Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate

January 1, 2014 Human Health and Nutrition Data 0 Comments

Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate

Year: 2014
Authors: Zarepoor, L. Lu, J.T. Zhang, C. Wu, W. Lepp, D. Robinson, L. Wanasundara, J. Cui, S. et al
Publication Name: Am J Phys Gastrointest Liver Phys
Publication Details: Volume 306; Pages G1042-G1055


Flaxseed (FS), a dietary oilseed, contains a variety of anti inflammatory bio actives, including fermentable fiber, phenolic compounds (lignans), and the n 3 polyunsaturated fatty acid (PUFA) linolenic acid.  The objective of this study was to determine the effects of FS and its n 3 PUFA rich kernel or lignan  and soluble fiber rich hull on colitis
severity in a mouse model of acute colonic inflammation. C57BL per 6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10 per cent  FS, 6 per cent  kernel, or 4 per cent hull for 3 wk prior to and during colitis induction via 5 days of 2 per cent  (wt per vol) dextran sodium sulfate (DSS) in their drinking water (n of 12 per group). An increase in anti inflammatory metabolites (hepatic n 3 PUFAs, serum mammalian lignans, and cecal short chain fatty acids) was associated with consumption of all FS based diets, but not with anti inflammatory effects in DSS exposed mice. Dietary FS exacerbated DSS induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL 6 and IL 1), and NF B signaling related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL 6, IFN, and IL1) and hepatic cholesterol levels were increased.  The adverse effects of FS were not associated with alterations in feca microbial load or systemic bacterial translocation (endotoxemia). Collectively, this study demonstrates that although consumption of a 10 per cent FS diet enhanced the levels of n 3 PUFAs, short chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS induced colonic injury and inflammation disorders and diseases, including inflammatory bowel disease (i.e., ulcerative colitis), intestinal infections, ischemia, injury, and colon cancer. It is associated with numerous clinical symptoms (i.e., abdominal pain, diarrhea, and rectal bleeding), colonic histological changes (immune cell infiltration, necrosis, or ulceration), increased production of colonic and systemic inflammatory chemokines and cytokines (i.e., IL 6, IL 1, and TNF) and various extra intestinal manifestations, including hepatic disorders. (Authors abstract)

Flaxseed (FS) is rich in numerous anti inflammatory gut health promoting bioactives, including fermentable dietary fibers, phenolic compounds (e.g., lignans), and the n 3 PUFA linolenic acid (ALA). Gut microbial fermentation of dietary fibers (e.g., FS gum, inulin, pectin, and resistant starch) results in the production of short chain fatty acids (SCFAs), including acetate, propionate, and butyrate, which play a role in the gut health promoting effects of prebiotics. FS is also the richest dietary source of plant lignans, predominantly secoisolariciresinol (SECO) diglycoside (SDG), which are metabolized by the colonic microbiota to their more biologically active forms, the mammalian lignans enterolactone (EL) and enterodiol (ED). Furthermore, FS is a rich source of ALA, which is the dietary precursor to the long-chain n 3 PUFAs [docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)]. Emerging data indicate that ALA can also reduce colonic inflammation through modulation of NF B signaling and reduction of oxidative stress.  Although dietary FS has demonstrated gut health promoting potential with regard to reducing colon cancer development, no study has determined its potential in attenuating colonic inflammation. The primary objective of this study was to determine if consumption of dietary FS, resulting in production of SCFAs, mammalian lignans, and n 3 PUFAs, could attenuate the severity of colonic inflammation induced by mucosal injury in a mouse model of acute colitis. Additionally, since FS bio actives are unequally distributed throughout the seed compartments, with the hull enriched in fiber and lignans and the kernel enriched in ALA. The secondary objective was to determine the potential use of FS hull and kernel as dietary modulators of colonic inflammation.  Although, FS kernel and hull are commercially available as natural health products, or neutraceuticals, there is limited research on the efficacy of different FS fractions in human health and disease. The results show that DSS exposure in male C57BL per 6 mice resulted in colonic mucosal injury and inflammation, as indicated by increased colonic histological damage, neutrophil infiltration, and levels of the pro inflammatory cytokine IL 6. However, in mice fed the 10 per cent FS diet, the severity of DSS induced mucosal injury and inflammation was increased.  Compared with BD fed DSS exposed mice, FS fed mice had increased DAI, colon histological damage scores, number of apoptotic cells, immune cell infiltration and inflammatory cytokine levels (IL1 and IL 6), and expression of NFB signaling related genes. The FS diet also exacerbated systemic indicators of colonic mucosal injury and inflammation by increasing serum inflammatory cytokines (IL1 , IL 6, and IFN) and impairing liver metabolic function.

Since the FS diet enhanced SCFA concentrations, cecum weight, and mammalian lignan production, indicative of increased microbial activity, it was hypothesized that the FS diet may have also modulated the intestinal microbiota, an effect caused by consumption of other prebiotics. FS induced modulation of the microbiota may have led to enhanced colitis severity in our DSS exposed mice. Further examination of the fecal microbiota using a metagenomic approach is required to determine if the FS diet induced changes in the intestinal microbiota profile.  Without feeding purified FS components [e.g., FS oil (ALA), SDG, or FS mucilage (soluble fiber)], it is difficult to conclude which FS component(s) was driving the adverse effects of the 10 per cent FS diet.  Although it is generally accepted that n 3 PUFAs mediate anti inflammatory effects, studies have demonstrated that they can also impair intestinal wound healing in vitro and exacerbate chemical or pathogen induced colitis severity in mice. The adverse effects of n 3 PUFAs in response to colonic injury may be through their incorporation into colonocyte and mitochondrial membranes, which may increase their susceptibility to oxidative stress, induce apoptosis, and impede cell signaling pathways necessary for colonocyte repair. The consumption of a FS supplemented diet, prior to and during DSS exposure, exacerbates colonic mucosal injury and inflammation in mice. The amount of ground FS supplemented into mouse diets in the current study (10 per cent ) has previously demonstrated anti inflammatory, anticancer, and cardio protective effects and thus, in addition to the lack of effects on DI and BW in the current study, indicates animal tolerance and safety of a 10 per cent FS supplemented diet.

Similar to previous studies utilizing dietary fish oil and its n 3 PUFAs, the FS diet may have aggravated the colitis phenotype in DSS exposed mice through n3 PUFA mediated impairments in mucosal repair responses and enhanced apoptosis, which would lead to increased colonic damage and inflammatory responses.  The relevance of these findings to colitis in humans and its associated diseases cannot be concluded on the basis of a single chemically induced model of murine colitis. It has been shown that dietary components can have different, opposing effects on colonic inflammation, depending on the model used. Additional experiments utilizing other models of colitis  are warranted to help better understand the implications of FS consumption in colonic inflammation. (Editors comments)

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