Histological Inflammation Research Articles

Early subclinical stages of the inflammatory bowel diseases - insights from human and animal studies.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication or prevention. Here we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of IBD patients and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

Impact of histological remission for predicting clinical relapse in Crohn's disease: a post-hoc analysis of the prospective STORI cohort.

Achieving deep remission, encompassing clinical, endoscopic, and biological remission, is the goal in managing Crohn's disease (CD). The role of histological remission remains unclear. This study aimed to examine the impact of histological inflammation on clinical relapse risk in CD and explore the relationship between histology, endoscopic scores, and biomarkers. Patients from the prospective STORI cohort underwent ileocolonoscopy with CDEIS calculation and 2 biopsies from the most inflamed or previously inflamed areas. Histological scores (Robarts, Geboes, modified Geboes, Nancy, and IBD-DCA) were determined by two independent pathologists in a central reading process. Histological remission was defined by specific score thresholds. Clinical relapse, defined by CDAI >250 or a CDAI increase of 70 points over two weeks, was monitored for at least one year. Out of 115 patients included in STORI, 160 biopsies (44 ileal and 116 colonic) from 76 patients were analyzed. Histological remission rates were 46% (Nancy), 55% (Robarts), 61% (Geboes), and 41% (IBD-DCA). During follow-up, 35 patients (46%) experienced a clinical relapse: 37% with histological remission and 56% without, based on the Nancy score. Among the mucosal healing (MH) subgroup (45 patients), 34% with histological remission and 44% without relapsed (p=0.18). Histological scores did not predict clinical relapse. Only faecal calprotectin (FC) was a significant predictor in multivariate analysis (p=0.029). Despite correlations with endoscopy and biomarkers, histological scores did not predict clinical relapse in CD patients in remission. Thus, these scores are not recommended for clinical practice to assess relapse risk in CD.

Incontinence-Associated Dermatitis-Like Skin Changes Induced by the Application of Absorbent Pads Containing Bacteria and Artificial Urine in Rats.

Incontinence-associated dermatitis (IAD) is one of the most serious complications in older people with incontinence. Controlling urine property in absorbent pads could be effective for preventing IAD caused by bacterial urine. However, no animal model has been established to evaluate their effectiveness. This study aimed to induce IAD-like skin changes using absorbent pads containing bacterial urine and to confirm their pathophysiology in rats. Hairless Wistar Yagi rats were divided into the bacteria-containing urine (BU) and the bacteria-free urine (U) groups. A 10-h-attachment of absorbent pads containing artificial urine with/without bacteria to the skin pretreated with sodium lauryl sulfate was performed repeatedly for 5 days. Macroscopic findings and skin barrier function were examined every day, and histological changes, inflammatory responses and bacterial quantification in tissue samples were examined on Day 5. The BU group exhibited significant skin redness from Day 3, significant elevation of transepidermal water loss from Day 1, and histological changes, including significantly thickened epidermis, abnormal keratinocyte differentiation and erythrocyte leakage. Inflammation, confirmed by higher myeloperoxidase-positive cells, elevated tumour necrosis factor-α expression, and vascular endothelial damage, indicated by CD31 and pentraxin 3-positive cells, were observed in the BU group. The bacterial quantification showed no significant difference between the groups. IAD-like skin changes including histological changes and inflammation were suggested to be caused by urine properties altered by bacteria. This study proposed a new animal model for evaluating the effectiveness of absorbent pads in controlling the urine properties of bacterial urine on preventing IAD.

Increased serum β-hydroxybutyrate/acetoacetate ratio and aggravated histological liver inflammation in females with metabolic dysfunction-associated steatotic liver disease and polycystic ovary syndrome.

Increased serum β-hydroxybutyrate/acetoacetate ratio and aggravated histological liver inflammation in females with metabolic dysfunction-associated steatotic liver disease and polycystic ovary syndrome.

Therapeutic potential of EVs loaded with CB2 receptor agonist in spinal cord injury via the Nrf2/HO-1 pathway

ABSTRACT Background Spinal cord injury (SCI) poses a challenge due to limited treatment options. Recently, the effect and mechanism of Exo-loaded cannabinoid receptor type 2 (CB2) agonist AM1241(Exo + AM1241) have been applied in other inflammatory diseases but not in SCI. Methods The SCI model was set up using C57BL/6 mice, followed by the treatment of Exo, AM1241, and Exo + AM1241. We assessed the effects of the following treatments on motor function recovery using BMS, and evaluated histological changes, apoptosis activity, inflammation, and oxidative stress in the SCI mice model. Additionally, the effect of following treatments on spinal cord neural stem cells (NSCs) was evaluated under lipopolysaccharides (LPS) induced inflammatory and oxidative models and, glutamate (Gluts) induced cell apoptosis models. Result Our results demonstrated that Exo + AM1241 treatment significantly improved motor function recovery, after SCI by decreasing proinflammatory cytokines, and suppressing astrocyte/microglia (GFAP/Iba1) activation in the injury zone. Additionally, this treatment reduces pro-apoptotic proteins (Bax and caspase 3), increases the levels of the anti-apoptotic protein Bcl-2, enhances antioxidant defenses by boosting SOD and GSH, and lowers oxidative stress markers such as MDA. It also activates the Nuclear factor erythroid-2 (Nrf2) related factor 2 signaling pathway, thereby enhancing tissue protection against damage and cell death.

Comparative Value of CRP and FCP for Endoscopic and Histologic Remissions in Ulcerative Colitis.

Aim: We have previously shown that CRP < 2.9 mg/L is a better predictor of endoscopic remission (ER) than CRP < 5 mg/L in ulcerative colitis (UC). Here, we prospectively evaluate CRP and FCP cut-offs and compare them in predicting ER and histological remission (HR) in UC. Method: One hundred thirty-five steroid-free UC patients were evaluated prospectively. ER was defined as Mayo endoscopic sub-score 0-1. In colonoscopy, the colon was evaluated as seven segments: rectum, sigmoid, descending, proximal-transverse, distal-transverse, ascending colon, and cecum. Two biopsies of each segment were evaluated for histological inflammation and graded using the Nancy and Geboes scores. All segment biopsies with Nancy < 1 and Geboes < 2 were defined as HR. Results: The optimum cut-off values for FCP and CRP were 120 μg/g and 2.75 mg/L for ER, respectively. AUC values of FCP and CRP were similar for ER and Mayo-0 disease in ROC analysis. CRP and FCP also had similar performances with these cut-offs regarding ER. While CRP was a predictor to assess the extensiveness of active UC, FCP was not. ROC analysis showed no difference between CRP and FCP regarding HR. Cut-off values for HR were 2.1 mg/L and 55 μg/g for CRP and FCP, respectively. CRP and FCP, in combination with the mentioned cut-off values, detected ER and HR in nearly 2/3 and ½ of the patients, respectively, with high specificity. Conclusions: Reappraised CRP (ER: 2.75 mg/L, HR: 2.1 mg/L) has as much diagnostic contribution as relevant FCP in predicting ER and HR and contributes more to revealing the proximal extension in active colitis compared to FCP. Relevant CRP and FCP combinations may improve the prediction rates.

6681 Age and Sex Disparity in NASH and the Potential Role of Estradiol Treatment for NASH

Abstract Disclosure: M. Tripathi: None. S. Sakthivel: None. A. Suzuki: None. B.K. Singh: None. P.M. Yen: None. Introduction: NAFLD (nonalcoholic fatty liver disease) and its more severe form, NASH (nonalcoholic steatohepatitis) are sexually dimorphic conditions that exhibit higher prevalence in men than women during reproductive ages but have similar prevalence after menopause. Reproductive age women are protected from hepatic fibrosis relative to men, although they lose this protection after menopause. These sex differences in NASH have been attributed, at least partly, to different circulating estrogen levels. However, the underlying mechanism(s) is not fully understood. We thus conducted animal experiments to investigate: 1) sex differences in the histologic severity of NASH, necroinflammatory and fibrogenic activities, and other relevant pathways in young and old male and female mice and 2) the effects of estradiol administration on these parameters in old male and female mice to evaluate the therapeutic potential of estradiol in NASH. Methodology: Young/reproductive age (12-weeks old) and old/post-reproductive age female and male (48∼50-weeks weeks old) C57BL/6J mice were fed control chow diet (NCD) or high-fat methionine/choline-deficient (MCD) diet for six weeks to induce NASH. The old mice were administered 200nM 17β-estradiol (physiological) in drinking water. We analyzed serum and hepatic NASH parameters, ER stress, and lysosome-autophagy defects. Results and Conclusion: Among reproductive age mice with NASH, females developed less severe histologic inflammation and fibrosis and decreased gene expression of Il1b, Il6, Tgfb, Col1a1, Ccl2, and Ccl5, and lower hepatic collagen than males. Females with NASH also had less inhibition of hepatic autophagy and lysosomal protein expression than males with NASH. Among old mice, post-reproductive age females fed NCD or MCD exhibited more severe hepatic inflammation and fibrosis and had higher gene expression of inflammatory and fibrogenic markers with comparable autophagic inhibition and lysosomal defects as similar age males. Physiological doses of estradiol significantly reduced hepatic gene expression of inflammatory and fibrogenic markers, ER stress and lysosomal-autophagic defects in post-reproductive age females. In conclusion, similar to clinical NASH, we observed marked sex and age-related differences in the severity of NASH. Furthermore, physiological doses of estradiol treatment improved the hepatic histology, lysosome-autophagy, inflammation, and fibrosis in post-reproductive age female mice with NASH and suggests that estradiol supplementation may decrease or reverse NASH progression in post-menopausal women with NASH. Presentation: 6/2/2024

Topical application of anti-inflammatory agents on burn wounds and their effect on healing

Advancements in the treatment of burns have considerably improved overall survival rates, but they have also highlighted several long-term sequelae related to the injury. Hypertrophic scars can impair function, reduce quality of life, and require multiple procedures as well as physical therapy. The purpose of this study was to investigate the effects of topical application of anti-inflammatory drugs in the treatment of burns. Up to 15 deep-partial thickness burns were created on the dorsum of four anesthetized swine. Subsequently, the burn wounds were randomized to receive amiloride, celecoxib, dexamethasone or minocycline mixed in a hydrogel. Silver sulfadiazine cream and blank hydrogel acted as controls. The animals were followed for 90 days and the wounds were assessed on days 3, 7, 14, 28 and 90 post-burn. Assessments were performed using photographs (macroscopic healing, contraction), laser-speckle imaging (blood perfusion), 3D camera (scarring, pigmentation), and histology (inflammation, burn depth, epidermal maturation). Inflammation was present in all burn wound histology specimens and peaked on day 7 in all groups. Regardless of the treatment the burns progressed and were deeper on day 7 in comparison to day 3. The burns were 50 – 80 % healed by day 14, but no significant differences were observed. No differences in epidermal thickness, rete ridges, contraction, hypopigmentation, or scar elevation were seen on day 90. Topical anti-inflammatories did not significantly decrease inflammation or mitigate burn wound progression in deep partial thickness burns in pigs. Also, no significant differences in wound healing or quality of healing were observed.

S1329 Effects of Mirikizumab versus Placebo on Histologic Inflammation Evaluated by Comprehensive Assessment in 5 Intestinal Segments in a Randomized, Controlled Phase 3 Trial of Participants With Crohn’s Disease

S1329 Effects of Mirikizumab versus Placebo on Histologic Inflammation Evaluated by Comprehensive Assessment in 5 Intestinal Segments in a Randomized, Controlled Phase 3 Trial of Participants With Crohn’s Disease

Evaluation of the histological Inflammation in the intestines of male mice infected with Entamoeba histolytica using immunohistochemistry technology

The current study was conducted during the period between May 1, 2021 and October 30, 2022 for the purpose of diagnosing infection with the Entamoeba histolytica parasite. The clinically infected patients suffered from diarrhea when the samples were examined microscopically using a sample of direct wet swab. In the experimental study, the Entamoeba histolytica was given to laboratory mice and it was observed that tissue damage appeared as a result of infection with the amoeba parasite, represented by necrosis and explosion in the intestinal villi, dissolution of the epithelial layer and the occurrence of a condensation of inflammatory cells in the intestine.

Ciclesonide exhibits lung-protective effects in neonatal rats exposed to intra-amniotic enterotoxin.

Despite the advances in perinatal care, bronchopulmonary dysplasia (BPD) continues to be a highly prevalent chronic lung disease that affects newborns, especially affecting premature newborns. There is no specific cure for BPD, and treatments aimed at reducing the risk of developing BPD focus mainly on lung-protective ventilation strategies, surfactant therapy, and/or corticosteroid administration. Our objective was to evaluate whether systemic postnatal administration of a new glucocorticoid, ciclesonide, can attenuate the alteration of lung structure and pulmonary hypertension in a rat model of chorioamnionitis-induced BPD, with minimal adverse effects on the developing brain. Endotoxin (ETX) or saline was administered to pregnant rats by intra-amniotic (i.a.) injection on day 20 of pregnancy, and pups were delivered by cesarean section on day 22. Ciclesonide (0.5 mg/kg) was administered postnatally for five consecutive days to pups previously exposed to i.a. ETX. On postnatal day 14, we assessed lung function (compliance), lung structure (radial alveolar count, mean linear intercept, pulmonary vessel density), pulmonary hypertension, and brain histology (edema, inflammation, apoptosis, hemorrhage, and infarction). On postnatal day 14, the effects of i.a. ETX administration were evident in neonatal rats not receiving treatment; these animals showed impaired lung compliance, disrupted lung structure, and developing pulmonary hypertension compared to those receiving i.a. saline. Postnatal administration of ciclesonide for 5 days was associated with significantly better outcomes in terms of lung compliance, alveolarization, lung vascular growth, and pulmonary hypertension, without affecting the brain histological parameters evaluated. Postnatal ciclesonide administration preserved lung function and structure and prevented pulmonary hypertension in a BPD model induced by antenatal i.a. ETX administration, without causing any adverse effects on brain development. These findings suggest that the new glucocorticoid, ciclesonide, may provide a novel strategy for the prevention of BPD; however, more long-term studies are required.

A nationwide cohort study of inflammatory bowel disease, histological activity and fracture risk

SummaryBackgroundIndividuals with inflammatory bowel disease (IBD) are at increased risk of fracture. It is unclear if this risk varies by recent histological activity.AimsTo determine the fracture risk in IBD during periods with and without histological inflammation.MethodsWe studied a nationwide cohort of 54,591 individuals diagnosed with IBD in 1990–2016 with longitudinal data on ileo‐colorectal biopsies. Fractures were identified by inpatient and hospital‐based outpatient diagnoses. We derived Cox regression estimated hazard ratios (HRs) for fracture during 12 months following a histological inflammation (vs. histological remission) record after adjusting for socio‐demographics, comorbidities, IBD duration, IBD‐related surgery and hospitalization. We adjusted sensitivity analyses for medical IBD treatment including corticosteroids.ResultsMean age of patients was 44.0 (SD = 18.3) and 45.5 (SD = 17.1) years at biopsy with histological inflammation and remission, respectively. For histological inflammation, there were 1.37 (95% CI 1.29–1.46) fractures per 100 years' follow‐up versus 1.31 (95% CI 1.19–1.44) for remission (adjusted [a]HR 1.12; 95% CI 1.00–1.26; p = 0.04). HRs were similar with histological inflammation of Crohn's disease (1.11; 95% CI 0.91–1.36) and ulcerative colitis (1.18; 95% CI 1.02–1.36). Estimates were consistent across age groups. An overall small excess risk of any fracture remained after accounting for corticosteroids. A more prominently raised fracture risk was observed in corticosteroid‐naïve IBD patients with histological inflammation versus histological remission (aHR 1.41; 95% CI 1.07–1.85). The aHR of hip fracture following histological inflammation was 1.29 (95% CI 0.87–1.92).ConclusionsHistological inflammation in IBD predicted a small increase in short‐term fracture risk. Measures to reduce disease activity may reduce fracture risk in IBD.

Clinical and histological impact of diffuse inflammation at pouchoscopy

PurposeThe anatomical location of inflammation in and around the ileal pouch affects the pouch survival rate, and diffuse inflammation has poor pouch survival rates. We aimed to clarify the symptoms and histological findings of diffuse inflammation of the pouch.MethodsWe evaluated the symptoms, treatment, and histological findings according to the endoscopic phenotypes of diffuse inflammation, focal inflammation, and normal as the pouch body phenotype and afferent limb involvement, inlet involvement, cuffitis, and fistula as the peripheral findings.ResultsOf the 318 pouchoscopies, 47 had diffuse inflammation, 201 had focal inflammation, and 70 were normal. Symptomatic patients had diffuse inflammation more frequently (46.8%) than focal inflammation (13.4%) and normal (14.2%), with no difference between focal inflammation and normal. Antibiotics and steroids were higher rate administered in cases of diffuse inflammation, but not in cases of focal inflammation or in normal cases. Histological inflammation, inflammatory bowel disease (IBD)–specific finding, and colonic metaplasia showed severity in the order of diffuse inflammation > focal inflammation > normal. The number of peripheral inflammatory findings overlapped in the following order: diffuse inflammation > focal inflammation > normal. The number of symptomatic patients increased as the number of peripheral inflammatory findings increased.ConclusionPouches with diffuse inflammation are more symptomatic, have a higher use of therapeutic agents, and have more severe histological inflammation, IBD-specific finding, and colonic metaplasia accompanying peripheral inflammatory findings than the other groups. The higher the overlap of inflammatory findings in the surrounding tissues, the more symptomatic the patients will appear.

α-Cyperone Antagonizes Intestinal Mucosal Inflammatory Response Through Modulation of TLR4/NF-κB Signaling Pathway to Alleviate Crohn's Disease-Like Colitis in Mice

To investigate the effect and potential mechanisms of α-cyperone (CYP) on Crohn's disease (CD) -like colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in mice. The mice were randomly and evenly divided into wild type (WT), TNBS, CYP and 5-aminosalicylic acid (5-ASA) groups, with 10 mice in each group. The symptoms of enteritis, the function and structure of the intestinal barrier, and the expression levels of inflammatory factors, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and gamma-interferon (IFN-γ), in the colon were assessed. The lipopolysaccharide (LPS)-induced inflammation model of Caco2 cells was constructed and the cells were divided into Control, LPS and LPS+CYP groups. The expression levels of tight junction protein and inflammatory factors in each group were assessed. Gene Ontology (GO) functional enrichment analysis was conducted to predict the possible pathways of action and potential molecular mechanisms of CYP, and to verify them in vivo and in vitro. In the in vivo study, compared with those of the TNBS group, the body mass and colon length of mice in the CYP group and the 5-ASA group were significantly increased, while the disease activity scores and histological inflammation scores were significantly decreased (P<0.05). The level of lucifcein-glucan isothiocyanate and the bacterial translocation rate (in the liver, the spleen, and mesenteric lymph nodes) were significantly decreased, while the transepithelial electric resistance (TEER) value and the expression levels of zonula occluden protein-1 (ZO-1), and claudin-1 were significantly increased (P<0.05). The expression of inflammatory factors was significantly decreased (P<0.05). In the in vitro study, compared with those of the LPS group, the TEER value and the expression of ZO-1 and claudin-1 in the Caco2 cells in the LPS+CYP group were significantly increased (P<0.05). The expression of inflammatory factors was significantly decreased (P<0.05). Enrichment analysis showed that CYP was correlated with inflammatory response (P<0.001). Western blot results showed that CYP could significantly reduce the expression of key proteins in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway in vivo and in vitro (P<0.05). CYP may protect the intestinal barrier by antagonizing the inflammatory response of the intestinal mucosa through regulating the expression of the TLR4/NF-κB signaling pathway, thereby alleviating TNBS-induced CD-like colitis in mice.

Can Inflammatory Indexes Predict the Severity of Mucosal Inflammation in Ulcerative Colitis?

Aim: Inflammatory indexes can relate to disease activity in ulcerative colitis (UC). This study aimed to evaluate whether the inflammatory indexes of neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP)-albumin ratio (CAR), CRP-lymphocyte ratio (CLR), and systemic immune-inflammation index (SIII) might predict the severity of mucosal inflammation in UC. Material and Methods: This retrospective case-control study included 184 UC patients and 101 healthy controls. The Mayo clinical score and Mayo endoscopic score were used for the clinical and endoscopic features of UC. Truelove and Richards’s method for the severity of mucosal inflammation determined the histological activity index (HAI). Results: The inflammatory index values, were higher in UC patients compared to the control group (p=0.007 for NLR, and p&amp;lt;0.001 for the others). The patients having endoscopic, clinic, and histologically active disease had higher inflammatory index values than those in remission (p&amp;lt;0.001 for all). UC patients with extensive disease had higher inflammatory index values than the patients who had limited disease (p&amp;lt;0.001 for all). The HAI values were positively correlated to all inflammatory indexes, and the correlation was the strongest between the HAI and CLR (rho=0.737, p&amp;lt;0.001). Regarding HAI, the diagnostic accuracy of all inflammatory indexes for detecting the clinically active disease was statistically significant, and there was no significant difference between them in terms of diagnostic accuracy. Conclusion: The inflammatory indexes of NLR, CAR, CLR, and SII might predict the severity of histological inflammation in UC.

Protective effect of astaxanthin on chronic prostatitis/chronic pelvic pain syndrome in rat through modulating NF-κB signaling pathway.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male urological disease characterized by chronic pelvic pain and various discomforts. Astaxanthin (AST) has multiple functions, including anti-inflammatory property, but it is unclear whether AST plays a key role in CP/CPPS and how it works. This study aimed to investigate the protective effect of AST on CP/CPPS in rats and the underlying mechanism. A CP/CPPS rat model was induced by intraprostatic injection of carrageenan and the blood specimens and prostates were harvested for further research after oral administration of AST for 4 weeks. Tactile allodynia test showed that AST ameliorated chronic pelvic pain in a dose-depended manner. In addition, histological evaluation indicated that AST alleviated CP/CPPS rat prostate histological inflammation. Meanwhile, AST suppressed the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Besides, AST inhibited the activities of prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2). Furthermore, AST decreased the activation of the nuclear factor-κB (NF-κB) signaling pathway. Our study has shown that AST exerts an anti-inflammatory and protective effect against CP/CPPS and the function is mediated at least through the suppression of NF-κB signaling pathway. These results provide evidence of AST as the potential agents for the treatment of CP/CPPS.

Modulation of the K/BxN arthritis mouse model and the effector functions of human fibroblast-like synoviocytes by liver X receptors.

The role of liver X receptors (LXR) in rheumatoid arthritis (RA) remains controversial. We studied the effect of LXR agonists on fibroblast-like synoviocytes (FLS) from RA patients and the K/BxN arthritis model in LXRα and β double-deficient (Nr1h2/3-/-) mice. Two synthetic LXR agonists, GW3965 and T0901317, were used to activate LXRs and investigate their effects on cell growth, proliferation and matrix metalloproteinases, and chemokine production in cultured FLS from RA patients. The murine model K/BxN serum transfer of inflammatory arthritis in Nr1h2/3-/- animals was used to investigate the role of LXRs on joint inflammation in vivo. LXR agonists inhibited the FLS proliferative capacity in response to TNF, the chemokine-induced migration, the collagenase activity in FLS supernatant and FLS CXCL12 production. In the K/BxN mouse model, Nr1h2/3-/- animals showed aggravated arthritis, histological inflammation, and joint destruction, as well as an increase in synovial metalloproteases and expression of proinflammatory mediators such as IL-1β and CCL2 in joints compared with wild type animals. Taken together, these data underscore the importance of LXRs in modulating the joint inflammatory response and highlight them as potential therapeutic targets in RA.

Effect of Mutant and Engineered High-Acetate-Producing Saccharomyces cerevisiae var. boulardii Strains in Dextran Sodium Sulphate-Induced Colitis.

Acetate-producing Saccharomyces cerevisiae var. boulardii strains could exert improved effects on ulcerative colitis, which here, was preclinically evaluated in an acute dextran sodium sulphate induced model of colitis. Nine-week-old female mice were divided into 12 groups, receiving either drinking water or 2.75% dextran sodium sulphate for 7 days, combined with a daily gavage of various treatments with different levels of acetate accumulation: sham control (phosphate buffered saline, no acetate), non-probiotic control (Baker's yeast, no acetate), probiotic control (Enterol®, transient acetate), and additionally several Saccharomyces cerevisiae var. boulardii strains with respectively no, high, and extra-high acetate accumulation. Disease activity was monitored daily, and feces samples were collected at different timepoints. On day 14, the mice were sacrificed, upon which blood and colonic tissue were collected for analysis. Disease activity in inflamed mice was lower when treated with the high-acetate-producing strain compared to sham and non-probiotic controls. The non-acetate-producing strain showed higher disease activity compared to the acetate-producing strains. Accordingly, higher histologic inflammation was observed in non- or transient-acetate-producing strains compared to the sham control, whereas this increase was not observed for high- and extra-high-acetate-producing strains upon induction of inflammation. These anti-inflammatory findings were confirmed by transcriptomic analysis of differentially expressed genes. Moreover, only the strain with the highest acetate production was superior in maintaining a stable gut microbial alpha-diversity upon inflammation. These findings support new possibilities for acetate-mediated management of inflammation in inflammatory bowel disease by administrating high-acetate-producing Saccharomyces cerevisae var. boulardii strains.

Assessing the Value of Histology and Anatomic Segment Evaluation Among Patients Undergoing Pouchoscopy.

The value of histologic assessment after ileal pouch-anal anastomosis (IPAA) has not been definitively determined. We evaluated the correlation between histology and endoscopic findings, as well as the proportion of patients with inflammation in areas beyond the pouch body on their initial pouchoscopy after IPAA. In a retrospective cohort study, we evaluated patients who underwent IPAA for UC between 2012 and 2020 and subsequently underwent a pouchoscopy with routine biopsies of the pouch body, pre-pouch ileum, and rectal cuff. We compared endoscopic and histologic assessments in each location using χ2 testing and Spearman correlation, as well as the development of pouchitis and Crohn's-like disease of the pouch (CLDP) in longitudinal follow-up. Among 126 patients, the median time to pouchoscopy after IPAA was 384 days, with 82 patients (65%) having inflammation of the pouch body. Significantly more patients with pouch body inflammation had histologic inflammation compared with patients without pouch body inflammation (96% vs 22%, P < .001, r = 0.769). Additionally, 16 patients (13%) were found to have endoscopic inflammation of the pre-pouch ileum with corresponding histologic inflammation in 88%; of these, 31% later developed CLDP. In contrast, 13% of patients with no endoscopic inflammation displayed histologic inflammation, with none later developing CLDP. Forty-six percent of patients had rectal cuff inflammation (correlation with histologic inflammation r = 0.580). In our evaluation, the added benefit of histology in the presence of visible endoscopic inflammation for disease activity assessment scores is unclear. The prognostic value of histologic inflammation without endoscopic inflammation warrants a longitudinal study.

Value of histological activity in predicting endoscopic relapse among patients of ulcerative colitis in endoscopic remission

Objective: To investigate the value of histological evaluation in predicting endoscopic relapse among patients with ulcerative colitis (UC) who were in endoscopic remission, and to compare the usefulness of various histological scoring systems. Methods: Histological sections from 61 patients with UC who were in endoscopic remission were retrospectively analyzed, at Peking University Third Hospital, Beijing, China from January 2015 to June 2021. They were subdivided into endoscopic persistent remission group (remission group, n=31, Mayo endoscopic score 0) and endoscopic relapse group (relapse group, n=30, Mayo endoscopic score≥1) according to the results of the first endoscopic reexamination after the biopsy. Histological evaluation was performed using the Geboes score (GS) and its simplified version (SGS), the Nancy index (NI) and the Robarts histopathological index (RHI). The median and maximum histological scores for each case in all biopsies were recorded. Univariate comparisons were performed using chi-squares and multivariate analysis using binary logistic regression. The values of four histological evaluation systems for predicting endoscopic relapse among UC patients in endoscopic remission were analyzed using receiver operating characteristic (ROC) curves. Results: Significant differences were observed between the remission and relapse groups. The differences were more pronounced in the maximum histological scores; the mean and highest results of area under the ROC curve scores (AUC) for GS, SGS, NI, and RHI were 0.657, 0.668, 0.682, 0.691, and 0.866, 0.863, 0.864, 0.869, respectively. The differences were statistically significant (P<0.05). The corresponding best cut-offs were GS≥2B.1, SGS≥2B.1, NI≥2, and RHI≥2.5, respectively, which meant mild active inflammation histologically, while there was no statistical difference of AUC among the four histological scoring indices (P>0.05). Univariate and multivariate analyses revealed statistically significant differences in the number of neutrophils in the epithelium and lamina propria (P<0.05). Conclusions: Biopsies from UC patients in endoscopic remission may still have histological active inflammation which appears to correlate with endoscopic relapse. Four commonly used histological scoring systems can be used to assess the risk of endoscopic relapse among UC patients in endoscopic remission. The patients who more likely have endoscopic relapse seem to have a histological score greater than the cut-off value (i.e., mild histological activity). The maximum histological scores can accurately predict the risk of endoscopic relapse, while the presence of epithelial and laminar propria neutrophil infiltrates can independently predict the endoscopic relapse in these patients. Considering the utility and convenience in routine practice, NI is recommended for evaluating histological inflammatory activity.