Meta-Analysis of Expression Profiling Data Indicates Need for Combinatorial Biomarkers in Pediatric Ulcerative Colitis

Background. Unbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative colitis (UC). However, clinical translation has been proven difficult. Here, we hypothesized that one reason could be differences between inflammatory responses in an inflamed gut and in peripheral blood cells. Methods. We performed meta-analysis of gene expression microarray data from intestinal biopsies and whole blood cells (WBC) from pediatric patients with UC and healthy controls in order to identify overlapping pathways, predicted upstream regulators, and potential biomarkers. Results. Analyses of profiling datasets from colonic biopsies showed good agreement between different studies regarding pathways and predicted upstream regulators. The most activated predicted upstream regulators included TNF, which is known to have a key pathogenic and therapeutic role in pediatric UC. Despite this, the expression levels of TNF were increased in neither colonic biopsies nor WBC. A potential explanation was increased expression of TNFR2, one of the membrane-bound receptors of TNF in the inflamed colon. Further analyses showed a similar pattern of complex relations between the expression levels of the regulators and their receptors. We also found limited overlap between pathways and predicted upstream regulators in colonic biopsies and WBC. An extended search including all differentially expressed genes that overlapped between colonic biopsies and WBC only resulted in identification of three potential biomarkers involved in the regulation of intestinal inflammation. However, two had been previously proposed in adult inflammatory bowel diseases (IBD), namely, MMP9 and PROK2. Conclusions. Our findings indicate that biomarker identification in pediatric UC is complicated by the involvement of multiple pathways, each of which includes many different types of genes in the blood or inflamed intestine. Therefore, further studies for identification of combinatorial biomarkers are warranted. Our study may provide candidate biomarkers for such studies.

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Transplantation of bacteriophages from ulcerative colitis patients shifts the gut bacteriome and exacerbates severity of DSS-colitis

10.1101/2021.09.10.459444 ◽

2021 ◽

Author(s):

Anshul Sinha ◽

Yue Li ◽

Mohammadali Khan Mirzaei ◽

Michael Shamash ◽

Rana Samadfam ◽

...

Keyword(s):

Ulcerative Colitis ◽

Bacterial Diversity ◽

Bacterial Communities ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Experimental Colitis ◽

Shotgun Metagenomics ◽

Dss Colitis ◽

Bowel Diseases

Inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC) are characterized by chronic and debilitating gut inflammation. Altered bacterial communities of the intestine are strongly associated with IBD initiation and progression. The gut virome, which is primarily composed of bacterial viruses (bacteriophages, phages) is thought to be an important factor regulating and shaping microbial communities in the gut. While alterations in the gut virome have been observed in IBD patients, the contribution of these viruses to alterations in the bacterial community and heightened inflammatory responses associated with IBD patients remains largely unknown. Here, we performed in vivo microbial cross-infection experiments to follow the effects of fecal virus-like particles (VLPs) isolated from UC patients and healthy controls on bacterial diversity and severity of experimental colitis in human microbiota-associated (HMA) mice. Shotgun metagenomics confirmed that several phages were transferred to HMA mice, resulting in treatment-specific alterations in the gut virome. VLPs from healthy and UC patients also shifted gut bacterial diversity of these mice, an effect that was amplified during experimental colitis. VLPs isolated from UC patients specifically altered the relative abundance of several bacterial taxa previously implicated in IBD progression. Additionally, UC VLP administration heightened colitis severity in HMA mice, as indicated by shortened colon length and increased pro-inflammatory cytokine production. Importantly, this effect was dependent on intact VLPs. Our findings build on recent literature indicating that phages are dynamic regulators of bacterial communities in the gut and implicate the intestinal virome in modulating intestinal inflammation and disease.

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Effect of corticosteroids on nitric oxide production in inflammatory bowel disease: are leukocytes the site of action?

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00336.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. G261-G267 ◽

Cited By ~ 13

Author(s):

John D. Linehan ◽

George Kolios ◽

Vassilis Valatas ◽

Duncan A. F. Robertson ◽

John Westwick

Keyword(s):

Nitric Oxide ◽

Ulcerative Colitis ◽

Mononuclear Cells ◽

Intestinal Inflammation ◽

Inos Mrna ◽

No Production ◽

Nitrite Production ◽

Ifn Γ ◽

Colonic Biopsies ◽

Ht 29

Nitric oxide (NO) production is increased in the human colonic mucosa in intestinal inflammation. We examined the effect of corticosteroids and the role of mononuclear cells in this production. Colonic biopsies from patients with ulcerative colitis and normal controls were cultured with either budesonide or prednisolone in the presence of proinflammatory cytokines. Human mixed mononuclear cells (MMCs) were cocultured with HT-29 cells stimulated with IFN-γ and LPS in the presence or absence of corticosteroids. Nitrite production was measured in supernatants by a modification of the Griess reaction, and inducible NO synthase (iNOS) mRNA expression was studied in colonic tissue by RT-PCR. Both steroids significantly suppressed the nitrite production and iNOS mRNA expression in inflamed colonic biopsies from ulcerative colitis patients and in cytokine-stimulated normal colonic biopsies but not in cytokine-stimulated HT-29 cells. Nitrite production by HT-29 cells was significantly increased ( P < 0.01) in cocultures with MMCs stimulated with IFN-γ and LPS. The presence of either prednisolone or budesonide significantly ( P < 0.01) suppressed nitrite production from cocultures of HT-29 cells and MMCs but not from cultures of HT-29 cells stimulated with conditioned media from activated MMCs. Interestingly, stimulation of HT-29 with conditioned media from MMCs pretreated with steroids before stimulation with LPS and IFN-γ induced a significantly ( P < 0.01) lower nitrite production. These results suggest that the inhibitory effect of corticosteroids on the NO production in the intestinal inflammation might be via the inhibition of MMC-produced mediators responsible for NO production by colonic epithelial cells.

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Comorbid Inflammatory Diseases of Digestive System and Eye

Ophthalmology in Russia ◽

10.18008/1816-5095-2021-1-20-29 ◽

2021 ◽

Vol 18 (1) ◽

pp. 20-29

Author(s):

S. A. Bulgakov ◽

G. M. Chernakova ◽

E. A. Kleshcheva ◽

S. V. Simonova

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Ophthalmological Examination ◽

Extraintestinal Manifestations ◽

Bowel Diseases ◽

Inflammatory Bowel

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases, which are often accompanied by inflammation of other organs. This article presents modern data on etiology, pathogenesis and clinical course of inflammatory bowel diseases, as well as information on extraintestinal eye manifestations of nonspecific ulcerative colitis and Crohn’s disease. The role of microbiota, genetic factors, immune system defects in pathogenesis of intestinal inflammation and extraintestinal eye manifestations is considered. The possibility the development of ophthalmopathology not only against the background of intestinal inflammation, but also as a consequence of therapeutic and surgical methods of treatment of ulcerative colitis and Crohn’s disease is noted. The peculiarities of the course of episcleritis/scleritis, keratitis, uveitis, chorioretinitis, optical neuritis for patients with inflammatory bowel diseases are considered. The presence of these complications may reflect the activity of the underlying disease, which in some cases requires correction of therapy. Anterior uveitis and episcleritis/scleritis are the most common extraintestinal manifestations of inflammatory bowel disease. Inflammation of tissues of the posterior segment of the eye and optic nerve against the background of ulcerative colitis and Crohn’s disease are less common, but are of clinical importance, as they can catastrophically damage the structures of the eye and, as a consequence, lead to complete blindness. Considering the possibility of mild clinical symptoms and asymptomatic course of inflammation in the eye envelopes, the importance of ophthalmological examination of all patients with ulcerative colitis and Crohn’s disease is emphasized. Aspects of modern therapy of ophthalmopathology and background intestinal inflammation are highlighted. Biological preparations — antagonists of pro-inflammatory cytokines — have been identified as the most promising in the treatment of inflammatory intestinal diseases and extraintestinal manifestations. The important role of proper nutrition and biologically active supplements containing omega-3 fatty acids, vitamin D, microelements, was noted as auxiliary therapy of both intestinal and extraintestinal inflammation.

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Mucosal Eosinophilia Is an Independent Predictor of Vedolizumab Efficacy in Inflammatory Bowel Diseases

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz251 ◽

2019 ◽

Vol 26 (8) ◽

pp. 1232-1238 ◽

Cited By ~ 2

Author(s):

Erin M Kim ◽

Cara Randall ◽

Renee Betancourt ◽

Staci Keene ◽

Amy Lilly ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Response ◽

Multivariable Analysis ◽

Patient Characteristics ◽

Predictors Of Response ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Negative Predictor ◽

Colonic Biopsies

Abstract Background Peripheral and mucosal eosinophilia may be associated with more aggressive disease in inflammatory bowel disease (IBD) patients. Vedolizumab blocks T lymphocytes, eosinophil adhesion, and extravasation in the gastrointestinal tract. It is not known if mucosal eosinophilia is a predictor for the therapeutic efficacy of vedolizumab. Methods This was a retrospective cohort study of IBD patients with ileal or colonic biopsies who were off steroids before starting vedolizumab. Biopsies were rereviewed by pathologists, and mean eosinophil density was quantified. Patient characteristics and steroid-free clinical response 6 months after beginning vedolizumab were determined. Features were compared between nonresponders and responders, and multivariable logistic regression was performed to identify predictors of clinical response. Results Of 251 IBD patients starting vedolizumab therapy, 65 patients (48% Crohn’s disease, 52% ulcerative colitis) met inclusion criteria. All IBD patients not responding to vedolizumab were more likely to have a higher baseline mean eosinophil count (340 ± 156 vs 236 ± 124; P = 0.004), be previously exposed to an anti-TNF (96% vs 56%; P = 0.001), and be male (58% vs 28%; P = 0.02). Mean eosinophil counts were significantly increased in colonic biopsies in UC nonresponders (438 ± 149 vs 299 ± 145; P = 0.01). A similar trend was seen in CD nonresponders. On multivariable analysis, colonic eosinophil density and prior anti-TNF exposure—and the combination of both—were independent predictors of response. Conclusion In ulcerative colitis, colonic eosinophilia and prior anti-TNF exposure were independent predictors of 6-month clinical nonresponse to vedolizumab. Mucosal eosinophil density as a novel biomarker should be explored in larger patient cohorts. Aside from the previous anti-TNF exposure, eosinophil density in the colon of patients with UC is a negative predictor for a steroid-free long-term response to vedolizumab. The degree colonic eosinophilia may be a novel biomarker that should be further explored.

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Immunopathophysiology of inflammatory bowel disease: how genetics link barrier dysfunction and innate immunity to inflammation

Innate Immunity ◽

10.1177/1753425917722206 ◽

2017 ◽

Vol 23 (6) ◽

pp. 497-505 ◽

Cited By ~ 9

Author(s):

Minesh Mehta ◽

Shifat Ahmed ◽

Gerald Dryden

Keyword(s):

Inflammatory Bowel Disease ◽

Innate Immunity ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Clinical Symptoms ◽

Barrier Dysfunction ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation

Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic or relapsing immune activation and corresponding inflammation within the gastrointestinal (GI) tract. Diverse genetic mutations, encoding important aspects of innate immunity and mucosal homeostasis, combine with environmental triggers to create inappropriate, sustained inflammatory responses. Recently, significant advances have been made in understanding the interplay of the intestinal epithelium, mucosal immune system, and commensal bacteria as a foundation of the pathogenesis of inflammatory bowel disease. Complex interactions between specialized intestinal epithelial cells and mucosal immune cells determine different outcomes based on the environmental input: the development of tolerance in the presence of commensal bacterial or the promotion of inflammation upon recognition of pathogenic organisms. This article reviews key genetic abnormalities involved in inflammatory and homeostatic pathways that enhance susceptibility to immune dysregulation and combine with environmental triggers to trigger the development of chronic intestinal inflammation and IBD.

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Colonic Mucosal Microbiota and Association of Bacterial Taxa with the Expression of Host Antimicrobial Peptides in Pediatric Ulcerative Colitis

International Journal of Molecular Sciences ◽

10.3390/ijms21176044 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6044

Author(s):

Jonna Jalanka ◽

Jing Cheng ◽

Kaisa Hiippala ◽

Jarmo Ritari ◽

Jarkko Salojärvi ◽

...

Keyword(s):

Ulcerative Colitis ◽

Antimicrobial Peptides ◽

Defense Mechanisms ◽

Unknown Etiology ◽

Rdna Sequencing ◽

Family Level ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Colonic Biopsies ◽

Host Genes

Inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are chronic debilitating disorders of unknown etiology. Over 200 genetic risk loci are associated with IBD, highlighting a key role for immunological and epithelial barrier functions. Environmental factors account for the growing incidence of IBD, and microbiota are considered as an important contributor. Microbiota dysbiosis can lead to a loss of tolerogenic immune effects and initiate or exacerbate inflammation. We aimed to study colonic mucosal microbiota and the expression of selected host genes in pediatric UC. We used high-throughput 16S rDNA sequencing to profile microbiota in colonic biopsies of pediatric UC patients (n = 26) and non-IBD controls (n = 27). The expression of 13 genes, including five for antimicrobial peptides, in parallel biopsies was assessed with qRT-PCR. The composition of microbiota between UC and non-IBD differed significantly (PCoA, p = 0.001). UC children had a decrease in Bacteroidetes and an increase in several family-level taxa including Peptostreptococcaceae and Enterobacteriaceae, which correlated negatively with the expression of antimicrobial peptides REG3G and DEFB1, respectively. Enterobacteriaceae correlated positively with the expression siderophore binding protein LCN2 and Betaproteobacteria negatively with DEFB4A expression. The results indicate that reciprocal interaction of epithelial microbiota and defense mechanisms play a role in UC.

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Preventive Effects of an UPLC-DAD-MS/MS Fingerprinted Hydroalcoholic Extract of Citrus aurantium in a Mouse Model of Ulcerative Colitis

Planta Medica ◽

10.1055/a-0604-2797 ◽

2018 ◽

Vol 84 (15) ◽

pp. 1101-1109 ◽

Cited By ~ 8

Author(s):

Youn-Hwan Hwang ◽

Jin Ma

Keyword(s):

Ulcerative Colitis ◽

Body Weight ◽

Intestinal Inflammation ◽

Clinical Signs ◽

Pathological Examination ◽

Array Detector ◽

Therapeutic Effects ◽

Citrus Aurantium ◽

Hydroalcoholic Extract ◽

Expression Levels

AbstractAlthough traditionally used to improve indigestion, diarrhea, dysentery, and constipation, the therapeutic effects of Citrus aurantium on intestinal inflammation remain unclear. The aim of this study was to evaluate the beneficial effects and to identify the active components of a hydroalcoholic extract of C. aurantium (HECA) on ulcerative colitis. HECA was prepared with 70% ethanol solution in water and extracted at 37 °C for 12 h in triplicate, filtered through a sieve, and lyophilized. Phytochemical identification of HECA was performed by ultra-performance liquid chromatography-diode array detector-tandem mass spectrometry (UPLC-DAD-MS/MS). Animals were randomly assigned to one of four groups based on the treatment conditions. Ulcerative colitis was induced by administration of 2.5% dextran sodium sulfate (DSS) in drinking water for 5 d. Body weight, clinical signs, colon length, pro-inflammatory cytokine expression levels, and histopathological findings were evaluated. In UPLC-DAD-MS/MS analysis, the identified phytochemical components of HECA included four alkaloids, seven coumarins, 18 flavonoids, two lignans, two phenolics, and 10 terpenoids. HECA markedly protected against body weight loss and colon shortening. In pathological examination, HECA alleviated DSS-related mucosal inflammatory lesions in the colon. Moreover, HECA markedly reduced the expression levels of interleukin-6, interferon-γ, tumor necrosis factor-α, and monocyte chemotactic protein-1 in colonic inflammation. Taken together, HECA has potential to relieve mucosal inflammation in the colon, suggesting that the putative active ingredients are responsible for the anti-ulcerative effects.

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Regulation of Intestinal Inflammation by Soybean and Soy-Derived Compounds

Foods ◽

10.3390/foods10040774 ◽

2021 ◽

Vol 10 (4) ◽

pp. 774

Author(s):

Abigail R. Basson ◽

Saleh Ahmed ◽

Rawan Almutairi ◽

Brian Seo ◽

Fabio Cominelli

Keyword(s):

Ulcerative Colitis ◽

Intestinal Inflammation ◽

Saturated Fat ◽

Rodent Models ◽

High Intake ◽

Disease Mechanisms ◽

Bowel Diseases ◽

Disease Induction ◽

Inflammatory Bowel ◽

Refined Carbohydrates

Environmental factors, particularly diet, are considered central to the pathogenesis of the inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis. In particular, the Westernization of diet, characterized by high intake of animal protein, saturated fat, and refined carbohydrates, has been shown to contribute to the development and progression of IBD. During the last decade, soybean, as well as soy-derived bioactive compounds (e.g., isoflavones, phytosterols, Bowman-Birk inhibitors) have been increasingly investigated because of their anti-inflammatory properties in animal models of IBD. Herein we provide a scoping review of the most studied disease mechanisms associated with disease induction and progression in IBD rodent models after feeding of either the whole food or a bioactive present in soybean.

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IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells

Journal of Experimental Medicine ◽

10.1084/jem.20111453 ◽

2012 ◽

Vol 209 (9) ◽

pp. 1595-1609 ◽

Cited By ~ 308

Author(s):

Margherita Coccia ◽

Oliver J. Harrison ◽

Chris Schiering ◽

Mark J. Asquith ◽

Burkhard Becher ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Intestinal Pathology ◽

Bowel Diseases ◽

Chronic Intestinal Inflammation

Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus–triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell–specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4+ T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4+ T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.

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Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome

Gut ◽

10.1136/gutjnl-2020-322670 ◽

2021 ◽

pp. gutjnl-2020-322670

Author(s):

Laura A Bolte ◽

Arnau Vich Vila ◽

Floris Imhann ◽

Valerie Collij ◽

Ranko Gacesa ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Dietary Patterns ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Meta Analysis ◽

Dietary Factors ◽

Metagenomic Sequencing ◽

Microbial Composition ◽

Anti Inflammatory

ObjectiveThe microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. We aim to unravel interactions between diet, gut microbiota and their functional ability to induce intestinal inflammation.DesignWe investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn’s disease, ulcerative colitis, irritable bowel syndrome and the general population. Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation.ResultsWe identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn’s disease and UC (false discovery rate<0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, Ruminococcus species of the Blautia genus and endotoxin synthesis pathways. The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism.ConclusionWe identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.

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