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Inflammatory bowel diseases (IBDs) are chronic conditions characterized by periods of spontaneous intestinal inflammation and are increasing in industrialized populations. Combined with host genetics, diet and gut bacteria are thought to contribute prominently to IBDs, but mechanisms are still emerging. In mice lacking the IBD-associated cytokine, interleukin-10, we show that a fiber-deprived gut microbiota promotes the deterioration of colonic mucus, leading to lethal colitis. Inflammation starts with the expansion of natural killer cells and altered immunoglobulin-A coating of some bacteria. Lethal colitis is then driven by Th1 immune responses to increased activities of mucin-degrading bacteria that cause inflammation first in regions with thinner mucus. A fiber-free exclusive enteral nutrition diet also induces mucus erosion but inhibits inflammation by simultaneously increasing an anti-inflammatory bacterial metabolite, isobutyrate. Our findings underscore the importance of focusing on microbial functions-not taxa-contributing to IBDs and that some diet-mediated functions can oppose those that promote disease., Competing Interests: Declaration of interests E.C.M. works as a consultant and an advisory board member at January, Inc., United States. M.S.D. works as a consultant and an advisory board member at Theralution GmbH, Germany., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Inflammatory bowel disease (IBD) is a chronic condition characterized by periods of spontaneous intestinal inflammation and is increasing in industrialized populations. Combined with host genetic predisposition, diet and gut bacteria are thought to be prominent features contributing to IBD, but little is known about the precise mechanisms involved. Here, we show that low dietary fiber promotes bacterial erosion of protective colonic mucus, leading to lethal colitis in mice lacking the IBD-associated cytokine, interleukin-10. Diet-induced inflammation is driven by mucin-degrading bacteria-mediated Th1 immune responses and is preceded by expansion of natural killer T cells and reduced immunoglobulin A coating of some bacteria. Surprisingly, an exclusive enteral nutrition diet, also lacking dietary fiber, reduced disease by increasing bacterial production of isobutyrate, which is dependent on the presence of a specific bacterial species, Eubacterium rectale . Our results illuminate a mechanistic framework using gnotobiotic mice to unravel the complex web of diet, host and microbial factors that influence IBD.

Sulforaphane is a bioactive metabolite with anti-inflammatory activity and is derived from the glucosinolate glucoraphanin, which is highly abundant in broccoli sprouts. However, due to its inherent instability its use as a therapeutic against inflammatory diseases has been limited. There are few studies to investigate a whole food approach to increase sulforaphane levels with therapeutic effect and reduce inflammation. In the current study, using a mouse model of inflammatory bowel disease, we investigated the ability of steamed broccoli sprouts to ameliorate colitis and the role of the gut microbiota in mediating any effects. We observed that despite inactivation of the plant myrosinase enzyme responsible for the generation of sulforaphane via steaming, measurable levels of sulforaphane were detectable in the colon tissue and feces of mice after ingestion of steamed broccoli sprouts. In addition, this preparation of broccoli sprouts was also capable of reducing chemically-induced colitis. This protective effect was dependent on the presence of an intact microbiota, highlighting an important role for the gut microbiota in the metabolism of cruciferous vegetables to generate bioactive metabolites and promote their anti-inflammatory effects., Competing Interests: Declaration of Competing Interests The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In the present work, we developed and evaluated the performance of a new flow cytometry-based single platform, referred to as "FC-Duplex IgG1 (HTLV-1/2)", for universal and differential serodiagnosis of HTLV-1/2 infection. The proposed technology employs a system for detection of IgG1 antibodies in a single competitive immunofluorescence platform by flow cytometry using fluorescently labeled MT-2/MoT cell line mix coupled to a highly sensitive development system (Biotin/Streptavidin/Phycoerythrin). The stability of fluorescent labeling and the antigenicity of MT-2 and MoT cell lines were confirmed upon storage at -20°C for 2, 6, and 12 months. The anti-HTLV-1/2 IgG1 reactivity, expressed as percentage of positive fluorescent cells (PPFC), was evaluated for each target antigen along the titration curve of test serum samples (1:32 to 1:4,096). Upon selection of target cell line and serum dilutions with higher segregation score between groups, the performance of "FIX" and "FIX & PERM" protocols was evaluated. The "FIX" protocol presented excellent performance indices (Se = 92%/Sp = 94%/AUC = 0.96; Se = 96%/Sp = 100%/AUC = 0.99) for the universal (HTLV-1/2 vs. NI) and differential (HTLV-1 vs. HTLV-2) diagnosis of HTLV-1 infection, respectively. Optimization of the "FIX" protocol using the principle of synchronous and asynchronous pairwise analysis further improved the performance of "FC-Duplex IgG1 (HTLV-1/2)", using the "FIX" protocol for differential diagnosis of HTLV-1 and HTLV-2 infections (Se = 100%/Sp = 100%/AUC = 1.00). In conclusion, the "FC-Duplex IgG1 (HTLV-1/2)" method represents an innovation in the biotechnology segment with the potential to compose a serological kit for differential diagnosis of HTLV-1/2 infection for reference laboratories and blood centers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pimenta de Paiva, Coelho-dos-Reis, Trindade, Peruhype-Magalhães, Silva Araújo, Gonçalves, Nogueira, Pereira Martins, Lopes Ribeiro, Starling, Alcântara, Ribeiro, Carneiro-Proietti, Sabino, Alves Bicalho, Teixeira-Carvalho and Martins-Filho.)

Cytomegalovirus (CMV) is a member of the Herpesviridae family, including viruses that are well-known agents of keratitis, anterior uveitis, scleritis and retinitis. CMV is usually associated with ocular diseases in immunosuppressed individuals, with a notable exception of hypertensive anterior uveitis with distinctive clinical features in immunocompetent patients. This syndrome was characterized in the last two decades in Europe and Southeast Asia, and then documented in the rest of world. Definitive diagnosis in these cases is usually made by Polymerase Chain Reaction (PCR) of the anterior chamber fluid. We report three immunocompetent Brazilian adults with history of multiple glaucomatocyclitic crises and presenting with chronic hypertensive anterior uveitis invariably with mild anterior chamber inflammation and characteristic scarce nummular keratic precipitates. CMV DNA was successfully amplified and detected in the aqueous humor of all patients. Corneal endothelial counts were significantly reduced in the involved eyes, with one patient developing bullous keratopathy. All patients were then treated with topical ganciclovir gel and corticosteroids, with subsequent control of the intraocular inflammation. CMV may represent an overlooked / underestimated etiology of hypertensive anterior uveitis that may progressively lead to endothelial dysfunction, culminating in bullous keratopathy. Management of patients is challenging, with the potential use of topical antivirals to decrease the number of relapses, and corticosteroids to control anterior uveitis / endotheliitis and to protect the corneal endothelium.

Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity., Competing Interests: Declarations of interest The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The impact of HIV co-infection on the plasma immunological biomarker profile of HTLV-1 infected patients was evaluated. The plasma levels of leukotrienes and chemokines/cytokines were quantified by ELISA and Cytometric Bead Array. A total of 138 volunteers were enrolled and divided into two subgroups ("HTLV-1(+)HIV(-)" and "HTLV-1(+)(HIV(+)"), which were categorized according to the HTLV-1-associated neurological disease (AS, pHAM and HAM). Reference controls were BD and HIV mono-infected patients. HAM(+) exhibited higher CD4 + T-cell counts as compared to HIV+ mono-infected patients and lower HTLV-1 proviral load as compared to mono-infected HAM(-) patients. AS(+) exhibited higher levels of CysLT, CXCL8/IL-8 and lower levels of CCL5/RANTES as compared to AS(-). Increased levels of IL-6 and TNF with reduced levels of CXCL10/IP10 and CCL5/RANTES were observed in co-infected pHAM(+) as compared to mono-infected pHAM(-). HAM(+) patients revealed an increase in CXCL8/IL-8, CCL2/MCP-1, CXCL-10/IP-10, TNF and a decrease in IL-2 as compared to HAM(-) subgroup., (Copyright © 2021 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Objectives: Traditional risk scores improved the definition of the initial therapeutic strategy in acute coronary syndrome (ACS), but they were not designed for predicting long-term individual risks and costs. In parallel, attempts to directly predict costs from clinical variables in ACS had limited success. Thus, novel approaches to predict cardiovascular risk and health expenditure are urgently needed. Our objectives were to predict the risk of major/minor adverse cardiovascular events (MACE) and estimate assistance-related costs., Methods: We used a 2-step approach that: (1) predicted outcomes with a common pathophysiological substrate (MACE) by using machine learning (ML) or logistic regression (LR) and compared with existing risk scores; (2) derived costs associated with noncardiovascular deaths, dialysis, ambulatory-care-sensitive-hospitalizations (ACSH), strokes, and MACE. With consecutive ACS individuals (n = 1089) from 2 cohorts, we trained in 80% of the population and tested in 20% using a 4-fold cross-validation framework. The 29-variable model included socioeconomic, clinical/lab, and coronarography variables. Individual costs were estimated based on cause-specific hospitalization from the Brazilian Health Ministry perspective., Results: After up to 12 years follow-up (mean = 3.3 ± 3.1; MACE = 169), the gradient-boosting machine model was superior to LR and reached an area under the curve (AUROC) of 0.891 [95% CI 0.846-0.921] (test set), outperforming the Syntax Score II (AUROC = 0.635 [95% CI 0.569-0.699]). Individuals classified as high risk (>90th percentile) presented increased HbA1c and LDL-C both at <24 hours post-ACS and 1-year follow-up. High-risk individuals required 33.5% of total costs and showed 4.96-fold (95% CI 3.71-5.48, P < .00001) greater per capita costs compared with low-risk individuals, mostly owing to avoidable costs (ACSH). This 2-step approach was more successful for finding individuals incurring high costs than predicting costs directly from clinical variables., Conclusion: ML methods predicted long-term risks and avoidable costs after ACS., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

It has been long recognized that NOD1 and NOD2 are critical players in the host immune response, primarily by their sensing bacterial peptidoglycan-conserved motifs. Significant advances have been made from efforts that characterize their upstream activators, assembly of signaling complexes, and activation of downstream signaling pathways. Disruption in NOD1 and NOD2 signaling has also been associated with impaired host defense and resistance to the development of inflammatory diseases. In this review, we will describe how NOD1 and NOD2 sense microbes and cellular stress to regulate host responses that can affect disease pathogenesis and outcomes., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Clostridium difficile infection (CDI) is one of the most common nosocomial infections worldwide and an urgent public health threat. Epidemiological and experimental studies have demonstrated an association between nonsteroidal anti-inflammatory drug (NSAID) exposure and enhanced susceptibility to, and severity of, CDI. NSAIDs target cyclooxygenase enzymes and inhibit the production of prostaglandins (PGs), but the therapeutic potential of exogenous introduction of PGs for the treatment of CDI has not been explored. In this study, we report that treatment with the FDA-approved stable PGE 1 analogue, misoprostol, protects mice against C. difficile-associated mortality, intestinal pathology, and CDI-mediated intestinal permeability. Furthermore, we report that the effect of misoprostol on the gastrointestinal tract contributes to increased recovery of the gut microbiota following antibiotic perturbation. Together, these data implicate PGs as an important host-factor associated with recovery to C. difficile-associated disease and demonstrate the potential for misoprostol in the treatment of CDI. Further studies to explore the safety and efficacy of misoprostol treatment of CDI in humans is needed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the effect on the nonsteroidal anti-inflammatory drug indomethacin on Clostridium difficile infection (CDI) severity., Materials & Methods: Indomethacin was administered in two different mouse models of antibiotic-associated CDI in two different facilities, using a low and high dose of indomethacin., Results: Indomethacin administration caused weight loss, increased the signs of severe infection and worsened histopathological damage, leading to 100% mortality during CDI. Indomethacin-treated, antibiotic-exposed mice infected with C. difficile had enhanced intestinal inflammation with increased expression of KC, IL-1β and IL-22 compared with infected mice unexposed to indomethacin., Conclusion: These results demonstrate a negative impact of nonsteroidal anti-inflammatory drugs on antibiotic-associated CDI in mice and suggest that targeting the synthesis or signaling of prostaglandins might be an approach to ameliorating the severity of CDI.

Purpose: To evaluate the effect on visual acuity of the implantation of a new intraocular pinhole device (Xtrafocus) in cases of irregular corneal astigmatism with significant visual impairment., Setting: University of São Paulo, São Paulo, Brazil., Design: Prospective case series., Methods: Pseudophakic eyes of patients with irregular corneal astigmatism were treated with the pinhole device. The causes of irregular corneal astigmatism were keratoconus, post radial keratotomy (RK), post-penetrating keratoplasty (PKP), and traumatic corneal laceration. The device was implanted in the ciliary sulcus in a piggyback configuration to minimize the effect of corneal aberrations. Preoperative and postoperative visual parameters were compared. The main outcome variables were manifest refraction, uncorrected and corrected distance and near visual acuities, subjective patient satisfaction, and intraoperative and postoperative adverse events and complications., Results: Twenty-one patients (ages 35 to 85 years) were included. There was statistically significant improvement in uncorrected and corrected (CDVA) distance visual acuities. The median CDVA improved from 20/200 (range 20/800 to 20/60) preoperatively to 20/50 (range 20/200 to 20/20) in the first month postoperatively and remained stable over the following months. Manifest refraction remained unchanged, while a subjective visual performance questionnaire revealed perception of improvement in all the tested working distances. No major complication was observed. One case presented with decentration of the device, which required an additional surgical intervention., Conclusions: The intraocular pinhole device performed well in patients with irregular astigmatism caused by keratoconus, RK, PKP, and traumatic corneal laceration. There was marked improvement in visual function, with high patient satisfaction., (Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Clostridium difficile infection (CDI) is a significant source of healthcare-associated morbidity and mortality. This study investigated whether serum 25-hydroxyvitamin D is associated with adverse outcomes from CDI. Patients with CDI were prospectively enrolled. Charts were reviewed and serum 25-hydroxyvitamin D was measured. The primary outcome was a composite definition of severe disease: fever (temperature >38°C), acute organ dysfunction, or serum white blood cell count >15,000 cells/µL within 24-48 hours of diagnosis; lack of response to therapy by day 5; and intensive care unit admission; colectomy; or death within 30 days. Sixty-seven patients were included in the final analysis. Mean (±SD) serum 25-hydroxyvitamin D was 26.1 (±18.54) ng/mL. Severe disease, which occurred in 26 (39%) participants, was not associated with serum 25-hydroxyvitamin D [odds ratio (OR) 1.00; 95% confidence interval (CI) 0.96-1.04]. In the adjusted model for severe disease only serum albumin (OR 0.12; 95%CI 0.02-0.64) and diagnosis by detection of stool toxin (OR 5.87; 95%CI 1.09-31.7) remained independent predictors. We conclude that serum 25-hydroxyvitamin D is not associated with the development of severe disease in patients with CDI.

This study aimed at establishing the immunological signature and an algorithm for clinical management of the different clinical stages of the HTLV-1-infection based on serum biomarkers. A panel of serum biomarkers was evaluated by four sets of innovative/non-conventional data analysis approaches in samples from 87 HTLV-1 patients: asymptomatic carriers (AC), putative HTLV-1 associated myelopathy/tropical spastic paraparesis (pHAM/TSP) and HAM/TSP. The analysis of cumulative curves and molecular signatures pointed out that HAM/TSP presented a pro-inflammatory profile mediated by CXCL10/LTB-4/IL-6/TNF-α/IFN-γ, counterbalanced by IL-4/IL-10. The analysis of biomarker networks showed that AC presented a strongly intertwined pro-inflammatory/regulatory net with IL-4/IL-10 playing a central role, while HAM/TSP exhibited overall immune response toward a predominant pro-inflammatory profile. At last, the classification and regression trees proposed for clinical practice allowed for the construction of an algorithm to discriminate AC, pHAM and HAM/TSP patients with the elected biomarkers: IFN-γ, TNF-α, IL-10, IL-6, IL-4 and CysLT. These findings reveal a complex interaction among chemokine/leukotriene/cytokine in HTLV-1 infection and suggest the use of the selected but combined biomarkers for the follow-up/diagnosis of disease morbidity of HTLV-1-infected individuals.

Clostridium difficile is the major cause of antibiotic-associated diarrhea and pseudomembranous colitis in healthcare settings. However, the host factors involved in the intestinal inflammatory response and pathogenesis of C. difficile infection (CDI) are largely unknown. Here we investigated the role of leukotrienes (LTs), a group of pro-inflammatory lipid mediators, in CDI. Notably, the neutrophil chemoattractant LTB4, but not cysteinyl (cys) LTs, was induced in the intestine of C57BL/6 mice infected with either C. difficile strain VPI 10463 or strain 630. Genetic or pharmacological ablation of LT production did not ameliorate C. difficile colitis or clinical signs of disease in infected mice. Histological analysis demonstrated that intestinal neutrophilic inflammation, edema and tissue damage in mice during acute and severe CDI were not modulated in the absence of LTs. In addition, CDI induced a burst of cytokines in the intestine of infected mice in a LT-independent manner. Serum levels of anti-toxin A immunoglobulin (Ig) G levels were also not modulated by endogenous LTs. Collectively, our results do not support a role for LTs in modulating host susceptibility to CDI in mice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In the present work we examine the contribution of 5-lipoxygenase- (5-LO-) derived lipid mediators to immune responses during the acute phase of Trypanosoma cruzi infection in 5-LO gene knockout (5-LO(-/-)) mice and wild-type (WT) mice. Compared with WT mice, the 5-LO(-/-) mice developed less parasitemia/tissue parasitism, less inflammatory cell infiltrates, and a lower mortality. This resistance of 5-LO(-/-) mice correlated with several differences in the immune response to infection, including reduced PGE2 synthesis; sustained capacity of splenocytes to produce high levels of interleukin (IL)-12 early in the infection; enhanced splenocyte production of IL-1β, IL-6, and IFN-γ; rapid T-cell polarization to secrete high quantities of IFN-γ and low quantities of IL-10; and greater numbers of CD8(+)CD44(high)CD62L(low) memory effector T cells at the end of the acute phase of infection. The high mortality in WT mice was associated with increased production of LTB4/LTC4, T cell bias to produce IFN-γ, high levels of serum nitrite, and marked protein extravasation into the peritoneal cavity, although survival was improved by treatment with a cys-LT receptor 1 antagonist. These data also provide evidence that 5-LO-derived mediators negatively affect host survival during the acute phase of T. cruzi infection.

In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4(+)HLA-DR(+), CD8(+) T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-α/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection.

Prostaglandins act as mediators of inflammation and, similar to cytokines, function as immune modulators during innate and adaptive immune responses. Therefore, using a pharmacological inhibitor, celecoxib, we investigated the role of prostaglandins in host defense against Histoplasma capsulatum infection in C57BL/6 mice. Our results showed that treatment with celecoxib inhibited cyclooxygenase 2, reduced the total fungal burden, and reduced the concentration of PGE2, cytokines, lymphocytes, neutrophils, and mononuclear cells in the bronchoalveolar space and lung parenchyma. In addition, celecoxib treatment increased the synthesis of nitric oxide, IFN- γ, LTB4, and the phagocytic capacity of alveolar macrophages. Moreover, celecoxib treatment increased the survival of mice after infection with a lethal inoculum of H. capsulatum. These results suggest that prostaglandins alter the host immune response and play an important role in the pathogenesis of histoplasmosis. Thus, the inhibition of prostaglandins could be a valuable immunomodulatory strategy and antifungal therapy for histoplasmosis treatment.

Leukotrienes (LTs) are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1) infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Bioactive LTB(4) and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB(4) and LTC(4) positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4(+) and CD8(+) T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring.