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Background: The disease severity index (DSI) for inflammatory bowel disease (IBD) combines measures of disease phenotype, inflammatory activity, and patient-reported outcomes. We aimed to validate the DSI and assess its utility in predicting a complicated IBD course., Methods: A multicenter cohort of adults with IBD was recruited. Intraclass correlation coefficients (ICCs) and weighted Kappa assessed inter-rater reliability. Cronbach's alpha measured internal consistency of DSI items. Spearman's rank correlations compared the DSI with endoscopic indices, symptom indices, quality of life, and disability. A subgroup was followed for 24 months to assess for a complicated IBD course. Area under the receiver operating characteristics curve (AUROC) and multivariable logistic regression assessed the utility of the DSI in predicting disease progression., Results: Three hundred and sixty-nine participants were included (Crohn's disease [CD], n = 230; female, n = 194; mean age, 46 years [SD, 15]; median disease duration, 11 years [interquartile range, 5-21]), of which 171 (CD, n = 99; ulcerative colitis [UC], n = 72) were followed prospectively. The DSI showed inter-rater reliability for CD (ICC 0.93, n = 65) and UC (ICC 0.97, n = 33). The DSI items demonstrated inter-rater agreement (Kappa > 0.4) and internal consistency (CD, α > 0.59; UC, α > 0.75). The DSI was significantly associated with endoscopic activity (CDn=141, r = 0.65, P < .001; UCn=105, r = 0.80, P < .001), symptoms (CDn=159, r = 0.69, P < .001; UCn=132, r = 0.58, P < .001), quality of life (CDn=198, r = -0.59, P < .001; UCn=128, r = -0.68, P < .001), and disability (CDn=83, r = -0.67, P < .001; UCn=52, r = -0.74, P < .001). A DSI of 23 best predicted a complicated IBD course (AUROC = 0.82, P < .001) and was associated with this end point on multivariable analyses (aOR, 9.20; 95% confidence interval, 3.32-25.49)., Conclusions: The DSI reliably encapsulates factors contributing to disease severity and accurately prognosticates the longitudinal IBD course., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Eosinophils have traditionally been viewed as pathological effector cells primarily involved in antiparasitic and allergic immune reactions; however, it is becoming increasingly apparent that eosinophils are multifaceted leukocytes that contribute to a variety of roles in both health and disease. Recent research shows that eosinophils play important immunoregulatory roles across various tissue sites including the gastrointestinal tract, adipose tissue, lung, liver, heart, muscles, thymus and bone marrow. With recent advances in our knowledge and appreciation of eosinophil immunoregulatory functions at these tissue sites, as well as emerging research demonstrating the existence of distinct subsets of eosinophils, a review of this topic is timely. Although some questions remain regarding eosinophil function and heterogeneity, this review summarizes the contemporary understanding of the immunoregulatory roles of eosinophils across various tissues and discusses the latest research on eosinophil heterogeneity and subsets., (© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Eosinophils play divergent roles in health and disease, contributing to both immunoregulatory and proinflammatory responses. Helminth infection is strongly associated with eosinophilia and the induction of the type 2 cytokines interleukin (IL)-5, IL-4 and IL-13. This study aimed to elucidate the heterogeneity of pulmonary eosinophils in response to helminth infection and the roles of IL-5, IL-4 and IL-13 in driving pulmonary eosinophil responses. Using the murine helminth model Nippostrongylus brasiliensis (Nb), we characterize a subtype of eosinophils, defined by high expression of CD101, that is induced in the lungs of Nb-infected mice and are phenotypically distinct from lung eosinophils that express low levels of CD101. Strikingly, we show that the two eosinophil subtypes have distinct anatomical localization within the lung: CD101 low eosinophils are predominantly localized in the lung vasculature, whereas Nb-induced CD101 hi eosinophils are predominantly localized in the extravascular lung niche. We show that CD101 hi eosinophils are also induced across other models of pulmonary infection and inflammation, including a nonlung-migrating helminth infection, house dust mite-induced allergic inflammation and influenza infection. Furthermore, we demonstrate that the induction of CD101 hi tissue eosinophils is independent of IL-5 and IL-4 signaling, but is dependent on intact IL-13 signaling. These results suggest that IL-13 produced during helminth infection and other disease states promotes a pulmonary tissue-infiltrating program in eosinophils defined by high expression of CD101., (© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Background: Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC., Methods: Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection., Results: At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang's blinding index 0.22; 95% CI, -0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35 × 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL., Conclusions: A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease., (© 2024 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed to prevent or treat various intestinal and extraintestinal diseases. However, full-scale clinical trials examining hookworm therapy are limited by the inability to scale-up the production of hookworm larvae to infect sufficient numbers of patients. With the aim of overcoming this challenge, this study infected four healthy individuals with hookworm larvae that had been reanimated from cryopreserved eggs to examine their viability and immunogenicity. We demonstrate that reanimated cryopreserved hookworm larvae establish a viable hookworm infection and elicit a similar immune response to larvae cultured from fresh stool. Furthermore, a refined understanding of the therapeutic mechanisms of hookworm is imperative to determine which diseases to target with hookworm therapy. To investigate potential therapeutic mechanisms, this study assessed changes in the immune cells, microbiome, and plasma metabolome in the four healthy individuals infected with cryopreserved hookworm larvae and another nine individuals infected with larvae cultured from freshly obtained stool. We identified potential immunoregulatory mechanisms by which hookworm may provide a beneficial effect on its host, including increased expression of CTLA-4 on regulatory T cells (Tregs) and upregulation of tryptophan metabolism. Furthermore, we found that a participant's baseline microbiome predicted the severity of symptoms and intestinal inflammation experienced during a controlled hookworm infection. In summary, our findings demonstrate the feasibility of full-scale clinical trials examining hookworm therapy by minimizing the reliance on human donors and optimizing the culturing process, thereby enabling viable hookworm larvae to be mass-produced and enabling on-demand inoculation of patients. Furthermore, this study provides insights into the complex interactions between helminths and their host, which could inform the development of novel therapeutic strategies.

The intestinal barrier is a dynamic multi-layered structure which can adapt to environmental changes within the intestinal lumen. It has the complex task of allowing nutrient absorption while limiting entry of harmful microbes and microbial antigens present in the intestinal lumen. Excessive entry of microbial antigens via microbial translocation due to 'intestinal barrier dysfunction' is hypothesised to contribute to the increasing incidence of allergic, autoimmune and metabolic diseases, a concept referred to as the 'epithelial barrier theory'. Helminths reside in the intestinal tract are in intimate contact with the mucosal surfaces and induce a range of local immunological changes which affect the layers of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory. This review will focus on the effect of helminths on intestinal barrier function and explore whether this could explain the proposed health benefits delivered by helminths., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Increased disease activity may be a risk factor for sexual dysfunction (SD) in patients with inflammatory bowel disease (IBD). This study investigated associations between objective measures of disease activity and sexual function., Methods: Adults with IBD undergoing ileocolonoscopy were prospectively recruited. Demographic, sexual function (Female Sexual Function Index and International Index of Erectile Function), disease activity (endoscopic, biomarker, and symptoms), psychological symptoms, and quality-of-life data were collected. Rates of SD and erectile dysfunction (ED) were compared between patients with active and inactive inflammation and symptoms using the Fisher's exact test. Logistic regression examined associations between SD and ED, and disease characteristics and psychological symptoms., Results: A total of 159 participants were included, 97 had Crohn's disease and 85 were women. SD was reported in 36 of 59 and 13 of 59 sexually active women and men, respectively and ED in 22 of 59 sexually active men. Rates of SD and ED were similar between individuals with active and inactive IBD based on endoscopic indices (P > .05) and biomarkers (P > .05). Women with active IBD symptoms experienced significantly higher rates of SD (P < .05), but men did not (P > .05). Multivariable logistic regression identified that symptoms of severe depression (odds ratio, 5.77; 95% confidence interval, 1.59-20.94) were associated with SD in women, and severe anxiety (odds ratio, 15.62; 95% confidence interval, 1.74-140.23) was associated with ED in men., Conclusions: Objective measures of disease activity are not associated with SD or ED in patients with IBD. Clinicians should consider concomitant psychological symptoms contributing to the sexual health of patients with IBD., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Aims: Inflammatory bowel disease [IBD], consisting of Crohn's disease [CD] and ulcerative colitis [UC], is a relapsing-remitting illness. Treat-to-target IBD management strategies require monitoring of gastrointestinal inflammation. This study aimed to investigate faecal myeloperoxidase [fMPO], a neutrophil granule enzyme, as a biomarker of IBD activity., Methods: Prospectively recruited participants with IBD, undergoing ileocolonoscopy for disease assessment, provided biological samples and completed symptom questionnaires prior to endoscopy. fMPO, C-reactive protein [CRP], and faecal calprotectin [fCal] were compared with validated endoscopic indices [simple endoscopic score for CD and UC endoscopic index of severity]. Receiver operating characteristic [ROC] curves assessed the performance of fMPO, CRP, and fCal in predicting endoscopic disease activity. Baseline biomarkers were used to predict a composite endpoint of complicated disease at 12 months [need for escalation of biologic/immunomodulator due to relapse, steroid use, IBD-related hospitalisation, and surgery]., Results: A total of 172 participants were recruited [91 female, 100 with CD]. fMPO was significantly correlated with endoscopic activity in both CD [r = 0.53, p < 0.01] and UC [r = 0.63, p < 0.01], and with fCal in all patients with IBD [r = 0.82, p < 0.01]. fMPO was effective in predicting moderate-to-severely active CD [AUROC 0.86, p < 0.01] and UC [AUROC 0.92, p < 0.01]. Individuals with a baseline fMPO > 26 µg/g were significantly more likely to reach the composite outcome at 12 months (hazard ratio [HR] 3.71, 95% confidence interval [CI] 2.07-6.64, p < 0.01)., Conclusions: Faecal myeloperoxidase is an accurate biomarker of endoscopic activity in IBD and predicted a more complicated IBD course during follow-up., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: The Disease Severity Index (DSI) is a novel tool to predict disease severity in inflammatory bowel disease (IBD). However, its ability to predict disease complications and the presence of psychosocial comorbidity is unclear., Aims: To assess prospectively associations between the DSI and psychological symptoms, quality-of-life (QoL) and disease outcomes in an IBD cohort., Methods: Patients with IBD undergoing ileocolonoscopy were followed prospectively for 12 months. DSI, psychological symptoms (perceived stress (PSS-10), depression (PHQ-9), anxiety (GAD-7)) and QoL (IBDQ-32) scores were assessed at baseline. Logistic regression identified variables predicting a complicated IBD course at 12 months (composite outcome of need for escalation of biological/immunomodulator for disease relapse, recurrent corticosteroid use, IBD-related hospitalisation and surgery). Receiver operating characteristics (ROC) analysis identified optimal DSI thresholds predicting a complicated disease course and multivariable logistic regression assessed the risk of reaching this outcome., Results: One hundred and seventy-two patients were recruited (100 Crohn's disease, 91 female). Median DSI was 21 (IQR 11-32) and 97 patients had endoscopically active disease at baseline. The DSI was significantly higher in patients with symptoms of moderate-severe stress (PSS-10 > 14, p < 0.01), depression (PHQ-9 ≥ 10, p < 0.01), anxiety (GAD-7 ≥ 10, p < 0.05) and impaired quality-of-life (IBDQ-32 < 168, p < 0.01). Only the baseline DSI (OR 1.05, p < 0.01) and endoscopically active disease (OR 6.12, p < 0.01) were associated with a complicated IBD course. A DSI > 23 was strongly predictive of a complicated IBD course (OR 8.31, p < 0.001)., Conclusions: The DSI is associated with psychological distress, impaired QoL and predicts a more complicated disease course in patients with IBD., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Disease activity may be a risk factor for psychological illness in patients with inflammatory bowel disease (IBD)., Aim: To correlate objective measures of disease activity with psychological symptoms., Methods: Adult patients with IBD undergoing ileocolonoscopy were prospectively recruited. Demographic, psychological symptoms (depression, anxiety, stress), disease activity (symptoms, biomarkers, endoscopy), and quality of life (QoL) data were collected. One-way ANOVA and multivariable analyses examined the associations between disease activity and symptoms of psychological illness, and identified other predictors of mental illness and reduced QoL., Results: A total of 172 patients were included, 107 with Crohn's disease (CD) and 65 with ulcerative colitis (UC). There was no significant association between objective disease activity (endoscopic scores, faecal calprotectin or C-reactive protein) and depression, anxiety or stress scores (P > 0.05 for all comparisons). Gastrointestinal symptoms were significantly associated with symptoms of depression, anxiety and stress in patients with CD and UC (P < 0.05). On multivariable analysis, only gastrointestinal symptoms were associated with severe symptoms of depression (OR 20.78 [6.71-92.37], P < 0.001) and anxiety (OR 4.26 [1.70-12.25], P = 0.004). Anti-TNF and corticosteroid use, the presence of severe depressive, moderate-severe stress and gastrointestinal symptoms, and endoscopically active IBD were associated with a reduced QoL (P < 0.05). Longer duration of IBD predicted an improved QoL (P < 0.05)., Conclusions: Objective measures of disease activity are not associated with symptoms of psychological illness in patients with IBD. Clinicians should consider underlying mental illness in patients with IBD with active gastrointestinal symptoms., (© 2021 John Wiley & Sons Ltd.)