Fecal Microbiota Transplantation as Emerging Treatment in European Countries 2.0.

Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections and one of the leading causes of morbidity and mortality in hospitalized patients in the world. Although several antibiotics effectively treat CDI, some individuals may not respond to these drugs and may be cured by transplanting stool from healthy donors. FMT has demonstrated extraordinary cure rates for the cure of CDI recurrences.Moreover, FMT has also been investigated in other disorders associated with the alteration of gut microbiota, such as inflammatory bowel disease (IBD), where the alterations of the gut microbiota ecology have been theorized to play a causative role. Although FMT is currently not recommended to cure IBD patients in clinical practice, several studies have been recently carried out with the ultimate goal to search new therapeutic options to patients.This review summarizes data on the use of FMT for the treatment of both CDI and IBD, with a special attention to highlight studies conducted in European countries.

Fecal microbiota transplantation for recurrent Clostridioides difficile infection in patients with concurrent ulcerative colitis.

AIMS: Clostridioides difficile infection (CDI) is a major challenge for healthcare systems. Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, is a risk factor for primary and recurrent CDI (rCDI). Moreover, CDI itself often worsens the clinical picture of IBD, increasing the risk of complications. Fecal microbiota transplantation (FMT) is a highly effective treatment for rCDI, but data from patients with IBD and CDI are limited and often referred to mixed cohorts. We aimed to report outcomes from a cohort of patients with UC treated with FMT for rCDI superinfection. METHODS AND RESULTS: In a retrospective, single-centre cohort study we evaluated characteristics and outcomes of patients with UC who received FMT for rCDI. The primary outcome was negative C. difficile toxin 8 weeks after FMT. Thirty-five patients were included in the analysis. Sixteen patients were cured after single FMT, while 19 patients received repeat FMT. Overall, FMT cured rCDI in 32 patients (91%), and repeat FMT was significantly associated with sustained cure of CDI compared with single FMT (84% vs 50%, p = 0.018). Twenty-four patients (69%) experienced remission or an amelioration of UC activity. Serious adverse events were not observed. CONCLUSIONS: In our cohort of patients with UC, FMT was highly effective in curing rCDI without severe adverse events and repeat FMT was significantly associated with CDI cure. Most patients also experienced remission or amelioration of UC activity after FMT. Our findings suggest that a sequential FMT protocol may be used routinely in patients with UC and rCDI.

Rummeliibacillus suwonensis: First Time Isolation from Human Feces by Culturomics.

Gut microbiota is a complex ecosystem composed by trillions of microorganisms that are crucial for human health or disease status. Currently, there are two methodological options to explore its complexity: metagenomics and culturomics. Culturomics is an approach that uses multiple culture conditions (days of incubation, enrichment factors and growth temperature) and MALDI-TOF mass spectrometry for the identification of bacterial species and sequencing when this method fails. In this paper, we describe how Colturomic's protocol has allowed the first isolation in human sample of Rummeliibacillus suwonensis, a Gram positive, facultative anaerobe bacterium. The bacterium was isolated from feces of a 69 years old male with amyotrophic lateral sclerosis (ALS) recruited for a clinical trial assessing safety and efficacy of fecal microbiota transplantation in ALS. The first isolation of the microorganism dates back to 2013 from the soil of a South Korean mountain area. In this report, morphological description, biochemical characterization and antibiotic susceptibility tests were performed to outline the bacterial properties.

Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic.

The COVID-19 pandemic has led to an exponential increase in SARS-CoV-2 infections and associated deaths, and represents a significant challenge to healthcare professionals and facilities. Individual countries have taken several prevention and containment actions to control the spread of infection, including measures to guarantee safety of both healthcare professionals and patients who are at increased risk of infection from COVID-19. Faecal microbiota transplantation (FMT) has a well-established role in the treatment of Clostridioides difficile infection. In the time of the pandemic, FMT centres and stool banks are required to adopt a workflow that continues to ensure reliable patient access to FMT while maintaining safety and quality of procedures. In this position paper, based on the best available evidence, worldwide FMT experts provide guidance on issues relating to the impact of COVID-19 on FMT, including patient selection, donor recruitment and selection, stool manufacturing, FMT procedures, patient follow-up and research activities.

Twice-a-day PPI, tetracycline, metronidazole quadruple therapy with Pylera® or Lactobacillus reuteri for treatment naïve or for retreatment of Helicobacter pylori. Two randomized pilot studies.

BACKGROUND: Bismuth is no longer available in Europe except as part of combination therapy. Lactobacillus reuteri has also been used as an adjuvant for Helicobacter pylori therapy. We aimed to investigate the efficacy of a b.i.d. quadruple therapy containing Pylera® or L reuteri for H pylori infection. MATERIALS AND METHODS: We performed two open-label randomized pilot studies. Adult patients positive for H pylori were randomly assigned to b.i.d therapy with quadruple therapy containing bismuth (2 capsules of Pylera® plus 250 mg each of tetracycline and metronidazole for a total of 500 mg of each), or the same dose of antibiotics plus 2 × 108  CFU L reuteri DSM 17 938 plus 2 × 108  CFU L reuteri ATCC PTA 6475 (Gastrus®) once daily and pantoprazole 20 mg b.i.d. Regimens were given with meals for 10 days. Cure was defined by negative 13C-UBT or stool antigen test. RESULTS: A total of 99 subjects (29% men) were enrolled; 92 completed the study. In the Pylera® group, H pylori infection was cured in 95.7%; 95% CI = 85%-99% (44/46) PP and 88%; 95% CI = 75%-95% (44/50) ITT vs. 84.8%; 95% CI = 71%-95% (39/46) PP and 79.6%; 95% CI = 65%-89% (39/49) ITT in the Gastrus® group, respectively. Cure rates in naїve patients were 100%; 95% CI = 85%-100% (25/25) PP with Pylera®, and 89.7%; 95% CI = 72%-97% (26/29) with Gastrus®. Compliance was excellent and side effects mild with both regimens. CONCLUSIONS: B.i.d. bismuth quadruple therapy was highly effective for H pylori eradication in treatment of naïve patients in Sardinia. Replacement of bismuth with Gastrus® might be considered when bismuth is contraindicated or unavailable.

Clinical features and natural history of idiopathic peptic ulcers: a retrospective case-control study.

Objectives: Peptic ulcer disease (PUD) is still common worldwide and is characterized by high mortality and morbidity. Following the decline of Helicobacter pylori infection, the detection of idiopathic PUD (IPUD) has become more frequent, making diagnosis and treatment more difficult. In this study, the clinical features and natural history of IPUD were analyzed.Methods: This was a retrospective case‒control study conducted in a tertiary care setting (University of Sassari, Italy). Records of 9,212 patients undergoing upper endoscopy from 2002 to 2018 were analyzed. Following the exclusion of H. pylori, NSAIDs, and unusual PUD causes, the remaining were labelled as IPUD. Cases (IPUD) and controls (PUD negative) were compared, adjusting for several covariates through multivariate logistic regression models.Results: Among 380 PUD, 95 were considered IPUD. The proportion rose over the study period in contrast to the decline of H. pylori-PUD. Factors significantly associated with IPUD, after adjusting for all covariates, were age (OR, 3.520; 95% CI, 1.634 - 7.585), male sex (OR, 3.126; 95% CI, 1.888 - 5.176), hospitalization (OR, 2.968; 95% CI, 1.926 - 4.575), and number of medications (OR, 2.808; 95% CI, 1.178 - 6.735). A clinical history positive for PUD was the major risk associated with IPUD (OR, 3.729; 95% CI, 2.050 - 6.785). Patients with IPUD were treated with the highest proton pump inhibitor (PPI) dose for 40-60 days. Follow up endoscopy showed a cure rate of 97.6%.Conclusion: The relative proportion of IPUD is increasing in our population in contrast to the drop of H. pylori-PUD. Treatment with high-dose PPI, and for a long duration, heals IPUD and protects from recurrence.

Fecal microbiota transplant for C. difficile infection: Just say yes.

The burden of Clostridium difficile associated diarrhea is a worrying clinical issue worldwide, mainly as regarding the high incidence of recurrences after standard antibiotic therapy and the risk for more severe clinical manifestations. For this reason, new and more effective therapies are needed for the treatment of recurrent episodes. Fecal microbiota transplantation seems to be a valid tool considering the mechanism of action and the growing number of studies that demonstrate its clinical efficacy.

Role of Probiotics in Helicobacter pylori Eradication: Lessons from a Study of Lactobacillus reuteri Strains DSM 17938 and ATCC PTA 6475 (Gastrus®) and a Proton-Pump Inhibitor.

BACKGROUND: Meta-analyses involving >4000 subjects with probiotics added to antimicrobial Helicobacter pylori eradication therapy have reported a mean increase in the eradication rate of 12 to 14%. It is unclear how to translate that result into clinical practice. AIM: To evaluate whether administration of Lactobacillus reuteri plus a PPI without antibiotics would eradicate H. pylori infections. METHODS: This was a double-blind placebo-controlled randomized 2-site study of L. reuteri (Gastrus®) at a dose of 2 × 108 CFU, 7 times per day, or matching placebo plus 20 mg pantoprazole b.i.d. for 4 weeks. Cure was defined by negative 13C-UBT, 4 weeks after therapy. Sample size required ≥50% cure rates for using probiotics as a clinically useful monotherapy. RESULTS: Recruitment was halted after 56 subjects because of the low cure rate; there were 8 dropouts; 48 subjects completed therapy (71% women, average age 49 years). The cure rates per protocol were 3/24 (12.5%; 95% CI 2.6-32%) with L. reuteri vs. 1/24 (4.1%) with placebo. Side effects (most often diarrhea) occurred infrequently (in 5/28 vs. 3/28; active vs. placebo therapy) (P=0.53). CONCLUSION: L. reuteri plus a PPI therapy was unable to provide a clinically important rate of H. pylori eradication. The cure rate albeit low (12.5%) was essentially identical to that achieved when probiotics were added to antibiotic therapy. The incremental improvement was additive and independent of antimicrobial resistance or antibiotics use. Probiotics can reliably increase the cure rate to ≥90% only in regimens achieving cure rates of ∼80%. This trial is registered with NCT03404440.

Constipation in the elderly from Northern Sardinia is positively associated with depression, malnutrition and female gender.

OBJECTIVES: Constipation is a common complaint in older adults. The rise in life expectancy may amplify the problem and increase social expenditure. We investigated the major risk factors associated with constipation in a large sample of elderly. METHODS: Outpatients from Northern Sardinia attending a Geriatric Unit between 2001 and 2014 were enrolled. Demographic and anthropometric data, income, education and self-reported bowel function were collected. The presence of constipation was adjusted for cognitive status, assessed by the Mini-Mental State Examination (MMSE) test; single and cumulative illness rating scale (CIRS); current or past symptomatic depression and anxiety measured by the Geriatric Depression Scale (GDS); nutritional status, evaluated using the Mini-Nutritional Assessment (MNA); type and number of different medications used. RESULTS: 1328 elderly patients (mean age 77.7 ± 7.2 years) were enrolled. Constipation was present in 32.1%, more commonly in women (35.4% vs 28.3%) and increased with age. The multivariate analysis showed a significantly greater risk of constipation in patients with a risk of malnutrition (OR = 1.745, 95% CI: 1.043-2.022; p = .034), female gender (OR = 1.735, 95% CI: 1.068-2.820; p = .026) and depression (OR = 1.079, 95% CI: 1.022-1.140; p = .006). Other potential predisposing factors assessed such as MMSE, CIRS, body mass index, marital status, smoking habit, education, income and number of taken drugs did not show a statistically significant association. Aging was a risk for constipation also in patients free of medications. CONCLUSIONS: Knowledge of risk factors associated with bowel alterations in elderly individuals may provide important clues for caregivers to prevent or reduce constipation.

Gut Microbiota as a Driver of Inflammation in Nonalcoholic Fatty Liver Disease.

The prevalence of nonalcoholic fatty liver disease and the consequent burden of metabolic syndrome have increased in recent years. Although the pathogenesis of nonalcoholic fatty liver disease is not completely understood, it is thought to be the hepatic manifestation of the dysregulation of insulin-dependent pathways leading to insulin resistance and adipose tissue accumulation in the liver. Recently, the gut-liver axis has been proposed as a key player in the pathogenesis of NAFLD, as the passage of bacteria-derived products into the portal circulation could lead to a trigger of innate immunity, which in turn leads to liver inflammation. Additionally, higher prevalence of intestinal dysbiosis, larger production of endogenous ethanol, and higher prevalence of increased intestinal permeability and bacterial translocation were found in patients with liver injury. In this review, we describe the role of intestinal dysbiosis in the activation of the inflammatory cascade in NAFLD.

Fecal microbiota transplantation: a new old kid on the block for the management of gut microbiota-related disease.

Gut microbiota is deeply involved in the regulation of both health and disease within our body. The restoration of a healthy gut microbiota is, therefore, a main clinical target in the management of diseases associated with its disruption. Fecal microbiota transplantation (FMT) is an old therapy that has recently been rediscovered, having proved a clear efficacy against recurrent Clostridium difficile infection. By restoring the altered gut microbiota in a substantial and durable manner, FMT is considered a cutting-edge promising option for the treatment of disease that recognize the alteration of the gut microbiota as having a pathogenic role. FMT has shown interesting (even if uncertain) results in diseases such as metabolic syndrome and inflammatory bowel diseases. Moreover, the definition of a standard procedural protocol for each specific disease, as well as exhaustive studies about the relationship between donor's microbiota composition and clinical results, will certainly improve the therapeutic potential of FMT. Both the application of cutting-edge technologies for the assessment of gut microbiota composition (such as metagenomics) and the development of well-designed, large randomized trials are needed to put such perspectives into practice.

Henoch-schonlein purpura following exposure to SARS-CoV2 vaccine or infection: a systematic review and a case report.

BACKGROUND: Henoch-Schonlein purpura (HSP) is an IgA-mediated systemic small-vessel vasculitis (IgAV) that typically presents with a variable tetrad of symptoms. HSP if often preceded by respiratory tract infections, vaccinations, drugs or malignancies. During the recent COVID-19 pandemic multiples cases of HSP have been described after both infection and vaccination for SARS-CoV2. This study aims to perform a systematic review of literature and describe an additional complicated case of de-novo HSP appeared after the administration of the third dose of a mRNA-SARS-CoV2 vaccination. METHODS: Electronic bibliographic research was performed to identify all the original reports describing cases of de-novo HSP or IgAV appeared after respiratory infection or vaccine administration for SARS-CoV2. We included all case series or case reports of patients who respected our inclusion and exclusion criteria. RESULTS: Thirty-eight publications met our pre-defined inclusion criteria, for an overall number of 44 patients. All patients presented with palpable purpura variable associated with arthralgia, abdominal pain or renal involvement. Increased levels of inflammation markers, mild leukocytosis and elevated D-dimer were the most common laboratory findings. Up to 50% of patients presented proteinuria and/or hematuria. Almost all skin biopsies showed leukocytoclastic vasculitis, with IgA deposits at direct immunofluorescence in more than 50% of cases. CONCLUSIONS: Our results suggest that the immune response elicited by SARS-CoV2 vaccine or infection could play a role in the development of HSP. Current research suggests a possible role of IgA in immune hyperactivation, highlighted by early seroconversion to IgA found in some COVID-19 patients who develop IgA vasculitis.

Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis: Clinical Protocol and Evaluation of Microbiota Immunity Axis.

The fecal microbial transplantation (FMT) is a therapeutic transplant of fecal microbiota from healthy donors to patients. This practice is aimed at restoring eubiosis and rebalancing the enteric and systemic immune responses, and then eliminating pathogenic triggers of multiple disease, including neurodegenerative diseases. Alterations of gut microbiota (GM) affect the central nervous system (CNS) health, impacting neuro-immune interactions, synaptic plasticity, myelination, and skeletal muscle function. T-regulatory lymphocytes (Treg) are among the most important players in the pathogenesis of amyotrophic lateral sclerosis (ALS), altering the disease course. Along with circulating neuropeptides, other immune cells, and the gut-brain axis, the GM influences immunological tolerance and controls Treg's number and suppressive functions. A double-blind, controlled, multicenter study on FMT in ALS patients has been designed to evaluate if FMT can modulate neuroinflammation, by restoring Treg number, thus modifying disease activity and progression.

Donor screening for fecal microbiota transplantation with a direct stool testing-based strategy: a prospective cohort study.

Fecal microbiota transplantation (FMT) is effective against recurrent Clostridioides difficile infection (rCDI), but its safety is jeopardized by the potential transmission of pathogens, so international guidelines recommend either a quarantine or a direct stool testing. Whereas reports of the quarantine-based approach are emerging, data on the direct testing-based approach are not available. Our aim is to report outcomes of a donor screening framework for FMT including direct stool testing. In this prospective cohort study, all donor candidates recruited at our FMT centre underwent a four-step screening process to be enrolled as actual donors. Each collected stool donation was then evaluated with a direct stool testing including a molecular assay for gut pathogens and a culture assay for multi-drug resistant organisms (MDRO). From January 2019 to June 2023, 72 of 227 candidates (32%) were considered eligible and provided 277 stool donations. Ninety-nine donations (36%) were discarded for positivity to intestinal pathogens, most commonly enteropathogenic Escherichia coli (n = 37) and Blastocystis hominis (n = 20). Overall, 337 stool aliquots were obtained from 165 approved donations. All suspensions were used for patients with rCDI, and no serious adverse events or clinically evident infections were observed at 12 weeks after procedures. In our study, screening of donor faeces including direct stool testing led to the discard of a considerable rate of stool donations but was also extremely safe. This approach may represent a reliable strategy to guarantee the safety of FMT programs, especially in countries with high prevalence of MDRO.

Histologic Disease Persists beyond Mucosal Healing and Could Predict Reactivation in Ulcerative Colitis.

Mucosal healing (MH) is the main target in ulcerative colitis (UC) treatment. Even if MH lowers the risk of disease reactivation, some patients still relapse. Histologic activity (HA) beyond MH could explain these cases. This study aims to assess how many patients with MH have HA and which lesions are associated with relapse. We retrospectively enrolled UC patients showing MH, expressed as a Mayo Endoscopic Subscore (MES) of 0 and 1 upon colonoscopy. We reviewed the histological reports of biopsies evaluating the presence of typical lesions of UC and assessed the number of clinical relapses after 12 months. Among 100 enrolled patients, 2 showed no histological lesions. According to univariate analysis, patients with a higher number of histological lesions at the baseline had a higher risk of relapse (OR 1.25, p = 0.012), as well as patients with basal plasmacytosis (OR 4.33, p = 0.005), lamina propria eosinophils (OR 2.99, p = 0.047), and surface irregularity (OR 4.70, p = 0.010). However, in the multivariate analysis, only basal plasmacytosis (OR 2.98, p = 0.050) and surface irregularity (OR 4.50, p = 0.024) were confirmed as risk factors for disease reactivation. HA persists in a significant percentage of patients with MH. Despite the presence of MH, patients with basal plasmacytosis and surface irregularity have a higher risk of relapse.

Metaproteomic assessment of gut microbial and host functional perturbations in Helicobacter pylori-infected patients subjected to an antimicrobial protocol.

The impact of therapeutic interventions on the human gut microbiota (GM) is a clinical issue of paramount interest given the strong interconnection between microbial dynamics and human health. Orally administered antibiotics are known to reduce GM biomass and modify GM taxonomic profile. However, the impact of antimicrobial therapies on GM functions and biochemical pathways has scarcely been studied. Here, we characterized the fecal metaproteome of 10 Helicobacter pylori-infected patients before (T0) and after 10 days (T1) of a successful quadruple therapy (bismuth, tetracycline, metronidazole, and rabeprazole) and 30 days after therapy cessation (T2), to investigate how GM and host functions change during the eradication and healing processes. At T1, the abundance ratio between microbial and host proteins was reversed compared with that at T0 and T2. Several pathobionts (including Klebsiella, Proteus, Enterococcus, Muribaculum, and Enterocloster) were increased at T1. Therapy reshaped the relative contributions of the functions required to produce acetate, propionate, and butyrate. Proteins related to the uptake and processing of complex glycans were increased. Microbial cross-feeding with sialic acid, fucose, and rhamnose was enhanced, whereas hydrogen sulfide production was reduced. Finally, microbial proteins involved in antibiotic resistance and inflammation were more abundant after therapy. Moreover, a reduction in host proteins with known roles in inflammation and H. pylori-mediated carcinogenesis was observed. In conclusion, our results support the use of metaproteomics to monitor drug-induced remodeling of GM and host functions, opening the way for investigating new antimicrobial therapies aimed at preserving gut environmental homeostasis.

Gut microbiota and immunotherapy of renal cell carcinoma.

The gut microbiome has recently been proposed as a key player in cancer development and progression. Several studies have reported that the composition of the gut microbiome plays a role in the response to immune checkpoint inhibitors (ICIs). The gut microbiome modulation has been investigated as a potential therapeutic strategy for cancer, mainly in patients undergoing therapy with ICIs. In particular, modulation through probiotics, FMT or other microbiome-related approaches have proven effective to improve the response to ICIs. In this review, we examine the role of the gut microbiome in enhancing clinical responses to ICIs in the treatment of renal cancer.

Diagnostic delay in adult coeliac disease: An Italian multicentre study.

BACKGROUND: There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD). AIMS: To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD. METHODS: CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted. RESULTS: Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay. CONCLUSION: We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.

High Frequency of Glucose-6-Phosphate Dehydrogenase Deficiency in Patients Diagnosed with Celiac Disease.

Celiac disease (CD) is characterized by a proinflammatory state associated with the production of reactive oxygen species, i.e., a condition of oxidative stress. In this study, we tested the hypothesis that the inherited deficiency of glucose-6-phosphate dehydrogenase (G6PD), by causing impaired antioxidant defense, may increase the risk of CD. METHODS: A retrospective monocentric case-control study was performed using the clinical records of 8338 outpatients (64.6% women) scheduled for upper endoscopy between 2002 and 2021 in Northern Sardinia. Overall, 627 were found to have CD (7.5%), and 1027 resulted to be G6PD-deficiency carriers (12.3%). Since randomization was impractical, the potential covariates imbalance between cases and controls was minimized using a 1:2 propensity-score-matched (PSM) analysis. RESULTS: Overall, G6PD deficiency was associated with increased risk of CD (odds ratio (OR) 1.50; 95% confidence interval (CI) 1.19-1.90). The PSM procedure identified 1027 G6PD-deficient and 2054 normal patients. Logistic regression including the propensity score detected for G6PD deficiency an OR of 1.48 (95%CI 1.13-1.95; p = 0.004). CONCLUSIONS: Our findings show that the enzyme defect was significantly and positively associated with CD, in line with the pro-oxidant impact of the enzyme defect observed in animal models and humans.