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Detection of human herpesviruses (HHVs) other than cytomegalovirus (CMV) in colonic mucosa of individuals with inflammatory bowel disease (IBD) remains unknown. This study identified eight HHVs in the colonic mucosa of individuals with IBD and compared the results with immunocompetent and human immunodeficiency virus (HIV)-infected individuals. A total of 89 individuals who had colorectal ulcer on colonoscopy were enrolled: 26 with immunocompetency (n = 26), 41 with IBD, and 22 with HIV infection. We examined the colonic ulcers for the presence of eight HHVs-herpes simplex virus (HSV)-1/2, varicella zoster virus (VZV), CMV, Epstein-Barr virus (EBV), HHV-6, HHV-7, and HHV-8-using mucosal PCR. The IBD group had positivity rates of 0%, 0%, 0%, 53.7%, 24.4%, 39%, 39%, and 0% for HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8, respectively. The positivity rates of EBV and CMV in colonic mucosa increased significantly in the order of the immunocompetent, IBD, and HIV groups (EBV: 23.1%, 53.7%, 72.7%, P for trend = 0.0005; CMV, 7.7%, 24.4%, 54.5%, P for trend = 0.0003, respectively), but no increase was found in the other HHVs. Median mucosal EBV DNA values in the immunocompetent, IBD, and HIV groups were 0, 76, and 287 copies/μg DNA, respectively (P for trend = 0.002). Corresponding median mucosal CMV DNA values were 0, 0, and 17 copies/μg DNA (P for trend = 0.0001). There was no significant difference in the positivity rates of the eight HHVs between ulcerative colitis and Crohn's disease. The HHVs of EBV, CMV, HHV-6, and HHV-7, but not of HSV-1, HSV-2, VZV, or HHV-8, were identified in the colonic mucosa of IBD individuals. EBV and CMV in colonic mucosa was correlated with host immune status in increasing order of immunocompetent, IBD, and HIV-infected individuals.

We aimed to identify the risk factors associated with colonic cytomegalovirus (CMV) infection in ulcerative colitis (UC) and to compare the clinical course between antiviral therapy-treated and -untreated groups in mucosal CMV-polymerase chain reaction (PCR) -positive cases. We retrospectively selected 46 UC patients (>15 years old) in active phase who underwent colonoscopy with biopsy and were analyzed for CMV infection by mucosal PCR between October 2011 and December 2015 at our institution. Colonic CMV in inflamed mucosa was detected using quantitative real-time PCR. The clinical course was evaluated, including need for drug therapy/surgery or drug therapy intensification. In addition, we evaluated the clinical course between CMV-DNA- cases and CMV-DNA+ cases with low viral load. At baseline, CMV-DNA+ patients were significantly older, had higher endoscopic scores, and required higher corticosteroid doses during the past 4 weeks than CMV-DNA- patients (p< 0.05). No significant differences were observed in disease duration, disease distribution, laboratory data, or use of other medication between CMV-DNA+ and CMV-DNA- patients. In the anti-CMV-treated group with a median (range) DNA load of 16,000 (9,000-36,400), 3patients achieved remission without additional UC therapy, 2 required additional UC therapy, and 1 required colectomy despite azathioprine and infliximab therapy. In the CMV-untreated group with a median (range) DNA load of 919 (157-5,480), all patients achieved remission with UC therapy alone. No significant difference was observed in the clinical course between CMV-DNA- cases and CMV-DNA+ cases with low viral loads. Aging, endoscopic UC activity, and corticosteroid dose predispose to colonic CMV infection, as determined by mucosal PCR, in UC. UC treatment without anti-CMV therapy may be warranted, particularly in patients with low-load CMV-DNA. Anti-CMV therapy alone does not always achieve clinical response in UC even in cases with high-load PCR.

BACKGROUND:Fecal microbiota transplantation (FMT) has proved its efficacy for treating recurrent Clostridium difficile infection, but an effective FMT protocol is still yet to be found for treating ulcerative colitis (UC). We previously demonstrated that fresh fecal-microbiota transplantation (FMT) following triple-antibiotic therapy [amoxicillin, fosfomycin, and metronidazole (AFM); A-FMT] induced dramatic changes in the phylum Bacteroidetes, which constitutes a critical factor correlated with clinical responses. Furthermore, we also reported that A-FMT combination therapy contributed to the microbiological improvement of intestinal dysbiosis in UC patients via successful transplantation of live Bacteroidetes cells from donors. Eradication of dysbiotic indigenous Bacteroidetes species by AFM pretreatment may promote the entry of living Bacteroidetes cells, thereby improving the dysbiosis of intestinal microbiota induced by UC. Here, we evaluated the efficacy of A-FMT compared to AFM monotherapy and examined factors correlated with clinical response.METHODS:This was an open label, non-randomized, prospective control study of the use of FMT in treating UC, following AFM pre-treatment. This clinical study included participants above 20 years of age. These patients were diagnosed with active UC, with a Lichtiger's Clinical Activity Index (CAI) of 5 or more, or with an endoscopic Mayo clinic score of 1 or more, between July 2014 and March 2017. Patients' spouses or relatives were selected as donor candidates. Donor fecal samples were collected on the day of administration and transferred into the patient's colon via colonoscopy within 6 h. The clinical features of UC were judged using CAI scores before treatment and 4 weeks after treatment. Clinical responses were defined as a CAI of less than 10 points and a decrease of 3 or more points, and clinical remission was defined as a CAI of 3 points or less.RESULTS:Patients with mild-to-severe active UC (n = 55 A-FMT group; n = 37 AFM monotherapy group) were included in this assessment. Seventy-nine patients completed this assessment (n = 47 A-FMT group; n = 32 AFM monotherapy group). Although the Mayo score was slightly higher in the A-FMT group, no significant difference was observed between the 2 treatment groups. No serious adverse events were observed during the study. At 4 weeks after treatment with FMT, the clinical responses were observed in 31 patients Per Protocol Set (PPS): 66.0%) in the A-FMT group, resulting higher than of the AFM monotherapy group (PPS: 56.3%). In A-FMT group, the clinical remission rate was observed to be significantly higher than AFM monotherapy (A-FMT group 40.4%, AFM monotherapy 18.6%; P = 0.04). The endoscopic sum score was associated with clinical responses (Responders 7.5 ± 3.2, Non-responders 5.1 ± 3.6; P = 0.03) in A-FMT.CONCLUSION(S):A-FMT combination therapy exhibited reassuring clinical outcomes in comparison to AFM monotherapy. Further follow-up studies are required to evaluate the long-term efficacy of this FMT protocol, and it is possible that this protocol may become a useful strategy for the management of patients with UC.

We previously demonstrated that fresh fecal microbiota transplantation (FMT) following triple antibiotic therapy (amoxicillin, fosfomycin, metronidazole (AFM); A-FMT) resulted in effective colonization of Bacteroidetes species, leading to short-term clinical response in ulcerative colitis (UC). Its long-term efficacy and criteria for donor selection are unknown. Here, we analyzed the long-term efficacy of A-FMT compared to AFM monotherapy (mono-AFM). AFM was administered to patients with mild to severe UC for 2 weeks until 2 days before fresh FMT. Clinical response and efficacy maintenance were defined by the decrease and no exacerbation in clinical activity index. The population for intention-to-treat analysis comprised 92 patients (A-FMT, n = 55; mono-AFM, n = 37). Clinical response was observed at 4 weeks post-treatment (A-FMT, 56.3%; mono-AFM, 48.6%). Maintenance rate of responders at 24 months post-treatment was significantly higher with A-FMT than mono-AFM (p = 0.034). Significant differences in maintenance rate according to the age difference between donors and patients were observed. Additionally, sibling FMT had a significantly higher maintenance rate than parent–child FMT. Microbial analysis of patients who achieved long-term maintenance showed that some exhibited similarity to their donors, particularly Bacteroidetes species. Thus, A-FMT exhibited long-term efficacy. Therefore, matching between donors and UC patients may be helpful in effectively planning the FMT regimen.

Background: Cytapheresis is a non-pharmacologic treatment option in which depleting elevated/activated leucocytes is known to exacerbate and perpetuate ulcerative colitis (UC) by releasing inflammatory cytokines. Therefore, it is a relevant treatment for elderly patients who wish to avoid pharmacologicals. Methods: The efficacy of Cytapheresis for remission induction in 72 patients who received Cytapheresis for active UC at our hospital was retrospectively evaluated. Patients included 11 elderly cases, patients on steroids, biologics, calcineurin inhibitor, and 13 with extra-intestinal complications. Lichtiger’s UC clinical activity index ≤4 meant remission was assessed at the end of therapy and then 1 month later. The efficacy on extra-intestinal manifestations meant improvement of the main morbidity. Results: At the end of Cytapheresis therapy, the remission rate in the elderly was 36.4%, and 54.2% in the non-elderly patients. One-month post Cytapheresis, the remission rate in the elderly had increased to 72.7% (p = 0.042), but to 58.3% in the non-elderly, suggesting a delayed response phenomenon in the elderly. The efficacy of Cytapheresis in 4 cases with loss of response to biologics was 75%, and 84.6% in the 13 patients with extra-intestinal complications, indicating a dramatic efficacy on dermatitis and arthralgia. Conclusions: Unlike pharmacologicals, the efficacy of Cytapheresis appears to be time dependent. Accordingly, in the elderly, we observed a delayed response, indicating that elderly patients may respond beyond the end of Cytapheresis therapy. Therefore, patients who do not show efficacy at the end of Cytapheresis therapy should be followed up for delayed response. Further, Cytapheresis is favored by patients for its good safety profile.

Fecal microbiota transplantation following triple-antibiotic therapy (amoxicillin/fosfomycin/metronidazole) improves dysbiosis caused by reduced Bacteroidetes diversity in patients with ulcerative colitis (UC). We investigated the correlation between Bacteroidetes species abundance and UC activity. Fecal samples from 34 healthy controls and 52 patients with active UC (Lichtiger’s clinical activity index ≥5 or Mayo endoscopic subscore ≥1) were subjected to next-generation sequencing with HSP60 as a target in bacterial metagenome analysis. A multiplex gene expression assay using colonoscopy-harvested mucosal tissues determined the involvement of Bacteroidetes species in the mucosal immune response. In patients with UC, six Bacteroides species exhibited significantly lower relative abundance, and twelve Bacteroidetes species were found significantly correlated with at least one metric of disease activity. The abundance of five Bacteroidetes species (Alistipes putredinis, Bacteroides stercoris, Bacteroides uniformis, Bacteroides rodentium, and Parabacteroides merdae) was correlated with three metrics, and their cumulative relative abundance was strongly correlated with the sum of Mayo endoscopic subscore (R = −0.71, p = 2 × 10−9). Five genes (TARP, C10ORF54, ITGAE, TNFSF9, and LCN2) associated with UC pathogenesis were expressed by the 12 key species. The loss of key species may exacerbate UC activity, serving as potential biomarkers.

Abstract Background We previously reported that fresh fecal microbiota transplantation (FMT) after triple-antibiotic therapy (amoxicillin, fosfomycin, and metronidazole [AFM]; A-FMT) synergistically contributed to the recovery of phylum Bacteroidetes composition associated with the endoscopic severity and treatment efficacy of ulcerative colitis (UC). Here, we performed further microbial analyses using a higher-resolution method to identify the key bacterial species in UC and determine whether viable Bacteroidetes species from donor feces were successfully colonized by A-FMT. Methods The taxonomic composition of Bacteroidetes in 25 healthy donors and 27 UC patients at baseline was compared at the species level using a heat-shock protein (hsp) 60-based microbiome method. Microbiota alterations before and after treatment of UC patients were also analyzed in 24 cases (n = 17 A-FMT; n = 3 mono-AFM; n = 4 mono-FMT). Results We found species-level dysbiosis within the phylum Bacteroidetes in UC samples, which was associated with reduced species diversity, resulting from hyperproliferation and hypoproliferation of particular species. Moreover, in responders treated with A-FMT, diversity was significantly recovered at 4 weeks after a fresh round of FMT, after which high degrees of similarity in Bacteroidetes species composition among recipients and donors were observed. Conclusions A-FMT alleviated intestinal dysbiosis, which is caused by the loss of Bacteroidetes species diversity in patients with UC. Eradication of dysbiotic indigenous Bacteroidetes species by AFM pretreatment might promote the colonization of viable Bacteroidetes cells, thereby improving the intestinal microbiota dysbiosis induced by UC. Our findings serve as a basis for further investigations into the mechanisms of FMT.

Abstract Background We have recently reported the efficacy of combination of triple-antibiotic therapy and fecal microbiota transplantation (A-FMT) for patients with ulcerative colitis (UC). It has been reported that FMT with frozen donor faeces (frozen-FMT) is as effective as fresh-FMT for Clostridium difficile infection. However, it is still unclear which donor and condition is suitable for FMT on UC. The aim of this study was to evaluate the effectiveness of frozen-FMT compared to fresh-FMT, and verify effective conditions. Moreover, we explore the concept of best donor for A-FMT success. Methods This prospective and randomized controlled study was conducted from July 2017 to September 2019 at Juntendo University Hospital. Eligible patients were at least 20 years of age, with a diagnosis of active UC which were required a Lichtiger’s clinical activity index (CAI) of 5 or more, or with an endoscopic Mayo score of 1 or more. Patients were randomly allocated fresh or frozen faecesfrom 2 healthy donors. Triple-antibiotic therapy (Amoxicillin, Fosfomycin, Metronidazole; AFM) was administered to patients with UC for 2 weeks, and up to 2 days before FMT. Clinical outcomes were assessed at8 weeks and 1 year after treatment. Clinical response was defined as a decrease of CAI of 3 points or more, and remission was defined as 3 points or less. Maintenance of efficacy was defined as no exacerbation of CAI and no intensification of treatments. Results 29 patients completed protocol (fresh-FMT; n = 15, frozen-FMT; n = 14). At 8 weeks after treatment, clinical response and remission were observed in fresh-FMT (46.7%, 33.3%), and in frozen-AFM (64.3%, 42.9%) respectively.There were no significant differencesin therapeutic effectsbetween frozen-FMT and fresh-FMT.On the other hand, in cases which age difference between donor and patient was more than 16 years, maintenance rate was significantly lower than 0–15 age difference (0–15 vs ≧16, n = 14, 15 p<0.05). Interestingly,in cases that age difference between patient and donor was 0–15 years, high therapeutic effect was observed in patients treated withfresh- FMT. Conclusion This study showed that A-FMT with frozen faeces is as effective as cases treated with fresh faeces. In addition, findings from this study indicate that donor selection influences treatment effects, and age difference between patient and donor might be an important factor for A-FMT success.

Abstract Background Fecal microbiota transplantation (FMT) has been investigated as a potential treatment for various disease. However, the therapeutic mechanism is still unclear. We previously demonstrated that fresh-fecal microbiota transplantation following triple-antibiotic therapy [amoxicillin, fosfomycin, and metronidazole (AFM); A-FMT] for ulcerative colitis (UC) patients induced changes in the phylum Bacteroidetes, which constitutes a critical factor correlated with clinical responses. Here, we analyzed microbiota to examine the beneficial species, and observed long-term course (12 months) of the patients who treated with AFM and A-FMT. Moreover, we explore the concept of best donor for FMT success. Methods This prospective and non-randomized controlled study was conducted from July 2014 to March 2017 at Juntendo University Hospital. Eligible patients were at least 20 years of age, with a diagnosis of active UC which were required a Lichtiger’s clinical activity index (CAI) of 5 or more, or with an endoscopic Mayo score of 1 or more. Patients’ spouses or relatives in the family were selected as donors. AFM was administered to patients with UC for 2 weeks, and up to 2 days before fresh FMT. Clinical response was defined as a decrease of CAI of 3 points or more, and remission was defined as 3 points or less. Maintenance of efficacy was defined as no exacerbation of CAI and no intensification of treatments. Results Seventy-nine patients completed protocol (A-FMT; n = 47, mono-AFM; n = 32). At 4 weeks after treatment, clinical response and remission were observed in 31 and 19 patients (65.9%, 40.4%) in A-FMT, which higher than in mono-AFM respectively (56.2%, 18.7%). The maintenance rate of clinical responder was shown to be significantly higher in A-FMT than in AFM at 12 months after treatment (A-FMT vs mono-AFM, n = 13, 10; P = 0.046). Furthermore, in case that the age difference between donor and patient is more than 11 years, maintenance rate was significantly lower than 0–10 age difference in A-FMT (≧11 vs 0–10, n = 14, 16; P = 0.004). Siblings relationship has a significantly higher maintenance rate compared to parent–child relationship (Siblings vs parent-child; n = 7, 13; P = 0.009). An analysis of some cases in which the microbiota was followed for 24 months revealed a tendency that some bacterial species such as Bacteroides dorei and Bacteroides uniformis maintained their effects. Conclusion A-FMT exhibited reassuring clinical outcomes in terms of both short and long term. This is the first report of FMT to reveal importance of donor selection for long-term maintenance for UC.

Abstract Background Fecal microbiota transplantation (FMT) has proved its efficacy for treating recurrent Clostridium difficile infection, but an effective FMT protocol is still yet to be found for treating ulcerative colitis (UC). We previously demonstrated that fresh fecal-microbiota transplantation (FMT) following triple-antibiotic therapy [amoxicillin, fosfomycin, and metronidazole (AFM); A-FMT] induced dramatic changes in the phylum Bacteroidetes, which constitutes a critical factor correlated with clinical responses. Furthermore, we also reported that A-FMT combination therapy contributed to the microbiological improvement of intestinal dysbiosis in UC patients via successful transplantation of live Bacteroidetes cells from donors. Here, we evaluated the efficacy of A-FMT compared to AFM monotherapy and examined factors correlated with clinical response. Methods This was an open label, non-randomized, prospective control study of the use of FMT in treating UC, following AFM pre-treatment. This clinical study included participants above 20 years of age. These patients were diagnosed with active UC, with a Lichtiger’s Clinical Activity Index (CAI) of 5 or more, or with an endoscopic Mayo clinic score of 1 or more, between July 2014 and March 2017. Patients’ spouses or relatives were selected as donor candidates. Donor fecal samples were collected on the day of administration and transferred into the patient’s colon via colonoscopy within 6 h. The clinical features of UC were judged using CAI scores before treatment and 4 weeks after treatment. Clinical responses were defined as a CAI of less than 10 points and a decrease of 3 or more points, and clinical remission was defined as a CAI of 3 points or less. Results Patients with mild-to-severe active UC (n = 55 A-FMT group; n = 37 AFM monotherapy group) were included in this assessment. Seventy-nine patients completed this assessment (n = 47 A-FMT group; n = 32 AFM monotherapy group). Although the Mayo score was slightly higher in the A-FMT group, no significant difference was observed between the 2 treatment groups. No serious adverse events were observed during the study. At 4 weeks after treatment with FMT, clinical responses were observed in 31 patients (66.0%) in A-FMT group, which higher than in AFM monotherapy group (56.3%), but not significantly. In A-FMT group, the clinical remission rate was observed to be significantly higher than AFM monotherapy (A-FMT group 40.4%, AFM monotherapy18.6%; p = 0.04). The endoscopic sum score was associated with clinical responses (Responders 7.5 ± 3.2, Non-responders 5.1 ± 3.6; p = 0.03) in A-FMT. Conclusion A-FMT combination therapy exhibited reassuring clinical outcomes in comparison to AFM monotherapy. Further follow-up studies are required to evaluate the long-term efficacy of this FMT protocol, and it is possible that this protocol may become a useful strategy for the management of patients with UC.