Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

Clostridioides difficile(C.difficile)is progressively colonizing humans and animals living with humans.During this process,hypervirulent strains and mutated toxin A and B of C.difficile(TcdA and TcdB)are originating and developing.While in healthy subjects colonization by C.difficile becomes a risk after the use of antibiotics that alter the microbiome,other categories of people are more susceptible to infection and at risk of relapse,such as those with inflammatory bowel disease(IBD).Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma(CKs).Therefore,in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C.difficile infection and its progression and relapses.TcdB is internalized in the cell via three receptors:chondroitin sulphate proteoglycan 4;poliovirus receptor-like 3;and Wnt receptor frizzled family.Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types,while poliovirus receptor-like 3 induces only necrosis.It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis.Therefore,in subjects with IBD there are the conditions:(1)For greater susceptibility to C.difficile infection,such as the inflammatory state,and abnormalities of the microbiome and of the immune system;(2)for the enhancement of the cytotoxic activity of TcdB+Cks;and(3)for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis.The only therapeutic approach currently possible in IBD patients is monitoring of C.difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins.The future perspective is to generate bacteriophages against C.difficile for targeted therapy.

Clostridioides difficile infection in patients with nonalcoholic fatty liver disease-current status

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,leading to fibrosis,cirrhosis and hepatocellular carcinoma and also associated with increased cardiovascular disease mortality.The pathogenesis of NAFLD is not fully understood,although NAFLD is thought to be a hepatic form of metabolic syndrome.There is an increasing understanding of the role of microbiota disturbances in NAFLD pathogenesis,and as with many other conditions affecting the microbiota,NAFLD may be a novel risk factor for Clostridioides difficile(C.difficile)colonization(CDC)and C.difficile infection(CDI).CDI is an emerging nosocomial disease,and community-acquired cases of infection are growing,probably due to an increase in CDC rates.The association of NAFLD with CDI has been shown in only 4 studies to date,three of which included less than 1000 patients,although the frequency of NAFLD in these studies was observed in almost 20%of the total patient cohort.These data revealed that NAFLD is a risk factor for CDI development and,moreover,is a risk factor for intestinal complications of CDI.More studies are needed to investigate this association and move forward CDC and CDI screening efforts for this group of patients.

Fecal microbiota transplantation as potential first-line treatment for patients with Clostridioides difficile infection and prior appendectomy

Clostridioides difficile infection(CDI)is a global health problem.The association of appendectomy on the severity and prognosis of CDI has been reported in many literatures,but there are still contradictions.In a retrospective study entitled“Patients with Closterium diffuse infection and prior appendectomy may be prone to word outcomes”published in World J Gastrointest Surg 2021,the author found that prior appendectomy affects the severity of CDI.Appendectomy may be a risk factor for increasing the severity of CDI.Therefore,it is necessary to seek alternative treatment for patients with prior appendectomy when they are more likely to have severe or fulminant CDI.

Nonalcoholic fatty liver disease is associated with worse intestinal complications in patients hospitalized for Clostridioides difficile infection

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)has become the leading cause of chronic liver disease with increasing prevalence worldwide.Clostridioides difficile infection(CDI)remains the most common cause of nosocomial diarrhea in developed countries.AIM To assess the impact of NAFLD on the outcomes of hospitalized patients with CDI.METHODS This study was a retrospective cohort study.The Nationwide Inpatient Sample database was used to identify a total of 7239 adults admitted as inpatients with a primary diagnosis of CDI and coexisting NAFLD diagnosis from 2010 to 2014 using ICD-9 codes.Patients with CDI and coexisting NAFLD were compared to those with CDI and coexisting alcoholic liver disease(ALD)and viral liver disease(VLD),individually.Primary outcomes included mortality,length of stay,and total hospitalization charges.Secondary outcomes were in-hospital complications.Multivariate regression was used for outcome analysis after adjusting for possible confounders.RESULTS CDI with NAFLD was independently associated with lower rates of acute respiratory failure(2.7%vs 4.2%,P<0.01;2.7%vs 4.2%,P<0.05),shorter length of stay(days)(5.75±0.16 vs 6.77±0.15,P<0.001;5.75±0.16 vs 6.84±0.23,P<0.001),and lower hospitalization charges(dollars)(38150.34±1757.01 vs 46326.72±1809.82,P<0.001;38150.34±1757.01 vs 44641.74±1660.66,P<0.001)when compared to CDI with VLD and CDI with ALD,respectively.CDI with NAFLD was associated with a lower rate of acute kidney injury(13.0%vs 17.2%,P<0.01),but a higher rate of intestinal perforation(P<0.01)when compared to VLD.A lower rate of mortality(0.8%vs 2.7%,P<0.05)but a higher rate of intestinal obstruction(4.6%vs 2.2%,P=0.001)was also observed when comparing CDI with NAFLD to ALD.CONCLUSION Hospitalized CDI patients with NAFLD had more intestinal complications compared to CDI patients with VLD and ALD.Gut microbiota dysbiosis may contribute to the pathogenesis of intestinal complications.

Therapies to modulate gut microbiota:Past,present and future

The human gut microbiota comprises of a complex and diverse array of microorganisms,and over the years the interaction between human diseases and the gut microbiota has become a subject of growing interest.Disturbed microbial milieu in the gastrointestinal tract is central to the pathogenesis of several diseases including antibiotic-associated diarrhea and Clostridioides difficile infection(CDI).Manipulation of this microbial milieu to restore balance by microbial replacement therapies has proven to be a safe and effective treatment for recurrent CDI.There is considerable heterogeneity in various aspects of stool processing and administration for fecal microbiota transplantation(FMT)across different centers globally,and standardized microbioal replacement therapies offer an attractive alternative.The adverse effects associated with FMT are usually mild.However,there is paucity of data on long term safety of FMT and there is a need for further studies in this regard.With our increasing understanding of the host-microbiome interaction,there is immense potential for microbial replacement therapies to emerge as a treatment option for several diseases.The role of microbioal replacement therapies in diseases other than CDI is being extensively studied in ongoing clinical trials and it may be a potential treatment option for inflammatory bowel disease,irritable bowel syndrome,obesity,multidrug resistant infections,and neuropsychiatric illnesses.Fecal microbiota transplantation for non-CDI disease states should currently be limited only to research settings.

Update on gut microbiota in gastrointestinal diseases

The human gut is a complex microbial ecosystem comprising approximately 100 trillion microbes collectively known as the“gut microbiota”.At a rough estimate,the human gut microbiome contains almost 3.3 million genes,which are about 150 times more than the total human genes present in the human genome.The vast amount of genetic information produces various enzymes and physiologically active substances.Thus,the gut microbiota contributes to the maintenance of host health;however,when healthy microbial composition is perturbed,a condition termed“dysbiosis”,the altered gut microbiota can trigger the development of various gastrointestinal diseases.The gut microbiota has consequently become an extremely important research area in gastroenterology.It is also expected that the results of research into the gut microbiota will be applied to the prevention and treatment of human gastrointestinal diseases.A randomized controlled trial conducted by a Dutch research group in 2013 showed the positive effect of fecal microbiota transplantation(FMT)on recurrent Clostridioides difficile infection(CDI).These findings have led to the development of treatments targeting the gut microbiota,such as probiotics and FMT for inflammatory bowel diseases(IBD)and other diseases.This review focuses on the association of the gut microbiota with human gastrointestinal diseases,including CDI,IBD,and irritable bowel syndrome.We also summarize the therapeutic options for targeting the altered gut microbiota,such as probiotics and FMT.

Risk factors for Clostridioides difficile infection in children and adolescents with inflammatory bowel disease: a systematic review and meta-analysis

Background Risk factors and consequences associated with Clostridioides difficile infection(CDI)in children and adolescents with inflammatory bowel disease(IBD)are still uncertain.We conduct a systematic review and meta-analysis to assess risk factors and outcomes associated with CDI in children and adolescents with IBD.Methods PubMed,EMBASE and Cochrane Library databases were searched from inception to 24th February,2021.Studies investigating risk factors,bowel surgery rate in pediatric IBD patients with and without CDI were included.Random-effects model was used for calculating summary estimates.Newcastle–Ottawa scale(NOS)was used for quality assessment.Results Fourteen studies,comprising 17,114 patients,were included.There was a significant association between 5-aminosalicylic acid(5-ASA)use and CDI[odds ratio(OR)=1.95,95%confidence interval(CI)1.26–3.03],with minimal heterogeneity(I^(2)=0.00%).Increased risk of active disease(OR=4.66,95%CI 2.16–10.07)were associated with CDI in those studies performed in high quality score(NOS>6)and significantly higher CDI rates in studies conducted outside USA(OR=2.94,95%CI 1.57–5.58).The bowel surgery rate in IBD with CDI was 3.8–57.1%,compared to that in IBD without CDI(0–21.3%).All studies were of moderate to high quality.Conclusions 5-ASA use and active disease might be risk factors associated with CDI in children and adolescents with IBD.Bowel surgery rates associated with CDI in IBD patients varied greatly.Large-scale clinical studies on CDI in children and adolescents with IBD are still needed to verify risk factors and outcomes.