatment. Treatment with MaxEPA increased red-cell membrane concentrations of eicosapentaenoic acid (EPA) at 3 months by three-fold and at 6 months by four-fold (both P < 0.01), and doubled docosahexaenoic acid (DHA) levels at 6 months (P < 0.05). Treatment with super evening primrose oil increased red-cell membrane concentrations of dihomogamma-linolenic acid (DGLA) by 40% at 6 months (P < 0.05), whilst treatment with placebo reduced levels of DGLA and DHA at 6 months (both P < 0.05). Clinical outcome was assessed by patient diary cards, sigmoidoscopy and histology of rectal biopsy specimens. Super evening primrose oil significantly improved stool consistency compared to MaxEPA and placebo at 6 months, and this difference was maintained 3 months after treatment was discontinued (P < 0.05). There was however, no difference in stool frequency, rectal bleeding, disease relapse, sigmoidoscopic appearance or rectal histology in the three treatment groups. Despite manipulation of cell-membrane fatty acids, fish oils do not exert a therapeutic effect in ulcerative colitis, while evening primrose oil may be of some benefit.
Patients with Crohn's disease may have periods of remission, interrupted by relapses. Because fish oil has antiinflammatory actions, it could reduce the frequency of relapses, but it is often poorly tolerated because of its unpleasant taste and gastrointestinal side effects.
We performed a one-year, double-blind, placebo-controlled study to investigate the effects of a new fish-oil preparation in the maintenance of remission in 78 patients with Crohn's disease who had a high risk of relapse. The patients received either nine fish-oil capsules containing a total of 2.7 g of n-3 fatty acids or nine placebo capsules daily. A special coating protected the capsules against gastric acidity for at least 30 minutes.
Among the 39 patients in the fish-oil group, 11 (28 percent) had relapses, 4 dropped out because of diarrhea, and 1 withdrew for other reasons. In contrast, among the 39 patients in the placebo group, 27 (69 percent) had relapses, 1 dropped out because of diarrhea, and 1 withdrew for other reasons (difference in relapse rate, 41 percentage points; 95 percent confidence interval, 21 to 61; P < 0.001). After one year, 23 patients (59 percent) in the fish-oil group remained in remission, as compared with 10 (26 percent) in the placebo group (P = 0.003). Logistic-regression analysis indicated that only fish oil and not sex, age, previous surgery, duration of disease, or smoking status affected the likelihood of relapse (odds ratio for the placebo group as compared with the fish-oil group, 4.2; 95 percent confidence interval, 1.6 to 10.7).
In patients with Crohn's disease in remission, a novel enteric-coated fish-oil preparation is effective in reducing the rate of relapse.
Relapse prevention by dietary n-3 fatty acids (5.1 g/day) was studied in a double-blind, placebo-controlled trial of 64 patients with ulcerative colitis in remission and off steroids. 5-ASA compounds were stopped three months after randomization and clinical disease activity monitored for two years. Macroscopic and histologic activity and extension was assessed by colonoscopy at entry and at exit. Both treatment groups were well matched at start. Nine patients on placebo and eight on n-3 fatty acids stopped taking their medication prematurely. Actuarial relapse-free survival was improved by n-3 fatty acids only during months 2 and 3 (2P < 0.05-0.01), but cumulative relapse rate at two years was similar for those taking placebo (18/33 = 55%) and n-3 fatty acids (18/31 = 58%). There was also no consistent difference in clinical, macroscopic, and histologic disease activity between treatment groups. The n-3 fatty acids temporarily retard, but do not prevent, relapse of ulcerative colitis.
Does dietary fish oil maintain the remission of Crohn's disease (CD): a study case control
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Kaplan-Meier life-table curves showing the percentage of patients remaining in clinical remission during the treatment period. Reprinted from reference 26
FIGURE 1. Kaplan-Meier life-table curves showing the percentage of patients remaining in clinical remission during the treatment period.
Reprinted from reference 26. Copyright 1996 Massachusetts Medical Society. All rights reserved.
Does dietary fish oil maintain the remission of Crohn’s disease (CD): a study case control
- Matè