Effects Of Fecal Microbiota Transplantation Research Articles

The Gastrointestinal Microbiome and Immune Checkpoint Inhibitors: A Review of Human Interventional Studies Among Melanoma Patients.

Immune checkpoint inhibitors (ICI) are widely utilized for the treatment of malignant melanoma. Interestingly, gastrointestinal microbiome composition has emerged as a predictive biomarker of immunotherapy outcomes. This review seeks to assess the effect of microbiota-modulatory interventions on the clinical and immunological response of metastatic melanoma treated with ICIs. A systematic search was performed to retrieve studies and cases involving any microbiota-modulating intervention. Three studies assessed the effect of fecal microbiota transplantation (FMT) on ICI efficacy, and one case report assessed its effect on clearance of ICI-associated colitis. Overall, 37.5% of melanoma patients who had been previously refractory to ICI immunotherapy demonstrated complete or partial response following FMT and subsequent immunotherapy. 65% of immunotherapy-naïve melanoma patients demonstrated an objective response. No severe FMT-associated adverse events were reported, and FMT depicted efficacy in the remission of ICI-associated colitis. The results suggest that FMT may be a safe and moderately effective microbiota-modulating intervention to improve the efficacy of therapy in ICI-treated melanoma patients. Large, randomized, controlled trials are needed to determine optimal FMT donors and assess other microbiota-modulating interventions, such as pre- and probiotics, in melanoma patients.  J Drugs Dermatol. 2024;23(2):78-84.     doi:10.36849/JDD.7674.

Beneficial Effect of Faecal Microbiota Transplantation on Mild, Moderate and Severe Dextran Sodium Sulphate-Induced Ulcerative Colitis in a Pseudo Germ-Free Animal Model.

Transplantation of faecal microbiota (FMT) is generally considered a safe therapeutic procedure with few adverse effects. The main factors that limit the spread of the use of FMT therapy for idiopathic inflammatory bowel disease (IBD) are the necessity of minimising the risk of infection and transfer of another disease. Obtaining the animal model of UC (ulcerative colitis) by exposure to DSS (dextran sodium sulphate) depends on many factors that significantly affect the result. Per os intake of DSS with water is individual for each animal and results in the development of a range of various forms of induced UC. For this reason, the aim of our study was to evaluate the modulation and regenerative effects of FMT on the clinical and histopathological responses and the changes in the bowel microenvironment in pseudo germ-free (PGF) mice of the BALB/c line subjected to chemical induction of mild, moderate and serious forms of UC. The goal was to obtain new data related to the safety and effectiveness of FMT that can contribute to its improved and optimised use. The animals with mild and moderate forms of UC subjected to FMT treatment exhibited lower severity of the disease and markedly lower damage to the colon, including reduced clinical and histological disease index and decreased inflammatory response of colon mucosa. However, FMT treatment failed to achieve the expected therapeutic effect in animals with the serious form of UC activity. The results of our study indicated a potential safety risk involving development of bacteraemia and also translocation of non-pathogenic representatives of bowel microbiota associated with FMT treatment of animals with a diagnosed serious form of UC.

Effect of fecal microbiota transplantation on early intestinal immune function and histomorphology of immune organs in chicks.

Modern management of eggs causes the normal vertical transmission of microbiota from hens to be significantly reduced. The risk of environmental threats to newborn chicks is raised. The microbial community helps to mature the immune system of chicks and protect them from pathogen invasion. We still have doubts about whether transplanting the microbiota can regulate gut immunity. Using the gut microbiota of hens as an excellent resource to improve the immunity of chicks may provide new ideas for the development of the poultry industry.

291. A Longitudinal Study of The Effect of Fecal Microbiota Transplantation on Klebsiella pneumoniae and its Bacteriophages in a Patient with Long-Term Colonization

Abstract Background Live biotherapeutic products such as fecal microbiota transplantation (FMT) show promise as therapies for conditions associated with gut microbiome composition and function, including colonization and recurrent infection with multidrug resistant organisms (MDRO). Although FMTs can reduce colonization with MDROs, much is still unknown about the mechanisms responsible for successful treatment with FMTs. The observation that bacteriophages (phages) are ubiquitous in all microbial communities including FMT doses and are being developed as therapies for MDROs suggests that phages contribute to FMT efficacy. We present results of a case study employing experimental and metagenomic analyses to test the hypothesis that phages contribute to the clinical efficacy of FMTs. A patient with recurrent urinary tract infections (UTI) with a multidrug resistant Klebsiella pneumoniae was treated with an FMT delivered by retention enema as part of a recent clinical trial (NCT02922816). Metagenomic analyses showed that this patient had baseline K. pneumoniae intestinal domination with relative abundance of 90%. At Day 2 post FMT, the relative abundance of K. pneumoniae was 0.5% and follow-up stool cultures with Klebsiella selective and differential media were negative. Methods We competitively aligned reads from the stool metagenomes to the gut phage database using bowtie2 and inStrain. We isolated K. pneumoniae and phages from the donor and patient samples and bacteria susceptibility. Methods For K. pneumoniae/Phage Isolation and Metagenomic Analysis Results We found 76 potential K. pneumoniae phages in the patient before treatment, of which 58 have a breadth of coverage > 0.10. Among these, 39/58 (67%) are known to be temperate and are able to incorporate in the host bacterial genomes as prophages. Breadth of Coverage of K. pneumoniae Phages in the Patient Prior to FMT Solid bars represent unknown free phages identified in the sample. Dashed bars represent phages that are known to be temperate found in the patients metagenome. Conclusion As resistance to host phages quickly emerges, we postulated that phages in the FMT dose contribute to the elimination of K. pneumoniae in this patient. To test the hypothesis, we follow the changes in relative densities of gut K. pneumoniae phages with metagenomic coverage analyses in longitudinally collected fecal samples post FMT. To further test this hypothesis, we isolated phages and bacteria from the FMT and sequential fecal samples from the patient and tested the susceptibility of the K. pneumoniae to the phages from both the FMT dose and the patient. Disclosures All Authors: No reported disclosures

Effects of fecal microbiota transplantation and fecal virome transplantation on LPS-induced intestinal injury in broilers

The interesting roles and efficiencies of fecal microbiota transplantation (FMT) have attracted considerable attention and have been gradually evidenced in specific animal models. While the growing evidence that bacteriophages play roles in FMT efficacy has attracted considerable interest. In this study, we aimed to explore the effects of FMT and fecal virome transplantation (FVT) in improving inflammatory damage and ileal microbiota disorder in broilers. A total of 224 Arbor Acres broilers were selected at 1-day-old and randomly divided into the following four groups, with 56 broilers in each group: the CON group (the negative control group, sterile physiological saline injection + sterile phosphate-buffered saline (PBS) solution gavage), LPS group (the positive control group, lipopolysaccharide (LPS) injection + sterile PBS solution gavage), LPS + FMT group (LPS injection + FMT solution gavage), LPS + FVT group (LPS injection + FVT solution gavage). The results showed that: LPS injection significantly upregulated the mRNA expression levels of IFN-γ (P < 0.05) and IL-8 (P < 0.001) in ileal mucosa of broiler chickens at 11th day of age (D11), while LPS + FMT and LPS + FVT did not; LPS injection significantly upregulated the mRNA expression of ZO-1 in ileal mucosa at D11 (P < 0.01), while LPS + FMT and LPS + FVT did not; at D11, compare to CON group, LPS injection and LPS + FMT significantly increased the relative abundance of virulence factor Rab2 interacting conserved protein A related genes in broiler ileum contents (P < 0.05), while LPS + FVT had no significant difference with CON group (P > 0.05); at D11, LPS injection significantly downregulated the biosynthesis of antibiotics pathway (P < 0.05) in the ileal contents, while LPS + FVT did not. In conclusion, both FMT and FVT could promote the recovery of inflammation caused by LPS. Furthermore, FVT had shown less disadvantage stimulation on the broiler chickens and could reduce the risk of transmission of pathogenic genes, compared to FMT.

Serial Fecal Microbiota Infusions via Colonoscopy for Active Ulcerative Colitis: A Feasibility, Safety, and Translational Monocentric Italian Study.

The effectiveness of fecal microbiota transplantation (FMT) in ulcerative colitis (UC) remains unclear. This study aimed to investigate the feasibility and effectiveness of serial fecal infusions via colonoscopy in patients with active UC. Subjects with mild-to-moderate UC received three consecutive fecal infusions via colonoscopy. A control population with the same baseline features receiving Infliximab treatment was enrolled. Adverse events and clinical, endoscopic, and microbial outcomes were investigated. Nineteen patients with mildly-to-moderately active UC were enrolled. Clinical response was obtained in six patients at week 2, in eight at week 6, and in nine at week 12. Clinical response was maintained in eight patients at week 24. Endoscopic remission at week 12 was reached in six patients. In the control population, 13/19 patients achieved clinical response at week 6, and 10/19 patients maintained clinical response after 6 months. Microbiota richness was higher in responders compared with the non-responders. Peptostreptococcus, Lactobacillus, and Veillonella were higher in non-responders, while Parabacteroides, Bacteroides, Faecalibacterium, and Akkermansia were higher in responders at all timepoints. Serial FMT infusions appear to be feasible, safe, and effective in UC patients, with a potential role in inducing and maintaining clinical response. Specific bacteria predict the response to FMT.

Effects of fecal microbiota transplantation for recurrent Clostridium difficile infection in children on kidney replacement therapy: a pilot study.

Recurrent Clostridium difficile infection (rCDI) is a rising problem in children with chronic diseases. Fecal microbiota transplantation (FMT) is a recent alternative for rCDI patients who do not respond to conventional treatment. FMT could have an additional positive effect on the intestinal dysbiosis and accumulation of uremic retention molecules (URM) associated with chronic kidney disease (CKD). Our aim was to investigate the clinical efficacy of FMT for rCDI in children with CKD together with the effect on dysbiosis and URM levels. We analyzed stool and blood samples before and until 3months after FMT in 3 children between 4 and 8years old with CKD and rCDI. The microbiome was analyzed by 16s rRNA sequencing. URM were analyzed with ultra-performance liquid chromatography-tandem mass spectrometry. CRP and fecal calprotectin were analyzed as parameters for systemic and gut inflammation, respectively. CDI resolved after FMT in all three without adverse events; one patient needed a second FMT. No significant effect on CRP and calprotectin was observed. Stool samples demonstrated a reduced richness and bacterial diversity which did not improve after FMT. We did observe a trend in the decrease of specific URM up to 3months after FMT. FMT is an effective treatment for rCDI in patients with CKD. Analysis of the microbiome showed an important intestinal dysbiosis that, besides a significant reduction in Clostridium difficile, did not significantly change after FMT. A trend for reduction was seen in some of the measured URM after FMT.

Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance.

In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice. Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice. Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis.

Fecal Microbiota Transplantation from Aged Mice Render Recipient Mice Resistant to MPTP-Induced Nigrostriatal Degeneration Via a Neurogenesis-Dependent but Inflammation-Independent Manner.

Accumulating data support a crucial role of gut microbiota in Parkinson's disease (PD). However, gut microbiota vary with age and, thus, will affect PD in an age-dependent, but unknown manner. We examined the effects of fecal microbiota transplantation (FMT) pretreatment, using fecal microbiota from young (7weeks) or aged mice (23months), on MPTP-induced PD model. Motor function, pathological changes, striatal neurotransmitters, neuroinflammation, gut inflammation and gut permeability were examined. Gut microbiota composition and metabolites, namely short-chain fatty acids (SCFAs), were analyzed. Neurogenesis was also evaluated by measuring the number of doublecortin-positive (DCX+) neurons and Ki67-positive (Ki67+) cells in the hippocampus. Expression of Cd133 mRNA, a cellular stemness marker, in the hippocampus was also examined. Mice who received FMT from young mice showed MPTP-induced motor dysfunction, and reduction of striatal dopamine (DA), dopaminergic neurons and striatal tyrosine hydroxylase (TH) levels. Interestingly and unexpectedly, mice that received FMT from aged mice showed recovery of motor function and rescue of dopaminergic neurons and striatal 5-hydroxytryptamine (5-HT), as well as decreased DA metabolism after MPTP challenge. Further, they showed improved metabolic profiling and a decreased amount of fecal SCFAs. High-throughput sequencing revealed that FMT remarkably reshaped the gut microbiota of recipient mice. For instance, levels of genus Akkermansia and Candidatus Saccharimonas were elevated in fecal samples of recipient mice receiving aged microbiota (AM + MPTP mice) than YM + MPTP mice. Intriguingly, both young microbiota and aged microbiota had no effect on neuroinflammation, gut inflammation or gut permeability. Notably, AM + MPTP mice showed a marked increase in DCX+ neurons, as well as Ki67+ cells and Cd133 expression in the hippocampal dentate gyrus (DG) compared to YM + MPTP mice. These results suggest that FMT from aged mice augments neurogenesis, improves motor function and restores dopaminergic neurons and neurotransmitters in PD model mice, possibly through increasing neurogenesis.

Randomized, double-blinded, placebo-controlled pilot study: efficacy of faecal microbiota transplantation on chronic fatigue syndrome

BackgroundChronic fatigue syndrome (CFS) is a disabling illness of unknown aetiology. Disruption of gut microbiota may play a role in several neurological disorders. In this study, the effect of faecal microbiota transplantation (FMT) on fatigue severity and health-related quality of life (HRQOL) in patients with CFS was evaluated.MethodsRandomized, placebo-controlled pilot trial. Patients and researchers were blinded to treatment assignment. 11 patients with CFS (10 female and 1 male, mean age 42.2 years and mean duration of CFS 6.3 years) were randomly assigned to receive either FMT from a universal donor (n = 5) or autologous FMT (n = 6) via colonoscopy. Patients’ HRQOL was assessed by using visual analog scale (VAS) and self-reporting questionnaires Modified Fatigue Impact Scale (MFIS), 15D and EQ-5D-3L. Patients’ HRQOL was evaluated at baseline, and 1 and 6 months after the FMT.ResultsThe baseline VAS scores in the FMT and placebo groups were 62.4 and 76.0 (p = 0.29). 1-month scores were 60.0 and 73.7 and 6-months scores 72.8 and 69.5, respectively. Total MFIS scores in the FMT and placebo groups were 59.6 and 61.0 at the baseline (p = 0.80), 53.5 and 62.0 at 1 month and 58.6 and 56.2 at 6 months. Compared to the baseline scores, differences at 1 and 6 months were statistically insignificant both in VAS and in MFIS. The 15D and EQ-5D-3L profiles did not change after the FMT or placebo. FMT-related adverse events were not reported.ConclusionFMT was safe but did not relieve symptoms or improve the HRQOL of patients with CFS. Small number of study subjects limits the generalizability of these results.Trial Registration ClinicalTrials.gov Identifier NCT04158427, https://register.clinicaltrials.gov, date of registration 08/08/2019.

Effects of fecal microbiota transplantation in metabolic syndrome: A meta-analysis of randomized controlled trials.

The prevalence of obesity and type 2 diabetes is rapidly increasing worldwide, posing serious threats to human health. This study aimed to evaluate the role of FMT in the treatment of obesity and/or metabolic syndrome and its impact on clinically important parameters. We searched Medline, Embase, and Cochrane Library databases up to April 31, 2022 and further assessed articles that met the eligibility criteria. Mean differences and 95% confidence intervals were used to analyze continuous data. The I2 statistic was used to measure study heterogeneity. Univariate meta-regression or subgroup analyses were performed to explore the covariates that might contribute to heterogeneity. Potential publication bias was assessed using the Egger's test. We used the GRADEpro guideline development tool to assess the quality of the evidence. Nine studies, comprising 303 participants, were included in the meta-analysis. In the short-term outcomes (<6 weeks after FMT), compared with the placebo group, patients in the FMT group had lower FBG (MD = -0.12 mmol/L, 95% Cl: -0.23, -0.01), HbA1c (MD = -0.37 mmol/mol, 95%Cl: -0.73, -0.01), and insulin levels (MD = -24.77 mmol/L, 95% Cl: -37.60, -11.94), and higher HDL cholesterol levels (MD = 0.07 mmol/L, 95% Cl: 0.02, 0.11). FMT, as an adjunctive therapy, does not produce any serious adverse effects and may be useful in the treatment of metabolic syndrome, especially in improving HbA1c, insulin sensitivity, and HDL cholesterol. However, there was no significant difference between the FMT group and the placebo group in terms of weight reduction.

Microbiota from healthy mice alleviates cognitive decline via reshaping the gut-brain metabolic axis in diabetic mice

Diabetic cognitive decline has been associated with the gut microbial disorders, but its potential gut-brain axis mechanisms remain unclear. Herein we transplanted the gut microbiota from healthy mice into type 1 diabetic (T1D) mice and then investigated the effect of fecal microbiota transplantation (FMT) on cognitive function and the gut-brain metabolic axis. The results demonstrate that FMT from healthy mice effectively improved the learning and memory abilities in T1D mice, and significantly reduced neuroinflammation and neuron injury in the cortex and hippocampus. Moreover, FMT partly reversed the gut microbiota and gut-brain metabolic disorders, particularly glutamate metabolism. In vitro study, we found that glutamate notably decreased microglia activation and the expression levels of proinflammatory factor. Hence, our study suggests that glutamate serves as a key signal metabolite connecting the gut to brain and affects cognitive functions.

Probiotic Yeast from Miso Ameliorates Stress-Induced Visceral Hypersensitivity by Modulating the Gut Microbiota in a Rat Model of Irritable Bowel Syndrome.

Recent studies indicate that probiotics, which have attracted attention as a treatment for irritable bowel syndrome, affect intestinal homeostasis. In this study, we investigated whether Zygosaccharomyces sapae (strain I-6), a probiotic yeast isolated from miso (a traditional Japanese fermented food), could improve irritable bowel syndrome symptoms. Male Wistar rats were exposed to water avoidance stress (WAS). The number of defecations during WAS and the visceral hypersensitivity before and after WAS were evaluated using colorectal distension. Tight junction changes were assessed by Western blotting. Some rats were fed with strain I-6 or β-glucan from strain I-6. Changes in the intestinal microbiota were analyzed. The effect of fecal microbiota transplantation after WAS was evaluated similarly. Caco-2 cells were stimulated with interleukin-1β and tight junction changes were investigated after coculture with strain I-6. The increased number of stool pellets and visceral hypersensitivity induced by WAS were suppressed by administering strain I-6. The decrease in tight junction protein occludin by WAS was reversed by the administration of strain I-6. β-Glucan from strain I-6 also suppressed those changes induced by WAS. In the rat intestinal microbiota, treatment with strain I-6 altered the β-diversity and induced changes in bacterial occupancy. Upon fecal microbiota transplantation, some symptoms caused by WAS were ameliorated. These results suggest that traditional fermented foods such as miso in Japan are valuable sources of probiotic yeast candidates, which may be useful for preventing and treating stress-induced visceral hypersensitivity.

What are the effects of fecal microbiota transplantation (FMT) for people with ulcerative colitis?

What are the effects of fecal microbiota transplantation (FMT) for people with ulcerative colitis?

Effects of fecal microbiota transplant on DNA methylation in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by multiple organ damage accompanied by the over-production of autoantibodies. Decreased intestinal flora diversity and disruption of homeostasis have been proven to be associated with pathogenesis of SLE. In previous study, a clinical trial was conducted to verify the safety and effectiveness of fecal microbiota transplantation (FMT) in the treatment of SLE. To explore the mechanism of FMT in the treatment of SLE, we included 14 SLE patients participating in clinical trials, including 8 in responders group (Rs) and 6 in non-responders group (NRs), and collected peripheral blood DNA and serum. We found that the serum of S-adenosylmethionine (SAM), methylation group donor, was upregulated after FMT, accompanied by an increase in genome-wide DNA methylation level in Rs. We further showed that the methylation levels in promoter regions of Interferon-γ (IFN-γ), induced Helicase C Domain Containing Protein 1 (IFIH1), endoplasmic reticulum membrane protein complex 8 (EMC8), and Tripartite motif-containing protein 58 (TRIM58) increased after FMT treatment. On the contrary, there was no significant change in the methylation of IFIH1 promoter region in the NRs after FMT, and the methylation level of IFIH1 in the Rs was significantly higher than that in the NRs at week 0. We included 850 K methylation chip sequencing, combining previous data of metagenomic sequencing, and metabolomic sequencing for multi-omics analysis to discuss the relationship between flora-metabolite-methylation in FMT. Finally, we found that hexanoic acid treatment can up-regulate the global methylation of peripheral blood mononuclear cells in SLE patients. Overall, our results delineate changes in methylation level after FMT treatment of SLE and reveal possible mechanisms of FMT treatment in terms of the recovery of abnormal hypomethylation.

The effect of FMT and vitamin C on immunity-related genes in antibiotic-induced dysbiosis in mice.

Antibiotics are double-edged swords. Although antibiotics are used to inhibit pathogenic bacteria, they also run the risk of destroying some of the healthy bacteria in our bodies. We examined the effect of penicillin on the organism through a microarray dataset, after which 12 genes related to immuno-inflammatory pathways were selected by reading the literature and validated using neomycin and ampicillin. The expression of genes was measured using qRT-PCR. Several genes were significantly overexpressed in antibiotic-treated mice, including CD74 and SAA2 in intestinal tissues that remained extremely expressed after natural recovery. Moreover, transplantation of fecal microbiota from healthy mice to antibiotic-treated mice was made, where GZMB, CD3G, H2-AA, PSMB9, CD74, and SAA1 were greatly expressed; however, SAA2 was downregulated and normal expression was restored, and in liver tissue, SAA1, SAA2, SAA3 were extremely expressed. After the addition of vitamin C, which has positive effects in several aspects, to the fecal microbiota transplantation, in the intestinal tissues, the genes that were highly expressed after the fecal microbiota transplantation effectively reduced their expression, and the unaffected genes remained normally expressed, but the CD74 gene remained highly expressed. In liver tissues, normally expressed genes were not affected, but the expression of SAA1 was reduced and the expression of SAA3 was increased. In other words, fecal microbiota transplantation did not necessarily bring about a positive effect of gene expression restoration, but the addition of vitamin C effectively reduced the effects of fecal microbiota transplantation and regulated the balance of the immune system.

Fecal microbiota transplantation inhibits colorectal cancer progression: Reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses.

Many lines of evidence demonstrate the associations of colorectal cancer (CRC) with intestinal microbial dysbiosis. Recent reports have suggested that maintaining the homeostasis of microbiota and host might be beneficial to CRC patients, but the underlying mechanisms remain unclear. In this study, we established a CRC mouse model of microbial dysbiosis and evaluated the effects of fecal microbiota transplantation (FMT) on CRC progression. Azomethane and dextran sodium sulfate were used to induce CRC and microbial dysbiosis in mice. Intestinal microbes from healthy mice were transferred to CRC mice by enema. The vastly disordered gut microbiota of CRC mice was largely reversed by FMT. Intestinal microbiota from normal mice effectively suppressed cancer progression as assessed by measuring the diameter and number of cancerous foci and significantly prolonged survival of the CRC mice. In the intestine of mice that had received FMT, there were massive infiltration of immune cells, including CD8+ T and CD49b+ NK, which is able to directly kill cancer cells. Moreover, the accumulation of immunosuppressive cells, Foxp3+ Treg cells, seen in the CRC mice was much reduced after FMT. Additionally, FMT regulated the expressions of inflammatory cytokines in CRC mice, including down-regulation of IL1a, IL6, IL12a, IL12b, IL17a, and elevation of IL10. These cytokines were positively correlated with Azospirillum_sp._47_25, Clostridium_sensu_stricto_1, the E. coli complex, Akkermansia, Turicibacter, and negatively correlated with Muribaculum, Anaeroplasma, Candidatus_Arthromitus, and Candidatus Saccharimonas. Furthermore, the repressed expressions of TGFb, STAT3 and elevated expressions of TNFa, IFNg, CXCR4 together promoted the anti-cancer efficacy. Their expressions were positively correlated with Odoribacter, Lachnospiraceae-UCG-006, Desulfovibrio, and negatively correlated with Alloprevotella, Ruminococcaceae UCG-014, Ruminiclostridium, Prevotellaceae UCG-001 and Oscillibacter. Our studies indicate that FMT inhibits the development of CRC by reversing gut microbial disorder, ameliorating excessive intestinal inflammation and cooperating with anti-cancer immune responses.

Clinical Effects of Faecal Microbiota Transplantation as Adjunctive Therapy in Dogs with Chronic Enteropathies—A Retrospective Case Series of 41 Dogs

Chronic enteropathies (CE) are common in dogs, but not all affected dogs respond to standard therapy. Successful responses to faecal microbial transplantation (FMT) in dogs with non-responsive CE have been reported in two case series. The objective of this retrospective study was to describe the clinical effects of FMT as an adjunctive therapy in a larger population of dogs with CE. Forty-one dogs aged 0.6-13.0 years (median 5.8) under treatment for CE at one referral animal hospital were included. Dogs were treated with 1-5 (median 3) FMTs as a rectal enema at a dose of 5-7 g/kg body weight. The canine inflammatory bowel disease activity index (CIBDAI) was compared at baseline versus after the last FMT. Stored faecal samples (n = 16) were analysed with the dysbiosis index. CIBDAI at baseline was 2-17 (median 6), which decreased to 1-9 (median 2; p < 0.0001) after FMT. Subsequently, 31/41 dogs responded to treatment, resulting in improved faecal quality and/or activity level in 24/41 and 24/41 dogs, respectively. The dysbiosis index at baseline was significantly lower for good responders versus poor responders (p = 0.043). Results suggest that FMT can be useful as an adjunctive therapy in dogs with poorly responsive CE.

Integrated Analysis of Gut Microbiome and Liver Metabolome to Evaluate the Effects of Fecal Microbiota Transplantation on Lipopolysaccharide/D-galactosamine-Induced Acute Liver Injury in Mice

Acute liver failure (ALF) refers to the occurrence of massive hepatocyte necrosis in a short time, with multiple complications, including inflammatory response, hepatic encephalopathy, and multiple organ failure. Additionally, effective therapies for ALF are lacking. There exists a relationship between the human intestinal microbiota and liver, so intestinal microbiota modulation may be a strategy for therapy of hepatic diseases. In previous studies, fecal microbiota transplantation (FMT) from fit donors has been used to modulate intestinal microbiota widely. Here, we established a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-gal) induced ALF to explore the preventive and therapeutic effects of FMT, and its mechanism of action. We found that FMT decreased hepatic aminotransferase activity and serum total bilirubin levels, and decreased hepatic pro-inflammatory cytokines in LPS/D-gal challenged mice (p < 0.05). Moreover, FMT gavage ameliorated LPS/D-gal induced liver apoptosis and markedly reduced cleaved caspase-3 levels, and improved histopathological features of the liver. FMT gavage also restored LPS/D-gal-evoked gut microbiota dysbiosis by modifying the colonic microbial composition, improving the abundance of unclassified_o_Bacteroidales (p < 0.001), norank_f_Muribaculaceae (p < 0.001), and Prevotellaceae_UCG-001 (p < 0.001), while reducing that of Lactobacillus (p < 0.05) and unclassified_f_Lachnospiraceae (p < 0.05). Metabolomics analysis revealed that FMT significantly altered LPS/D-gal induced disordered liver metabolites. Pearson's correlation revealed strong correlations between microbiota composition and liver metabolites. Our findings suggest that FMT ameliorate ALF by modulating gut microbiota and liver metabolism, and can used as a potential preventive and therapeutic strategy for ALF.

Shifts and importance of viable bacteria in treatment of DSS-induced ulcerative colitis mice with FMT.

Ulcerative colitis (UC) has become a global public health concern, and is in urgent need of novel therapies. Fecal microbiota transplantation (FMT) targeting gut microbiota has recently been applied to the treatment of UC. Despite its recent successes, it is still largely unknown how FMT functionally modulates the gut microbiota and improves the disease. We prospectively collected fecal samples from the 40 mice (30 mice for dextran sulfate sodium (DSS)-induced, 10 for controls), followed by Propidium monoazide treatment for 16S rRNA gene sequencing. These 30 mice were divided equally into 3 groups, which were transplanted with original donor microbiota (DO), inactivated donor microbiota (DI) and saline, respectively. Subsequently, we used 16S rRNA gene sequencing to analyze the viable gut bacteria of ulcerative colitis (UC) mice and histological analysis to evaluate the effects of fecal microbiota transplantation (FMT) with viable microbiota. We demonstrated that the community structure of viable bacteria was significantly different from fecal bacteria based on total DNA. Furthermore, the intestinal viable microbiota and colonic mucosal structure of mice were significantly changed by DSS induction. The histological analysis showed that only the mice treated with original donor microbiota group (HF) achieved a significant improvement. Compared with inactivated donor microbiota group (IF) and saline (NF), Lactobacillus and Halomonas were significantly enriched in the HF group. We inferred that only live bacteria from human donor reversed the histopathology and symptoms of UC in mice and altered the gut microbiota. The activity of gut microbiota in donor samples should be considered in FMT and that detailed analysis of viable microbiota is essential to understand the mechanisms by which FMT produces therapeutic effects in the future.