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Title: Association between short-chain fatty acids, selected inflammatory mediators, and intestinal barrier integrity in patients with inflammatory bowel diseases


Introduction Inflammatory bowel disease (IBD) is an umbrella term for chronic inflammatory diseases of the gastrointestinal tract, including ulcerative colitis (UC) and Crohn disease (CD). The etiopathogenesis of IBD is complex and remains unclear. The mutual influence of genetic and immune factors as well as the disruption of the intestinal microbiota (dysbiosis) and its metabolites, particularly short-chain fatty acids (SCFAs), are considered in the development of these diseases. SCFAs are the main products of fiber fermentation by large intestinal microbiota. The main SCFAs found in the intestines are butyric, acetic, and propionic acids. They have numerous benefits for the human body, such as anti-inflammatory effects and improved integrity and function of the intestinal barrier. The SCFA profile has not been fully explored in patients with IBD so far. Moreover, there are no data on factors that may affect SCFA levels, such as diet or medications. Chronic inflammation of the intestinal mucosa is associated with impaired intestinal barrier, its increased permeability, and increased antigens presentation on the surface of host’s immune cells. At the same time, an increased expression of inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), is observed. Moreover, there are disturbances in the expression of intercellular junction proteins, ; including occludin and claudin. Research is needed to investigate how the SCFA profile is linked to intestinal barrier integrity and severity of intestinal mucosal inflammation as well as severity of clinical symptoms in patients with IBD. Such data would facilitate developments in SCFA supplementation as an adjunctive treatment for patients with IBD aimed at relieving symptoms and intestinal mucosal healing. Objectives The aim of the study was to assess the qualitative and quantitative changes in fecal SCFA levels in patients with IBD during remission and active disease, as compared with controls, using capillary electrophoresis with spectrophotometric detection (CE-UV). Another objective was to determine an association between the fecal SCFA profile and selected inflammatory markers (C-reactive protein [CRP], calprotectin) as well as serum proinflammatory and anti-inflammatory markers (TNF-α, IL-6, IL-10, IL-17, and IL-22) in patients with inactive and active IBD as well as controls. Finally, the aim of the study was to assess mucosal mRNA expression in large intestinal mucosa for selected inflammatory markers (IL-6), enzymes (peroxisome proliferator-activated receptor gamma [PPAR-γ], inducible nitric oxide synthase [iNOS]), and tight junction proteins (zonula occludens-1 [ZO-1], claudin-2, occludin) in patients with inactive and active IBD as well as controls, using real ; -time polymerase chain reaction (RT-PCR). Methods The study included 77 participants: 43 patients with UC (14 with inactive disease and 29 with active disease), 18 patients with CD (8 with inactive disease and 10 with active disease), and 16 controls. The activity of UC was assessed using Mayo criteria, and the activity of CD, using Crohn’s Disease Activity Index. All participants completed a questionnaire on enrollment, including a food questionnaire developed specifically for the purpose of this study with a clinical dietitian. In all participants, complete blood count, albumin, ferritin, CRP, and fecal calprotectin levels were measured. In addition, fecal levels of the following organic acids were measured using CE-UV: acetic, lactic, succinic, propionic, butyric, isovaleric, isobutyric, and valeric acids. The serum levels of TNF-α, IL-6, IL-10, IL-17, and IL-22 were measured using an enzyme-linked immunosorbent assay. In addition, in 35 participants (11 patients with inactive IBD, 18 patients with active IBD, and 6 controls), biopsy samples were obtained from the large intestinal mucosa during colonoscopy to assess mRNA expression for selected markers of inflammation and intestinal mucosal integrity. The biopsy samples were used to assess the mRNA expression for IL-6, PPAR-γ, iNOS, hypoxia-inducible factor 1-α (HIF-1α), ZO-1, claudin-2, occludin, and succinate receptor ; 1 (SUCNR1) using RT-PCR. Results Patients with active IBD had lower fecal levels of butyric, acetic, valeric, and isovaleric acids but higher levels of lactic acid, as compared with the control group. Moreover, patients with active IBD had lower median levels of butyric acid, as compared with patients with inactive IBD (54.7 μg/g vs 334 μg/g; p < 0.05). There were no significant differences in SCFA levels between patients with UC and those with CD, irrespective of disease activity, and the control group. Hemoglobin levels were positively correlated with acetic and butyric acid levels (R = 0.266 and R = 0.346, respectively; p < 0.05). CRP levels were positively correlated with lactic acid levels (R = 0.534; p < 0.05) and inversely correlated with butyric acid levels (R = −0.573; p < 0.05). Patients with active IBD had higher serum TNF-α levels than controls (6.64 pg/ml vs 2.05 pg/ml, p < 0.05). There was no correlation between the SCFA profile and cytokine levels (TNF-α, IL-6, IL-10, IL-17, and IL-22). The mRNA expression for iNOS and PPAR-γ was higher in patients with active IBD than in those with inactive IBD (p < 0.05). Moreover, the mRNA expression for claudin-2 and ZO-1 was lower in patients with active IBD than in those with inactive IBD (p < 0.05 for both comparisons). The mRNA expression for HIF-1α and IL-6 was higher in patients with active and inactive IBD, as co ; mpared with controls, but the difference was not significant (p > 0.05). Conclusions The results of this study confirm the clinical utility of the presented method for stool sampling and CE-UV for SCFA identification and measurement. The fecal SCFA profile may be used for a noninvasive assessment of IBD activity. Our study showed that patients with active IBD have reduced fecal SCFA levels as well as isovaleric acid levels, while they have increased fecal lactic acid levels. The SCFA profile does not differ between the types of IBD (UC vs CD). Serum TNF-α levels may serve as a marker of IBD activity. However, no such potential was revealed for the other cytokines: IL-6, IL-10, IL-17, and IL-22. There was no correlation between serum cytokine levels and the individual SCFAs. Patients with active IBD show a lower mRNA expression for tight junction proteins (claudin 2 and ZO-1) and a higher mRNA expression for iNOS and PPAR-γ, as compared with IBD patients in remission.

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2 - studia doktoranckie

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Rada Dyscypliny Nauki medyczne


Zwolińska-Wcisło, Małgorzata ; Woźniakiewicz, Michał

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pol; eng

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tylko w bibliotece

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Apr 17, 2024

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Apr 17, 2024

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UJCMf8ea435beafa4964938f38352a9a906b Apr 17, 2024


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