Patients with ulcerative colitis undergoing total proctocolectomy with ileal pouch-anal anastomosis may develop pouchitis. Alpha-1-antitrypsin (AAT) is an acute phase reactant produced mainly by ...hepatocytes, but also locally in the gut. Data on noninvasive biomarkers of pouchitis are scarce.
To identify biomarkers that correlate with pouch inflammation, ulcerative colitis pouch patients were prospectively recruited and underwent clinical, endoscopic, and histologic evaluations. The Pouchitis Disease Activity Index (PDAI) was calculated, and pouchitis was defined by a score ≥7. Serum and fecal AAT, C-reactive protein (CRP), fecal calprotectin, ferritin and albumin levels were measured.
Seventy-one ulcerative colitis pouch patients (mean age 43.8 ± 8.3 yr, 50.7% males) were included. The main indication for ileal pouch-anal anastomosis was intractable colitis (83.1%). Median serum AAT level (183.0 mg/dL, 155.1-232.0) was significantly higher in patients with a PDAI ≥7 compared with those with a PDAI <7 (167.6 mg/dL, 151.0-181.0) (P = 0.03). Serum AAT, CRP, and fecal calprotectin levels significantly correlated with PDAI scores: r = 0.583, P < 0.001; r = 0.584, P < 0.001; and r = 0.606, P = 0.001, respectively. Serum AAT and CRP levels correlated significantly (r = 0.650, P < 0.001), as did serum AAT and fecal calprotectin levels (r = 0.663, P < 0.001). Fecal AAT levels did not correlate with any tested biomarker. Receiver operating characteristic analysis demonstrated sensitivity, specificity, and positive predictive value of 55.6%, 100%, and 100%, respectively, for diagnosing pouchitis at a serum AAT cutoff level of 189 mg/dL.
Serum AAT is a specific noninvasive biomarker of pouchitis. AAT levels correlate with disease activity and CRP and calprotectin levels.
Pouchitis may develop in patients with ulcerative colitis undergoing pouch surgery. We aimed to evaluate the de novo inflammation developing in the ileal pouch, hypothesizing that it may be similar ...to ileitis in Crohn's disease (CD).
Patients with ulcerative colitis pouch were prospectively recruited, stratified according to disease behavior into normal pouch, chronic pouchitis, and Crohn's-like disease of the pouch groups, and compared with controls. Gene expression analysis was performed using microarrays, validated by real-time polymerase chain reaction. Gene ontology and clustering were evaluated using bioinformatic tools.
Sixty-six subjects were recruited. Although in ulcerative colitis ileum there were no significant gene expression alterations, patients with normal pouch had 168 significant alterations (fold change ≥ 2, corrected P ≤ 0.05). In chronic pouchitis and Crohn's-like disease of the pouch, 490 and 1152 alterations were detected, respectively. High degree of overlap in gene expression alterations between the pouch subgroups was demonstrated. The magnitude of change correlated with pouch disease behavior. Gene expression profiles were more reflective of disease behavior compared with inflammatory indices. CD ileitis had 358 alterations, with a 90% overlap with pouchitis. Gene ontology analyses revealed multiple biological processes associated with pouch inflammation, including response to chemical stimulus, small molecule metabolic and immune system processes, and specific infection-related pathways such as Staphylococcus aureus, leishmaniasis, and tuberculosis.
Gene alterations in pouch inflammation and CD overlap, suggesting that inflammatory bowel diseases is a spectrum, rather than distinct diseases. Pouchitis may serve as a model of CD. The novel pathways associated with inflammatory bowel diseases may decipher pathophysiology and suggest targets for intervention.
BACKGROUNDAdenomatous polyposis syndromes (APS) patients with ileal pouch anal anastomosis (IPAA) suffer frequent symptoms with scarce signs of inflammation, distinct from ulcerative colitis ...patients. While the management of pouchitis in ulcerative colitis patients is well established, data regarding response to treatment modalities targeting pouch-related disorders in APS patient population is scarce. AIMTo assess clinical, endoscopic and histologic response to various treatment modalities employed in the therapy of pouch related disorders. METHODSAPS patients who underwent IPAA between 1987-2019 were followed every 6-12 mo and pouch-related symptoms were recorded at every visit. Lower endoscopy was performed annually, recording features of the pouch, cuff and terminal ileum. A dedicated gastrointestinal pathologist reviewed biopsies for signs and severity of inflammation. At current study, files were retrospectively reviewed for initiation and response to various treatment modalities between 2015-2019. Therapies included dietary modifications, probiotics, loperamide, antibiotics, bismuth subsalicylate, mebeverine hydrochloride, 5-aminosalicylic acid compounds and topical rectal steroids. Symptoms and endoscopic and histologic signs of inflammation before and after treatment were assessed. Pouchitis disease activity index (PDAI) and its subscores was calculated. Change of variables before and after therapy was assessed using Wilcoxon signed rank test for continuous variables and using McNemar's test for categorical variables. RESULTSThirty-three APS patients after IPAA were identified. Before treatment, 16 patients (48.4%) suffered from abdominal pain and 3 (9.1%) from bloody stools. Mean number of daily bowel movement was 10.3. Only 4 patients (12.1%) had a PDAI ≥ 7. Mean baseline PDAI was 2.5 ± 2.3. Overall, intervention was associated with symptomatic relief, mainly decreasing abdominal pain (from 48.4% to 27.2% of patients, P = 0.016). Daily bowel movements decreased from a mean of 10.3 to 9.3 (P = 0.003). Mean overall and clinical PDAI scores decreased from 2.58 to 1.94 (P = 0.016) and from 1.3 to 0.87 (P = 0.004), respectively. Analyzing each treatment modality separately, we observed that dietary modifications decreased abdominal pain (from 41.9% of patients to 19.35%, P = 0.016), daily bowel movements (from 10.5 to 9.3, P = 0.003), overall PDAI (from 2.46 to 2.03, P = 0.04) and clinical PDAI (1.33 to 0.86, P = 0.004). Probiotics effectively decreased daily bowel movements (from 10.2 to 8.8, P = 0.007), overall and clinical PDAI (from 2.9 to 2.1 and from 1.38 to 0.8, P = 0.032 and 0.01, respectively). While other therapies had minimal or no effects. No significant changes in endoscopic or histologic scores were seen with any therapy. CONCLUSIONAPS patients benefit from dietary modifications and probiotics that improve their pouch-related symptoms but respond minimally to anti-inflammatory and antibiotic treatments. These results suggest a functional rather than inflammatory disorder.
Intestinal epithelial cells (IECs) are the first to encounter luminal antigens and may be involved in intestinal immune responses. Fungi are important components of the intestinal microflora. The ...potential role of fungi, and in particular their cell wall component beta-glucan, in modulating human intestinal epithelial responses is still unclear. Here we examined whether human IECs are capable of recognizing and responding to beta-glucans, and the potential mechanisms of their activation. We show that human IECs freshly isolated from surgical specimens, and the human IEC lines HT-29 and SW480, express the beta-glucan receptor Dectin-1. The beta-glucan-consisting glycans curdlan and zymosan stimulated IL-8 and CCL2 secretion by IEC lines. This was significantly inhibited by a Dectin-1 blockade using its soluble antagonist laminarin. Spleen tyrosine kinase (Syk), a signaling mediator of Dectin-1 activation, is expressed in human IECs. beta-glucans and Candida albicans induced Syk phosphorylation, and Syk inhibition significantly decreased beta-glucan-induced chemokine secretion from IECs. Thus, IECs may respond to beta-glucans by the secretion of pro-inflammatory chemokines in a Dectin-1- and Syk-dependent pathway, via receptors and a signaling pathway described to date only for myeloid cells. These findings highlight the importance of fungi-IEC interactions in intestinal inflammation.
Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6C
monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of ...orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6C
monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6C
monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6C
monocyte fate decisions and reparative behavior in the diseased liver.
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