Role of gut microbiota in Crohn’s disease pathogenesis:Insights from fecal microbiota transplantation in mouse model

BACKGROUND Inflammatory bowel disease,particularly Crohn’s disease(CD),has been associated with alterations in mesenteric adipose tissue(MAT)and the phenomenon termed“creeping fat”.Histopathological evaluations showed that MAT and intestinal tissues were significantly altered in patients with CD,with these tissues characterized by inflammation and fibrosis.AIM To evaluate the complex interplay among MAT,creeping fat,inflammation,and gut microbiota in CD.METHODS Intestinal tissue and MAT were collected from 12 patients with CD.Histological manifestations and protein expression levels were analyzed to determine lesion characteristics.Fecal samples were collected from five recently treated CD patients and five control subjects and transplanted into mice.The intestinal and mesenteric lesions in these mice,as well as their systemic inflammatory status,were assessed and compared in mice transplanted with fecal samples from CD patients and control subjects.RESULTS Pathological examination of MAT showed significant differences between CDaffected and unaffected colons,including significant differences in gut microbiota structure.Fetal microbiota transplantation(FMT)from clinically healthy donors into mice with 2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced CD ameliorated CD symptoms,whereas FMT from CD patients into these mice exacerbated CD symptoms.Notably,FMT influenced intestinal permeability,barrier function,and levels of proinflammatory factors and adipokines.Furthermore,FMT from CD patients intensified fibrotic changes in the colon tissues of mice with TNBS-induced CD.CONCLUSION Gut microbiota play a critical role in the histopathology of CD.Targeting MAT and creeping fat may therefore have potential in the treatment of patients with CD.

Fecal microbiota transplantation for treatment of non-alcoholic fatty liver disease:Mechanism,clinical evidence,and prospect

The population of non-alcoholic fatty liver disease(NAFLD)patients along with relevant advanced liver disease is projected to continue growing,because currently no medications are approved for treatment.Fecal microbiota transplantation(FMT)is believed a novel and promising therapeutic approach based on the concept of the gut-liver axis in liver disease.There has been an increase in the number of pre-clinical and clinical studies evaluating FMT in NAFLD treatment,however,existing findings diverge on its effects.Herein,we briefly summarized the mechanism of FMT for NAFLD treatment,reviewed randomized controlled trials for evaluating its efficacy in NAFLD,and proposed the prospect of future trials on FMT.

Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions

Fecal microbiota transplantation(FMT)offers a potential treatment avenue for hepatic encephalopathy(HE)by leveraging beneficial bacterial displacement to restore a balanced gut microbiome.The prevalence of HE varies with liver disease severity and comorbidities.HE pathogenesis involves ammonia toxicity,gut-brain communication disruption,and inflammation.FMT aims to restore gut microbiota balance,addressing these factors.FMT's efficacy has been explored in various conditions,including HE.Studies suggest that FMT can modulate gut microbiota,reduce ammonia levels,and alleviate inflammation.FMT has shown promise in alcohol-associated,hepatitis B and C-associated,and non-alcoholic fatty liver disease.Benefits include improved liver function,cognitive function,and the slowing of disease progression.However,larger,controlled studies are needed to validate its effectiveness in these contexts.Studies have shown cognitive improvements through FMT,with potential benefits in cirrhotic patients.Notably,trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care.Although evidence is promising,challenges remain:Limited patient numbers,varied dosages,administration routes,and donor profiles.Further large-scale,controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy.While FMT holds potential for HE management,ongoing research is needed to address these challenges,optimize protocols,and expand its availability as a therapeutic option for diverse hepatic conditions.

The role of a novel antibacterial substance,cyclic opine-producing Lacticaseibacillus rhamnosus LS8 in ameliorating ulcerative colitis:a fecal microbiota transplantation study

Intestinal microbiota imbalance may worsen the progression of ulcerative colitis(UC).Lacticaseibacillus rhamnosus LS8(LR)has the potential ability to regulate microbiota through producing a novel antibacterial substance,cyclic opine:cycloalanopine.This study aimed to investigate whether LR could ameliorate dextran sulfate sodium-induced UC in mice via modulating intestinal microbiota using fecal microbiota transplantation(FMT)experiment.The results showed that both LR and FMT attenuated UC as evidenced by 1)alleviating disease activity index and colonic pathology;2)up-regulating MUCs and tight junction proteins;3)increasing oxidative mediators and decreasing antioxidant mediators;4)down-regulating proinflammatory cytokines and chemokines.These results were mainly attributable to the microbiota-regulating effect of LR,including increasing beneficial bacteria(like Akkermansia)and its related SCFAs,while decreasing harmful bacteria(like Proteobacteria)and its related LPS,thereby suppressing the hyperactivation of TLR4/NF-κB pathway.Consequently,LR can alleviate UC and is a potential dietary supplement to attenuate UC.

Fecal microbiota transplantation for irritable bowel syndrome:Current evidence and perspectives

In this editorial we comment on the article published in the recent issue of the World journal of Gastroenterology.We focus specifically on the mechanisms underlying the effects of fecal microbiota transplantation(FMT)for irritable bowel syndrome(IBS),the factors which affect the outcomes of FMT in IBS patients,and challenges.FMT has emerged as a efficacious intervention for clostridium difficile infection and holds promise as a therapeutic modality for IBS.The utilization of FMT in the treatment of IBS has undergone scrutiny in numerous randomized controlled trials,yielding divergent outcomes.The current frontier in this field seeks to elucidate these variations,underscore the existing knowledge gaps that necessitate exploration,and provide a guideline for successful FMT implementation in IBS patients.At the same time,the application of FMT as a treatment for IBS confronts several challenges.

Dual-targeted treatment for inflammatory bowel disease:Whether fecal microbiota transplantation can be an important part of it

Inflammatory bowel disease(IBD)is a chronic gastrointestinal inflammatory disease.With the emergence of biologics and other therapeutic methods,two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD.Although treatment strategies for IBD are being optimized,their efficacy and risks still warrant further consideration.This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation(FMT)may have for use in combination therapy for IBD.We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment.In this new therapy regimen,FMT represents a promising combination therapy.

Does young feces make the elderly live better? Application of fecal microbiota transplantation in healthy aging

As we are facing an aging society,anti-aging strategies have been pursued to reduce the negative impacts of aging and increase the health span of human beings.Gut microbiota has become a key factor in the anti-aging process.Modulation of gut microbiota by fecal microbiota transplantation(FMT)to prevent frailty and unhealthy aging has been a hot topic of research.This narrative review summarizes the benefits of FMT for health span and lifespan,brains,eyes,productive systems,bones,and others.The mechanisms of FMT in improving healthy aging are discussed.The increased beneficial bacteria and decreased pathological bacteria decreased gut permeability and systemic inflammation,increased short-chain fatty acid(SCFA)and SCFA-producing bacteria,and other factors are listed as mechanisms of FMT to improve healthy aging.The points that need to be considered to ensure the optimal outcomes of FMT are also discussed,such as recipients’age,sex,genetic background,and gut microbiota after FMT.Although thisfield is still in its infancy,it has shown that FMT has great potential to improve healthy aging.

Efficacy and safety of fecal microbiota transplantation for treatment of ulcerative colitis:A post-consensus systematic review and metaanalysis

BACKGROUND Numerous studies have assessed the efficacy and safety of fecal microbiota transplantation(FMT)as a therapy for ulcerative colitis(UC).However,the treatment processes and outcomes of these studies vary.AIM To evaluate the efficacy and safety of FMT for treating UC by conducting a systematic meta-analysis.METHODS The inclusion criteria involved reports of adult patients with UC treated with FMT,while studies that did not report clinical outcomes or that included patients with infection were excluded.Clinical remission(CR)and endoscopic remission(ER)were the primary and secondary outcomes,respectively.RESULTS We included nine studies retrieved from five electronic databases.The FMT group had better CR than the control group[relative risk(RR)=1.53;95%confidence interval(CI):1.19-1.94;P<0.0008].ER was statistically significantly different between the two groups(RR=2.80;95%CI:1.93-4.05;P<0.00001).Adverse events did not differ significantly between the two groups.CONCLUSION FMT demonstrates favorable performance and safety;however,well-designed randomized clinical trials are still needed before the widespread use of FMT can be recommended.Furthermore,standardizing the FMT process is urgently needed for improved safety and efficacy.

Fecal microbiota transplantation for the treatment of irritable bowel syndrome:A systematic review and meta-analysis

BACKGROUND Irritable bowel syndrome(IBS)is the most prevalent gastrointestinal disorder in developed countries and reduces patients’quality of life,hinders their ability to work,and increases health care costs.A growing number of trials have demonstrated an aberrant gut microbiota composition in IBS,also known as‘gut dysbiosis’.Fecal microbiota transplantation(FMT)has been suggested as a treatment for IBS.AIM To assess the efficacy and safety of FMT for the treatment of IBS.METHODS We searched Cochrane Central,MEDLINE,EMBASE and Web of Science up to 24 October 2022 for randomised controlled trials(RCTs)investigating the effectiveness of FMT compared to placebo(including autologous FMT)in treating IBS.The primary outcome was the number of patients with improvements of symptoms measured using a validated,global IBS symptoms score.Secondary outcomes were changes in quality-of-life scores,non-serious and serious adverse events.Risk ratios(RR)and corresponding 95%CI were calculated for dichotomous outcomes,as were the mean differences(MD)and 95%CI for continuous outcomes.The Cochrane risk of bias tool was used to assess the quality of the trials.GRADE criteria were used to assess the overall quality of the evidence.RESULTS Eight RCTs(484 participants)were included in the review.FMT resulted in no significant benefit in IBS symptoms three months after treatment compared to placebo(RR 1.19,95%CI:0.68-2.10).Adverse events were reported in 97 participants in the FMT group and in 45 participants in the placebo group(RR 1.17,95%CI:0.63-2.15).One serious adverse event occurred in the FMT group and two in the placebo group(RR 0.42,95%CI:0.07-2.60).Endoscopic FMT delivery resulted in a significant improvement in symptoms,while capsules did not.FMT did not improve the quality of life of IBS patients but,instead,appeared to reduce it,albeit non significantly(MD-6.30,95%CI:-13.39-0.79).The overall quality of the evidence was low due to moderate-high inconsistency,the small number of patients in the studies,and imprecision.CONCLUSION We found insufficient evidence to support or refute the use of FMT for IBS.Larger trials are needed.

Fecal microbiota transplantation in patients with metabolic syndrome and obesity:A randomized controlled trial

BACKGROUND Metabolic syndrome is a multifactorial disease,and the gut microbiota may play a role in its pathogenesis.Obesity,especially abdominal obesity,is associated with insulin resistance,often increasing the risk of type two diabetes mellitus,vascular endothelial dysfunction,an abnormal lipid profile,hypertension,and vascular inflammation,all of which promote the development of atherosclerotic cardiovascular disease.AIM To evaluate the outcomes of fecal microbiota transplantation(FMT)in patients with metabolic syndrome.METHODS This was a randomized,single-blind placebo-controlled trial comparing FMT and a sham procedure in patients with metabolic syndrome.We selected 32 female patients,who were divided into eight groups of four patients each.All of the patients were submitted to upper gastrointestinal endoscopy.In each group,two patients were randomly allocated to undergo FMT,and the other two patients received saline infusion.The patients were followed for one year after the procedures,during which time anthropometric,bioimpedance,and biochemical data were collected.The patients also had periodic consultations with a nutritionist and an endocrinologist.The primary end point was a change in the gut microbiota.RESULTS There was evidence of a postprocedural change in microbiota composition in the patients who underwent FMT in relation to that observed in those who underwent the sham procedure.However,we found no difference between the two groups in terms of the clinical parameters evaluated.CONCLUSION There were no significant differences in biochemical or anthropometric parameters,between the two groups evaluated.Nevertheless,there were significant postprocedural differences in the microbiota composition between the placebo group.To date,clinical outcomes related to FMT remain uncertain.

Fecal microbiota transplantation alleviates experimental colitis through the Toll-like receptor 4 signaling pathway

BACKGROUND Fecal microbiota transplantation(FMT)has shown promising therapeutic effects on mice with experimental colitis and patients with ulcerative colitis(UC).FMT modulates the Toll-like receptor 4(TLR4)signaling pathway to treat some other diseases.However,it remains unknown whether this modulation is also involved in the treatment of UC.AIM To clarify the necessity of TLR4 signaling pathway in FMT on dextran sodium sulphate(DSS)-induced mice and explain the mechanism of FMT on UC,through association analysis of gut microbiota with colon transcriptome in mice.METHODS A mouse colitis model was constructed with wild-type(WT)and TLR4-knockout(KO)mice.Fecal microbiota was transplanted by gavage.Colon inflammation severity was measured by disease activity index(DAI)scoring and hematoxylin and eosin staining.Gut microbiota structure was analyzed through 16S ribosomal RNA sequencing.Gene expression in the mouse colon was obtained by transcriptome sequencing.RESULTS The KO(DSS+Water)and KO(DSS+FMT)groups displayed indistinguishable body weight loss,colon length,DAI score,and histology score,which showed that FMT could not inhibit the disease in KO mice.In mice treated with FMT,the relative abundance of Akkermansia decreased,and Lactobacillus became dominant.In particular,compared with those in WT mice,the scores of DAI and colon histology were clearly decreased in the KO-DSS group.Microbiota structure showed a significant difference between KO and WT mice.Akkermansia were the dominant genus in healthy KO mice.The ineffectiveness of FMT in KO mice was related to the decreased abundance of Akkermansia.Gene Ontology enrichment analysis showed that differentially expressed genes between each group were mainly involved in cytoplasmic translation and cellular response to DNA damage stimulus.The top nine genes correlating with Akkermansia included Aqp4,Clca4a,Dpm3,Fau,Mcrip1,Meis3,Nupr1 L,Pank3,and Rps13(|R|>0.9,P<0.01).CONCLUSION FMT may ameliorate DSS-induced colitis by regulating the TLR4 signaling pathway.TLR4 modulates the composition of gut microbiota and the expression of related genes to ameliorate colitis and maintain the stability of the intestinal environment.Akkermansia bear great therapeutic potential for colitis.

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.

Fecal microbiota transplantation cured epilepsy in a case with Crohn's disease: The first report

Fecal microbiota transplantation(FMT)is a promising strategy that involves reconstruction of gut microbiota.Recently,it has been considered as a treatment of Crohn’s disease(CD)and certain neurological diseases.Here,to the best of our knowledge,we report the first case that used FMT to achieve remission of intestinal and neurological symptoms in a girl with CD and a 17-year history of epilepsy.During the 20 mo of follow-up,FMT has proved its efficacy in preventing relapse of seizures after withdrawing the antiepileptic drugs.Furthermore,this finding highlights the role of microbiota-gut-brain axis and inspires a novel treatment for epilepsy through remodeling gut microbiota.

Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction

AIM To investigate whether fecal microbiota transplantation (FMT) prevents hepatic encephalopathy (HE) in rats with carbon tetrachloride (CCl4)-induced acute hepatic dysfunction. METHODS A rat model of HE was established with CCl4. Rat behaviors and spatial learning capability were observed, and hepatic necrosis, intestinal mucosal barrier, serum ammonia levels and intestinal permeability were determined in HE rats receiving FMT treatment. Furthermore, the expression of tight junction proteins (Claudin-1, Claudin-6 and Occludin), Toll-like receptor (TLR) 4/TLR9, interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha was examined. RESULTS FMT improved rat behaviors, HE grade and spatial learning capability. Moreover, FMT prevented hepatic necrosis and intestinal mucosal barrier damage, leading to hepatic clearance of serum ammonia levels and reduced intestinal permeability. The expression of TLR4 and TLR9, two potent mediators of inflammatory response, was significantly downregulated in the liver of rats treated with FMT. Consistently, circulating proinflammatory factors such as interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-alpha were remarkably decreased, indicating that FMT is able to limit systemic inflammation by decreasing the expression of TLR4 and TLR9. Importantly, HE-induced loss of tight junction proteins (Claudin-1, Claudin-6 and Occludin) was restored in intestinal tissues of rats receiving FMT treatment. CONCLUSION FMT enables protective effects in HE rats, and it improves the cognitive function and reduces the liver function indexes. FMT may cure HE by altering the intestinal permeability and improving the TLR response of the liver.

Intestinal microbiota pathogenesis and fecal microbiota transplantation for inflammatory bowel disease

The intestinal microbiota plays an important role in inflammatory bowel disease(IBD).The pathogenesis of IBD involves inappropriate ongoing activation of the mucosal immune system driven by abnormal intestinal microbiota in genetically predisposed individuals.However,there are still no definitive microbial pathogens linked to the onset of IBD.The composition and function of the intestinal microbiota and their metabolites are indeed disturbed in IBD patients.The special alterations of gut microbiota associated with IBD remain to be evaluated.The microbial interactions and hostmicrobe immune interactions are still not clarified.Limitations of present probiotic products in IBD are mainly due to modest clinical efficacy,few available strains and no standardized administration.Fecal microbiota transplantation(FMT)may restore intestinal microbial ho-meostasis,and preliminary data have shown the clinical efficacy of FMT on refractory IBD or IBD combined with Clostridium difficile infection.Additionally,synthetic microbiota transplantation with the defined composition of fecal microbiota is also a promising therapeutic approach for IBD.However,FMT-related barriers,including the mechanism of restoring gut microbiota,standardized donor screening,fecal material preparation and administration,and long-term safety should be resolved.The role of intestinal microbiota and FMT in IBD should be further investigated by metagenomic and metatranscriptomic analyses combined with germfree/human flora-associated animals and chemostat gut models.

Fecal microbiota transplantation and prednisone for severe eosinophilic gastroenteritis

Eosinophilic gastroenteritis is a rare disease of unknown etiology. It is characterized by patchy or diffuse eosinophilic infiltration of the bowel wall to a variable depth and various gastrointestinal manifestations. We describe a case of severe eosinophilic gastroenteritis presenting as frequent bowel obstruction and diarrhea in a 35-year-old man. The patient was misdiagnosed and underwent surgery because of intestinal obstruction when he was first admitted to a local hospital. Then he was misdiagnosed as having Crohn&#x02019;s disease in another university teaching hospital. Finally, the patient asked for further treatment from our hospital because of the on-going clinical trial for treating refractory Crohn&#x02019;s disease by fecal microbiota transplantation. Physical examination revealed a slight distended abdomen with diffuse tenderness. Laboratory investigation showed the total number of normal leukocytes with neutrophilia as 90.5%, as well as eosinopenia, monocytopenia and lymphocytopenia. Barium radiography and sigmoidoscopy confirmed inflammatory stenosis of the sigmoid colon. We diagnosed the patient as having eosinophilic gastroenteritis by multi-examinations. The patient was treated by fecal microbiota transplantation combined with oral prednisone, and was free from gastrointestinal symptoms at the time when we reported his disease. This case highlights the importance of awareness of manifestations of a rare disease like eosinophilic gastroenteritis.

Fecal microbiota transplantation ameliorates experimental colitis via gut microbiota and T-cell modulation

BACKGROUND Emerging evidence has demonstrated that fecal microbiota transplantation(FMT)has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis(UC),although the mechanism of FMT is unclear.AIM To evaluate the protective effect of FMT on UC and clarify its potential dependence on the gut microbiota,through association analysis of gut microbiota with colon transcriptome in mice.METHODS Dextran sodium sulfate(DSS)-induced experimental colitis was established and fecal microbiota was transplanted by gavage.Severity of colon inflammation was measured by body weight,disease activity index,colon length and histological score.Gut microbiota alteration was analyzed through 16S ribosomal ribonucleic acid sequencing.The differentially expressed genes(DEGs)in the colon were obtained by transcriptome sequencing.The activation status of colonic T lymphocytes in the lamina propria was evaluated by flow cytometry.RESULTS Compared with the DSS group,the weight loss,colon length shortening and inflammation were significantly alleviated in the FMT group.The scores of disease activity index and colon histology decreased obviously after FMT.FMT restored the balance of gut microbiota,especially by upregulating the relative abundance of Lactobacillus and downregulating the relative abundance of Clostridium_sensu_stricto_1 and Turicibacter.In the transcriptomic analysis,128 DEGs intersected after DSS treatment and FMT.Functional annotation analysis suggested that these DEGs were mainly involved in T-lymphocyte activation.In the DSS group,there was an increase in colonic T helper CD4^(+)and T cytotoxic CD8^(+)cells by flow cytometry.FMT selectively downregulated the ratio of colonic CD4^(+)and CD8^(+)T cells to maintain intestinal homeostasis.Furthermore,Clostri dium_sensu_stricto_1 was significantly related to inflammation-related genes including REG3G,CCL8 and IDO1.CONCLUSION FMT ameliorated DSS-induced colitis in mice via regulating the gut microbiota and T-cell modulation.

Can fecal microbiota transplantation cure irritable bowel syndrome?

To verify the utility of treatment with fecal microbiota transplantation (FMT) in patients with irritable bowel syndrome (IBS).METHODSWe searched EMBASE, Cochrane Library and PubMed in March, 2017. The reviewed literature was based on two systematic searches in each of the databases. The MeSH terms used were IBS and fecal microbiota transplantation and the abbreviations IBS and FMT. Reference lists from the articles were reviewed to identify additional pertinent articles.RESULTSA total of six conference abstracts, one case report, one letter to the editor, and one clinical review were included. In the final analysis, treatment of 48 patients was evaluated. Treatment revealed an improvement in 58% of cases. The varying structure of the nine included studies must be taken into consideration.CONCLUSIONData on FMT and IBS are too limited to draw sufficient conclusions. Standardized double blinded randomized clinical trials need to be carried out to evaluate the effect of FMT on IBS.

Fecal microbiota transplantation in the metabolic diseases:Current status and perspectives

With the development of microbiology and metabolomics,the relationship between the intestinal microbiome and intestinal diseases has been revealed.Fecal microbiota transplantation(FMT),as a new treatment method,can affect the course of many chronic diseases such as metabolic syndrome,malignant tumor,autoimmune disease and nervous system disease.Although the mechanism of action of FMT is now well understood,there is some controversy in metabolic diseases,so its clinical application may be limited.Microflora transplantation is recommended by clinical medical guidelines and consensus for the treatment of recurrent or refractory Clostridium difficile infection,and has been gradually promoted for the treatment of other intestinal and extraintestinal diseases.However,the initial results are varied,suggesting that the heterogeneity of the donor stools may affect the efficacy of FMT.The success of FMT depends on the microbial diversity and composition of donor feces.Therefore,clinical trials may fail due to the selection of ineffective donors,and not to faulty indication selection for FMT.A new understanding is that FMT not only improves insulin sensitivity,but may also alter the natural course of type 1 diabetes by modulating autoimmunity.In this review,we focus on the main mechanisms and deficiencies of FMT,and explore the optimal design of FMT research,especially in the field of cardiometabolic diseases.

Microbiota shaping — the effects of probiotics, prebiotics, and fecal microbiota transplant on cognitive functions: A systematic review

BACKGROUND Dementia is a chronic progressive neurological disease affecting millions of people worldwide,and represents a relevant economic burden for healthcare systems.Although its pathogenesis is still unknown,recent findings have reported that a dysregulated gut-brain axis communication,a fundamental relationship mediated by several host and microbial molecules,is associated with cognitive disorders.In addition,gut microbiota manipulation reduces neuroinflammation,improving cognitive function by restoring the functional gut-brain axis.AIM To better define the effects of probiotics,prebiotics,synbiotics,and fecal microbiota transplant(FMT)on cognitive function.METHODS We performed a literature search of human randomized clinical trials to examine the effects of the administration of probiotics,prebiotics,synbiotics,or FMT on cognition outcomes in healthy or sick people of every age,sex,and nationality.We systematically searched Embase,Medline/PubMed,Cochrane Library,central and clinicaltrials.gov databases with a combination of comprehensive terms related to cognition and gut microbiota manipulation.Then we carefully reviewed and synthesized the data by type of study design and setting,characteristics of the studied population,kind of intervention(strain type or mixture type,dosage,and frequency of administration),control treatment,inclusion and exclusion criteria,follow-up duration,and cognitive or memory outcomes.RESULTS After examining the titles and abstracts,the initial literature screening identified 995 articles,but we added 23 papers in our systematic review.The analyses of these selected studies highlighted that both probiotic supplementation and FMT improved cognitive function regardless of the type and posology of administration and the adopted cognitive tests and questionnaires.We found that most of the studies conducted in healthy people showed a significant positive effect of the intervention on at least one of the performed cognitive tests.Regarding unhealthy subjects,while FMT and especially probiotic administration had multiple beneficial effects on different cognitive functions,supplementation with prebiotics did not provide any cognitive improvement.CONCLUSION Probiotic supplementation and FMT may represent a promising strategy to restore gut eubiosis and enhance the cognitive functions of healthy people and patients with neurological disorders.