Sea bass (Lateolabrax maculatus) has been used for dietary therapy practice in China. In traditional Chinese medicinal books, it has been indicated that sea bass can be applied for managing many inflammation associated conditions. However, the studies on the pharmacological mechanisms of anti-inflammation of sea bass remain scarce. Hence, this study aims to illustrate the pharmacological and chemical basis for the folk use of sea bass in managing inflammation- associated conditions. For in vivo studies, dietary effect of sea bass on inflammation-associated conditions in ulcerative colitis, skin wounds, and intestinal dysbiosis were evaluated. A series of inflammatory mediators associated with wound healing and ulcerative colitis, and the proliferation effects of fibroblasts upon treatments were studied via Western blotting, enzyme-linked immunosorbent assay (ELISA), hematological parameters, histopathological and Immunofluorescence analysis, using cutaneous wound model and DSS induced colitis model, respectively. β-diversity analysis and species variance statistics were conducted to evaluate the effect of ASB on the microbial communities with colitis and discovered the high dimensional biomarkers. Results showed that ASB could significantly ameliorate several pathophysiological and morphological features in DSS induced colitis. ASB has a potential in accelerating the proliferation phase of wound healing via well-organized abundant collagen deposition, angiogenesis, strengthening the skin contraction and skin organ maturation in wounds. Moreover, the study also found that ASB could significantly down-regulated the expression levels of inflammatory associated mediators in colitis and skin wound. Additionally, principal coordinate analysis (PCoA) and relative abundance at phylum level among groups were indicated that ASB possess a potential amelioration on intestinal dysbiosis in colitis. Histogram of linear discriminant analysis (LDA) scores and Cladogram as the results of LEfSe analysis identified that Christensenellaceae might be treated as the the biomarker for treating colitis. For in vivo studies, macrophages and fibroblasts were used for further evaluation. Result showed that ASB could significantly inhibited the production of pro-inflammatory mediators in lipopolysaccharide (LPS) induced macrophages. The mRNA and protein expression level of inflammatory associated mediators were significantly down-regulated upon ASB treatment. Moreover, results also suggested that ASB treatment has a closely link to accelerate the wound healing through migration and proliferation enhancement. Furthermore, the characterization of the aqueous extract of sea bass (ASB) was conducted. Six kinds of peptides and two protein identified from fraction F1 by LC-QE-HF-MS might be responsible for anti-inflammatory activity. It confirmed that Fraction F1 could be treated as the main component for contributing the potential anti-inflammatory activities to ASB. Current results illustrated that fraction F1 (kDa) is a kind of nanoparticles with stability separated from ASB. It can be treated as a promising candidate for treating inflammation associated conditions, providing the chemical basis for the folk use of sea bass in managing inflammation-associated conditions. Current studies established a pharmacological and chemical basis for the folk use of sea bass in managing inflammation-associated conditions. A further justification for the clinical application of sea bass in treating inflammation associated conditions is necessary. Keywords: sea bass; inflammation; ulcerative colitis; wound healing; gut microbiota; peptides

BACKGROUND: Inflammatory Bowel Disease (IBD) is a collective term that refers to chronic inflammatory diseases involving the gastrointestinal (GI) tract. The most common forms of IBD include Crohn’s Disease (CD) and ulcerative colitis (UC). GOALS: The goal of this study is to compare baseline and one-year follow-up measures of anxiety, depression, and quality of life in children with newly diagnosed IBD. A secondary goal of this study is to determine if there are parallel changes in the psychologic parameters in the parents of these children over a similar one-year interval. METHODS: This prospective cohort study was conducted in the Center for Inflammatory Bowel Diseases at Boston Children’s Hospital (BCH). The parents and children with newly diagnosed IBD completed validated questionnaires about their disease at baseline (within six months of their diagnosis) and then again 12-18 months later. RESULTS: Baseline data were collected from 75 patients with IBD, and 15 of these patient/parent dyads have completed follow-up questionnaires. The incidence of anxiety and depression trended downwards after the first year, and overall quality of life trended upwards, indicating an improvement in a global state of adjustment. Measures of anxiety and depression, as well as the reported frequency and difficulty of adverse events, all decreased in parental responses after the first year. CONCLUSION: While a larger sample size is necessary to better assess changes in psychometrics over time, existing data suggests that parents manifest the most significant change in anxiety and depression over the course of the first year from diagnosis. Children appear to be less anxious and depressed at baseline. Further enrollment and data collection will permit a more definitive assessment of the relationship between patient and parent coping strategies. Ideally, the results of this ongoing study will determine if impaired parental coping lowers a patient’s quality of life, contributes to higher childhood anxiety and depression scores, and results in higher healthcare utilization.

BACKGROUND: Characterized as inflammation of the gastrointestinal tract, pediatric inflammatory bowel disease has become increasingly more prevalent throughout the world. Inflammatory bowel disease is chronic, and no definitive cure exists. Instead, patients aim to achieve remission from flair-ups. Adequate transition into adult gastrointestinal care has been shown to be critical for future patient outcomes. Hence, successful transition from pediatric to adult inflammatory bowel disease care plays an important role in maintaining patient wellbeing. Identifying factors that contribute to patient transition readiness may be able to improve the transition process. OBJECTIVE: To elucidate sociodemographic and disease related parameters that influence transition, synthesize models that can predict transition readiness, and make recommendations to improve the process. METHODS: As part of a larger quality improvement project conducted by Massachusetts General Hospital for Children, 274 patients with inflammatory bowel disease ranging from ages 12 to 27 were enrolled between June 2019 and October 2020. Sociodemographic information was gathered via chart review. The Abbreviated Pediatric Crohn’s Disease Activity Index, Disease Activity Index Score, and Physician Global Assessment were completed by patients and physicians to assess disease severity. Patients also completed PROMIS questionnaires to assess anxiety, depression, sleep disturbance and impairment. Patients completed the Transition Readiness Assessment Questionnaire to gauge transition readiness. Bivariate analyses were conducted to elucidate the relationships between sociodemographic information, disease related parameters, and transition readiness. Multivariate regressions were conducted to synthesize models aimed at predicting transition readiness. RESULTS: Females had significantly worse disease severity, mental health, and sleep quality compared to males. Poor sleep quality had a significant relationship with disease severity and mental health status. Females had significantly higher transition readiness scores compared to males. Older age had a significant relationship with greater transition readiness. More patient anxiety was significantly associated with weaker communication skills. Otherwise, no disease related parameters significantly correlated with transition readiness. Disease duration demonstrated a significant positive relationship with transition readiness, particularly for patients diagnosed between the ages of 10 – 17. Models synthesized to predict transition readiness demonstrated substantial variability in predictive value. CONCLUSION: Transitioning from pediatric to adult inflammatory bowel disease care is a complex process. Future research should be aimed at elucidating discrepancies in transition readiness between genders, and further understanding the role disease duration plays in the transition process. Providers should work towards incorporating structured transition programs and improving patients’ disease-related knowledge, as well as patient familiarity with logistical aspects of the current US healthcare system. / 2023-11-09T00:00:00Z

INTRODUCTION: Acute severe ulcerative colitis (ASUC) is a severe complication of ulcerative colitis (UC) that is associated with significant morbidity, treatment refractoriness and need for colectomy. Patients who do not adequately respond to the initial intravenous steroid therapy receive medical rescue therapy with infliximab or cyclosporine or undergo surgery for their refractory disease. However, there is limited guidance on management of steroid responders in this setting. While it is well established that Crohn’s disease (CD) is progressive and benefits from early institution of immunosuppressive therapy, such a paradigm is less well established in UC and thresholds for therapy escalation remain poorly defined. In immunosuppression-naïve patients, whether a single hospitalization for ASUC is a sufficient threshold to escalate to immunomodulator or biologic therapy is unknown. METHODS: From a single tertiary referral center, we identified all patients with ASUC hospitalized for intravenous steroids who were immunosuppression naïve (new UC diagnosis, no therapy, or 5-aminosalicylate (5-ASA) therapy) at their index hospitalization. We excluded patients who were refractory to steroids and initiated medical rescue therapy or required surgery during the index hospitalization. Our primary exposure of interest was initiation of biologic therapy within 1 month of hospital discharge or immunomodulator therapy (thiopurine, methotrexate) within 3 months. Our primary outcomes were need for colectomy within 12 months following hospitalization. Secondary outcomes include re-hospitalization rate within 12 months and late colectomy ( between 91-365 days). RESULTS: Our study included a total of 133 immunosuppressive-naïve ASUC patients among whom 56 (42%) escalated therapy to thiopurine (93%) or biologic (7%) post-hospitalization. The median age of the cohort was 29 years (range 16 – 88 years) and 46% were male. 82 patients (62%) had pancolitis on disease distribution. 38% and 58% were noted to have moderate to severe disease on sigmoidoscopic evaluation. Thirteen patients (10%) underwent surgery by 1 year. At 12 months, there was no difference in the rate of colectomy among those with therapy escalation (13%) compared to those who did not undergo such escalation (8%, unadjusted OR= 1.69 p=0.53). This lack of difference remained robust on multivariable regression analysis and propensity score adjusted models (OR 0.90, 95% confidence interval (CI) 0.18 – 4.45). There was no difference in the rates of hospitalization within 1 year (OR 2.24 95% CI 0.16 – 4.22) or in the time to colectomy between the two groups (log-rank p=0.27). CONCLUSION: Immunosuppression-naïve ASUC patients who respond to intravenous steroids remain at high risk for colectomy with 10% (13/133) receiving such surgery within 1 year. Therapy escalation was not associated with a reduction in this risk. There is an important need for larger prospective studies defining the benefit of early therapy escalation in UC, and appropriate thresholds for the same.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24492号 / 医博第4934号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 今中 雄一, 教授 川上 浩司, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Diet is a key factor in the development and progression of Inflammatory Bowel Disease (IBD). A variety of diets have been studied with IBD patients. This cross-sectional survey identified current healthcare practitioner views on different diets and their efficacy with IBD patients. Diets were rated on awareness, compliance, and contributors to success by participants (n = 181). Frequencies were conducted, and ANOVA with Duncan pairwise comparison or chi-square analysis were used to determine significant differences. Most participants (96%) and 98% of registered dietitians (RD) considered using diet to help treat IBD patients. RDs perceived the low fiber or low residue diet easiest for patient compliance (4.2 ± 1.0, P < .05), and the specific carbohydrate diet hardest for patient compliance (2.4 ± 1.4). Initial and follow up consultations with a RD significantly contributed to patient success across all diets, and greater involvement from the RD may solve issues with compliance.

<p>   </p> <p>Ulcerative colitis is a chronic disease that affects more than 770,000 U.S individuals and the number will increase to 1 million by 2025, resulting in $7 billion cost to manage the disease. Ulcerative colitis is characterized by inflammation along the colon and is a risk factor for the deadly colitis-associated colon cancer (CAC). Emerging research shows that gut microbes, the microorganisms living in our intestine, regulate colon inflammation. Specifically, an imbalanced microbial community may promote the growth of pathogens that invade the host to cause or exacerbate colitis. Therefore, researchers have been searching for safe and cost-effective approaches to keep gut microbes balanced in a long run and thus to control colitis. To this end, my research investigates the microbial modulatory capacities of dietary phytochemicals including polyphenols and vitamin E forms, delineates the role of microbial interaction in their protective effects against colon inflammation and further utilizes such interactions to develop anti-colitis therapies. To address the research questions, I have performed three independent projects and discussed them separately in chapters 2-4. </p> <p>The first project (chapter 2) focused on the anti-CAC and anti-colitis effects of grape polyphenols supplemented through a whole grape powder. Polyphenols are natural chemicals found in plants and have been shown to alleviate colon inflammation in both clinical and animal studies, but the underlying mechanisms are not completely understood. In particular, the role of microbial modulation in polyphenol-mediated benefits is not fully established. Here we hypothesized that, polyphenols may attenuate colon inflammation via interacting with gut microbes. Through two animal studies, we found that 10% grape powder (10GP) diet, which contains 0.033% polyphenols, attenuated colitis-associated tumorigenesis, and prevented disease-induced microbial dysbiosis. Moreover, 10GP diet only mitigated colitis in conventional animals, but not antibiotic-treated, gut microbe-depleted animals. Collectively, these two studies demonstrated that the interaction with gut microbes played a causative role in the protective effects of 10GP against colon inflammation. </p> <p>Like polyphenols, vitamin E forms are also phytochemicals with phenolic structures and undergo liver metabolism followed by biliary excretion to the gut. In the second project, we investigated the anti-colitis effects of vitamin E-based synbiotics therapies. Previously, we found that d-tocotrienol 13-carboxychromanol (dTE-13’), a metabolite of the natural vitamin E form dTE, inhibited colitis-associated tumorigenesis in mice, modulated their gut microbiota and increased the relative abundance of a lactic acid bacterium, which is commonly used in food industry. Interestingly, a subspecies of this bacterium, named <em>Lactococcus. lactis</em> subsp. <em>cremoris</em> (<em>L. cremoris</em>), has been reported to attenuate ulcerative colitis in mice. Therefore, we reasoned that combining dTE-13’with <em>L. cremoris</em> may offer synergistic protection against ulcerative colitis by modulating gut microbes. Through two animal studies coupled with anaerobic cell culture, we found that combining <em>L. cremoris</em> with dTE-13’, not the parental dTE, showed superior anti-colitis effects, rendered gut microbes resistant to disease-associated dysbiosis and facilitated the microbial reduction of a double bond on dTE-13’ into dTE-13’ (2DB). Overall, these data suggested that dTE-13’ interacted with <em>L. cremoris</em> to benefit the host. </p> <p>To further corroborate the microbial metabolism of vitamin E forms under <em>in vivo</em> settings, we launched the third project (chapter 4) where we compared the metabolites formation of dTE and dTE-13’ between antibiotic-treated mice that had reduced gut bacterial load and conventional ones. We found that in dTE-gavaged animals, antibiotics treatment decreased the fecal amounts of dTE and its metabolites by 61% and 98%, respectively, while increased dTE level in the adipose tissue. Similarly, in animals gavaged with dTE-13’, antibiotics treatment led to a 98% reduction in its downstream metabolites. More importantly, antibiotics treatment reduced the ratio of the parental dTE and dTE-13’ to their metabolites in feces, especially the reduction from dTE-13’ (3DB) to dTE-13’ (2DB), suggesting the active role of gut microbes in the metabolism of dTE and dTE-13’. This observation is consistent with the results from the anaerobic study performed in the second project.</p> <p>In summary, we showed that grape polyphenols and vitamin E form-based synbiotics offered strong protection against colon inflammation and their interaction with gut microbes likely contributed to the observed benefits. In the study of grape polyphenols, we proved the causal role of gut microbes in polyphenol-mediated alleviation of colitis. In the subsequent study of vitamin E forms, we presented evidence that the superiority of the synbiotics might be rooted in the enhanced microbial metabolism of vitamin E forms. Together, these results supported the central role of gut microbes in the management of colitis and proposed two different classes of dietary phytochemicals that can manipulate gut microbes to benefit the host. Natural bioactive compounds like polyphenols and vitamin E forms are ideal candidates for long-term preventive measures as they have less side effects and are more cost-effective compared to drugs. Moreover, by understanding the targeting microbes of different phytochemical compounds, hopefully we will be able to customize phytochemical supplementation based on individual microbial profile and dietary habits. For instance, we may optimize the dosage and type used based on the microbes present in the gut, or add in probiotics to design more effective synbiotics just like the combination of dTE-13’ and <em>L.cremoris</em>.</p> <p>  </p>

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23806号 / 医博第4852号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森信 暁雄, 教授 上野 英樹, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM