Efficacy of fecal microbiota transplantation in patients with Parkinson's disease: clinical trial results from a randomized, placebo-controlled design.

The occurrence and development of Parkinson's disease (PD) have been demonstrated to be related to gut dysbiosis, however, the impact of fecal microbiota transplantation (FMT) on microbiota engraftment in PD patients is uncertain. We performed a randomized, placebo-controlled trial at the Department of Neurology, Army Medical University Southwest Hospital in China (ChiCTR1900021405) from February 2019 to December 2019. Fifty-six participants with mild to moderate PD (Hoehn-Yahr stage 1-3) were randomly assigned to the FMT and placebo group, 27 patients in the FMT group and 27 in the placebo group completed the whole trial. During the follow-up, no severe adverse effect was observed, and patients with FMT treatment showed significant improvement in PD-related autonomic symptoms compared with the placebo group at the end of this trial (MDS-UPDRS total score, group×time effect, B = -6.56 [-12.98, -0.13], P < 0.05). Additionally, FMT improved gastrointestinal disorders and a marked increase in the complexity of the microecological system in patients. This study demonstrated that FMT through oral administration is clinically feasible and has the potential to improve the effectiveness of current medications in the clinical symptoms of PD patients.

The role of complex interactions between the intestinal flora and host in regulating intestinal homeostasis and inflammatory bowel disease.

Pharmacological treatment of inflammatory bowel disease (IBD) is inefficient and difficult to discontinue appropriately, and enterobacterial interactions are expected to provide a new target for the treatment of IBD. We collected recent studies on the enterobacterial interactions among the host, enterobacteria, and their metabolite products and discuss potential therapeutic options. Intestinal flora interactions in IBD are affected in the reduced bacterial diversity, impact the immune system and are influenced by multiple factors such as host genetics and diet. Enterobacterial metabolites such as SCFAs, bile acids, and tryptophan also play important roles in enterobacterial interactions, especially in the progression of IBD. Therapeutically, a wide range of sources of probiotics and prebiotics exhibit potential therapeutic benefit in IBD through enterobacterial interactions, and some have gained wide recognition as adjuvant drugs. Different dietary patterns and foods, especially functional foods, are novel therapeutic modalities that distinguish pro-and prebiotics from traditional medications. Combined studies with food science may significantly improve the therapeutic experience of patients with IBD. In this review, we provide a brief overview of the role of enterobacteria and their metabolites in enterobacterial interactions, discuss the advantages and disadvantages of the potential therapeutic options derived from such metabolites, and postulate directions for further research.

Development and validation of a deep learning-based approach to predict the Mayo endoscopic score of ulcerative colitis.

Background: The ulcerative colitis (UC) Mayo endoscopy score is a useful tool for evaluating the severity of UC in patients in clinical practice. Objectives: We aimed to develop and validate a deep learning-based approach to automatically predict the Mayo endoscopic score using UC endoscopic images. Design: A multicenter, diagnostic retrospective study. Methods: We collected 15120 colonoscopy images of 768 UC patients from two hospitals in China and developed a deep model based on a vision transformer named the UC-former. The performance of the UC-former was compared with that of six endoscopists on the internal test set. Furthermore, multicenter validation from three hospitals was also carried out to evaluate UC-former's generalization performance. Results: On the internal test set, the areas under the curve of Mayo 0, Mayo 1, Mayo 2, and Mayo 3 achieved by the UC-former were 0.998, 0.984, 0.973, and 0.990, respectively. The accuracy (ACC) achieved by the UC-former was 90.8%, which is higher than that achieved by the best senior endoscopist. For three multicenter external validations, the ACC was 82.4%, 85.0%, and 83.6%, respectively. Conclusions: The developed UC-former could achieve high ACC, fidelity, and stability to evaluate the severity of UC, which may provide potential application in clinical practice. Registration: This clinical trial was registered at the ClinicalTrials.gov (trial registration number: NCT05336773).

Why was this study done? The development of an auxiliary diagnostic tool can reduce the workload of endoscopists and achieve rapid assessment of ulcerative colitis (UC) severity. What did the researchers do? We developed and validated a deep learning-based approach to automatically predict the Mayo endoscopic score using UC endoscopic images. What did the researchers find? The model that was developed in this study achieved high accuracy, fidelity, and stability, and demonstrated potential application in clinical practice. What do the findings mean? Deep learning could effectively assist endoscopists in evaluating the severity of UC in patients using endoscopic images.

PHF3 Technique: A Pyramid Hybrid Feature Fusion Framework for Severity Classification of Ulcerative Colitis Using Endoscopic Images.

Evaluating the severity of ulcerative colitis (UC) through the Mayo endoscopic subscore (MES) is crucial for understanding patient conditions and providing effective treatment. However, UC lesions present different characteristics in endoscopic images, exacerbating interclass similarities and intraclass differences in MES classification. In addition, inexperience and review fatigue in endoscopists introduces nontrivial challenges to the reliability and repeatability of MES evaluations. In this paper, we propose a pyramid hybrid feature fusion framework (PHF3) as an auxiliary diagnostic tool for clinical UC severity classification. Specifically, the PHF3 model has a dual-branch hybrid architecture with ResNet50 and a pyramid vision Transformer (PvT), where the local features extracted by ResNet50 represent the relationship between the intestinal wall at the near-shot point and its depth, and the global representations modeled by the PvT capture similar information in the cross-section of the intestinal cavity. Furthermore, a feature fusion module (FFM) is designed to combine local features with global representations, while second-order pooling (SOP) is applied to enhance discriminative information in the classification process. The experimental results show that, compared with existing methods, the proposed PHF3 model has competitive performance. The area under the receiver operating characteristic curve (AUC) of MES 0, MES 1, MES 2, and MES 3 reached 0.996, 0.972, 0.967, and 0.990, respectively, and the overall accuracy reached 88.91%. Thus, our proposed method is valuable for developing an auxiliary assessment system for UC severity.

Clinical study on sequential treatment of severe diarrhea irritable bowel syndrome with precision probiotic strains transplantation capsules, fecal microbiota transplantation capsules and live combined bacillus subtilis and enterococcus faecium capsules.

Objective: To study the effect of precision probiotic strains transplantation capsules on diarrhea irritable bowel syndrome compared with fecal microbiota transplantation capsules and live combined bacillus subtilis and enterococcus faecium capsules. Methods: Two patients with severe irritable bowel syndrome were treated with precision probiotic strains transplantation capsules, fecal microbiota transplantation capsules and live combined bacillus subtilis and enterococcus faecium capsules in sequence. IBS-SSS, IBS-QoL, GSRS, stool frequency, stool character, degree of abdominal pain, GAD-7, and PHQ9 scores of patients at 0, 2, 4, 6, 8, 10, and 12 weeks of treatment were monitored and recorded, and stool samples were collected for metagenomics and metabolomics. Results: It was found that the IBS-SSS score of patient case 1 decreased by 175 points and that of patient case 2 decreased by 100 points after treatment of precision probiotic strains transplantation capsules. There was no significant decrease after fecal microbiota transplantation capsules and live combined bacillus subtilis and enterococcus faecium capsules were used. At the same time, compared with fecal microbiota transplantation and live combined bacillus subtilis and enterococcus faecium capsules, the IBS QoL, stool frequency, stool character, degree of abdominal pain and GAD-7 score of patient case 1 improved more significantly by the precision probiotic strains transplantation capsules. And the stool frequency and stool character score of patient case 2 decreased more significantly. Intestinal microbiota also improved more significantly after the precise capsule transplantation treatment. And we found Eubacterium_ Eligens showed the same change trend in the treatment of two patients, which may play a role in the treatment. Conclusion: precision probiotic strains transplantation capsules is more beneficial to improve the intestinal microbiota of patients than microbiota transplantation capsule and live combined bacillus subtilis and enterococcus faecium capsules, so as to better alleviate clinical symptoms. This study provides a more perfect and convenient therapeutic drugs for the treatment of IBS.

Gut microbiota: A new target for T2DM prevention and treatment.

Type 2 diabetes mellitus (T2DM), one of the fastest growing metabolic diseases, has been characterized by metabolic disorders including hyperglycemia, hyperlipidemia and insulin resistance (IR). In recent years, T2DM has become the fastest growing metabolic disease in the world. Studies have indicated that patients with T2DM are often associated with intestinal flora disorders and dysfunction involving multiple organs. Metabolites of the intestinal flora, such as bile acids (BAs), short-chain fatty acids (SCFAs) and amino acids (AAs)may influence to some extent the decreased insulin sensitivity associated with T2DM dysfunction and regulate metabolic as well as immune homeostasis. In this paper, we review the changes in the gut flora in T2DM and the mechanisms by which the gut microbiota modulates metabolites affecting T2DM, which may provide a basis for the early identification of T2DM-susceptible individuals and guide targeted interventions. Finally, we also highlight gut microecological therapeutic strategies focused on shaping the gut flora to inform the improvement of T2DM progression.

Roseburia intestinalis and Its Metabolite Butyrate Inhibit Colitis and Upregulate TLR5 through the SP3 Signaling Pathway.

The pathogenesis of ulcerative colitis (UC) is unclear, but it is generally believed to be closely related to an imbalance in gut microbiota. Roseburia intestinalis (R. intestinalis) might play a key role in suppressing intestinal inflammation, but the mechanism of its anti-inflammatory effect is unknown. In this study, we investigated the role of R. intestinalis and Toll-like receptor 5 (TLR5) in relieving mouse colitis. We found that R. intestinalis significantly upregulated the transcription of TLR5 in intestinal epithelial cells (IECs) and improved colonic inflammation in a colitis mouse model. The flagellin of R. intestinalis activated the release of anti-inflammatory factors (IL-10, TGF-ß) and reduced inflammation in IECs. Furthermore, butyrate, the main metabolic product secreted by R. intestinalis, regulated the expression of TLR5 in IECs. Our data show that butyrate increased the binding of the transcription factor Sp3 (specificity protein 3) to the TLR5 promoter regions, upregulating TLR5 transcription. This work provides new insight into the anti-inflammatory effects of R. intestinalis in colitis and a potential target for UC prevention and treatment.

Development and Validation of a Deep Neural Network for Accurate Identification of Endoscopic Images From Patients With Ulcerative Colitis and Crohn's Disease.

Background and Aim: The identification of ulcerative colitis (UC) and Crohn's disease (CD) is a key element interfering with therapeutic response, but it is often difficult for less experienced endoscopists to identify UC and CD. Therefore, we aimed to develop and validate a deep learning diagnostic system trained on a large number of colonoscopy images to distinguish UC and CD. Methods: This multicenter, diagnostic study was performed in 5 hospitals in China. Normal individuals and active patients with inflammatory bowel disease (IBD) were enrolled. A dataset of 1,772 participants with 49,154 colonoscopy images was obtained between January 2018 and November 2020. We developed a deep learning model based on a deep convolutional neural network (CNN) in the examination. To generalize the applicability of the deep learning model in clinical practice, we compared the deep model with 10 endoscopists and applied it in 3 hospitals across China. Results: The identification accuracy obtained by the deep model was superior to that of experienced endoscopists per patient (deep model vs. trainee endoscopist, 99.1% vs. 78.0%; deep model vs. competent endoscopist, 99.1% vs. 92.2%, P < 0.001) and per lesion (deep model vs. trainee endoscopist, 90.4% vs. 59.7%; deep model vs. competent endoscopist 90.4% vs. 69.9%, P < 0.001). In addition, the mean reading time was reduced by the deep model (deep model vs. endoscopists, 6.20 s vs. 2,425.00 s, P < 0.001). Conclusion: We developed a deep model to assist with the clinical diagnosis of IBD. This provides a diagnostic device for medical education and clinicians to improve the efficiency of diagnosis and treatment.

Neurotransmitter and Intestinal Interactions: Focus on the Microbiota-Gut-Brain Axis in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology. IBS is caused by a disruption in the gut-brain axis. Given the importance of the gut microbiota in maintaining local and systemic homeostasis of immunity, endocrine, and other physiological processes, the microbiota-gut-brain axis has been proposed as a key regulator in IBS. Neurotransmitters have been shown to affect blood flow regulation, intestinal motility, nutrient absorption, the gastrointestinal immune system, and the microbiota in recent studies. It has the potential role to play a function in the pathophysiology of the gastrointestinal and neurological systems. Transmitters and their receptors, including 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and histamine, play an important role in IBS, especially in visceral sensitivity and gastrointestinal motility. Studies in this field have shed light on revealing the mechanism by which neurotransmitters act in the pathogenesis of IBS and discovering new therapeutic strategies based on traditional pharmacological approaches that target the nervous system or novel therapies that target the microbiota.

The role of Th17 cells in inflammatory bowel disease and the research progress.

Th17 cells play an important role in the abnormal immune response in inflammatory bowel disease (IBD) and are involved in the development and progression of inflammation and fibrosis. An increasing amount of data has shown that gut microbes are important parts of intestinal immunity and regulators of Th17 cellular immunity. Th17 cell differentiation is regulated by intestinal bacteria and cytokines, and Th17 cells regulate the intestinal mucosal immune microenvironment by secreting cytokines, such as IL-17, IL-21, and IL-26. Solid evidence showed that, regarding the treatment of IBD by targeting Th17 cells, the therapeutic effect of different biological agents varies greatly. Fecal bacteria transplantation (FMT) in the treatment of IBD has been a popular research topic in recent years and is safe and effective with few side effects. To further understand the role of Th17 cells in the progression of IBD and associated therapeutic prospects, this review will discuss the progress of related research on Th17 cells in IBD by focusing on the interaction and immune regulation between Th17 cells and gut microbiota.

Corrigendum: Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study.

[This corrects the article DOI: 10.3389/fcimb.2021.759435.].

Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study.

Autism spectrum disorder (ASD) is a severe brain development disorder that is characterized by deficits in social communication and restricted, repetitive and stereotyped behaviors. Accumulating evidence has suggested that gut microbiota disorders play important roles in gastrointestinal symptoms and neurodevelopmental dysfunction in ASD patients. Manipulation of the gut microbiota by fecal microbiota transplantation (FMT) was recently shown to be a promising therapy for the treatment of various diseases. Here, we performed a clinical trial to evaluate the effect of FMT on gastrointestinal (GI) and ASD symptoms and gut microbiota alterations in children with ASD. We found that there was a large difference in baseline characteristics of behavior, GI symptoms, and gut microbiota between children with ASD and typically developing (TD) control children. FMT could improve GI symptoms and ASD symptoms without inducing any severe complications. Similarly, FMT significantly changed the serum levels of neurotransmitters. We further observed that FMT could promote the colonization of donor microbes and shift the bacterial community of children with ASD toward that of TD controls. The abundance of Eubacterium coprostanoligenes pre-FMT was positively correlated with high GSRS scores, whereas a decrease in Eubacterium coprostanoligenes abundance induced by FMT was associated with the FMT response. Our data suggest that FMT might be a promising therapeutic strategy to improve the GI and behavioral symptoms of patients with ASD, possibly due to its ability to alter gut microbiota and highlight a specific microbiota intervention that targets Eubacterium coprostanoligenes that can enhance the FMT response. This trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) (trial registration number ChiCTR1800014745).

RFWD3 Participates in the Occurrence and Development of Colorectal Cancer via E2F1 Transcriptional Regulation of BIRC5.

Objectives: Colorectal cancer (CRC) is one of the most common human malignancies. It was reported that the alterations in the DNA damage response (DDR) pathways are emerging as novel targets for treatment across different cancer types including CRC. RFWD3 plays a critical role in replication protein A (RPA)-mediated DNA damage in cancer cells. More importantly, RFWD3 can response to DNA damage by positively regulating p53 stability when the G1 cell cycle checkpoint is activated. However, the functional significance of RFWD3 in CRC has not been reported in the existing documents. Materials and Methods: Here, we revealed high expression of RFWD3 in CRC tissues by IHC analysis and The Cancer Genome Atlas (TCGA) database. Besides, overexpression of RFWD3 in CRC cell lines was also confirmed by qRT-PCR and western blot assay. The Celigo cell counting method and wound-healing/transwell migration assay were applied to evaluate CRC cell proliferation and migration. The tumor growth indicators were quantified in nude mice xenografted with shRFWD3 and shCtrl RKO cells. Results: The results indicated that RFWD3 knockdown restricted CRC development in vitro and in vivo. In exploring the downstream mechanism of RFWD3's action, we found that RFWD3 could transcriptionally activate BIRC5 by interacting with E2F transcription factor 1 (E2F1). Accordingly, we identified BIRC5 as a downstream gene of RFWD3 regulating CRC. Subsequent loss- and gain- of function experiments demonstrated that upon overexpressing BIRC5 in RKO cells with down-regulated RFWD3, the inhibitory effects of cell proliferation, migration and colony formation could be reversed, while the capacity of cell apoptosis was ameliorated, suggesting that the effects of RFWD3 depletion was mainly due to BIRC5 suppression. Conclusion: Taken together, this study revealed that RFWD3 participates in the occurrence and development of colorectal cancer via E2F1 transcriptional regulation of BIRC5.

New pathway ameliorating ulcerative colitis: focus on Roseburia intestinalis and the gut-brain axis.

BACKGROUND: The community of gut microbes is a key factor controlling the intestinal barrier that communicates with the nervous system through the gut-brain axis. Based on our clinical data showing that populations of Roseburia intestinalis are dramatically decreased in the gut of patients with ulcerative colitis, we studied the efficacy of a strain belonging to this species in the context of colitis and stress using animal models. METHODS: Dextran sulfate sodium was used to induce colitis in rats, which then underwent an enema with R. intestinalis as a treatment. The disease activity index, fecal changes and body weight of rats were recorded to evaluate colitis, while histological and immunohistochemical analyses were carried out to examine colon function, and 16S rRNA sequencing was performed to evaluate the gut microbiota change. Behavioral assays and immunohistochemical staining of brain were performed to assess the effect of R. intestinalis on the gut-brain axis. RESULTS: Colitis-related symptoms in rats were significantly relieved after R. intestinalis enema, and the stool traits and colon length of rats were significantly recovered after treatment. The gut epithelial integrity and intestinal barrier were restored in treated rats, as evidenced by the higher expression of Zo-1 in colon tissues, accompanied by the restoration of gut microbiota. Meanwhile, depressive-like behaviors of rats were reduced after treatment, and laboratory experiments on neuronal cells also showed that IL-6, IL-7 and 5-HT were downregulated by R. intestinalis treatment in both serum and brain tissue, while Iba-1 expression was reduced in treated rats. CONCLUSIONS: The administration of R. intestinalis contributes to restoration of the gut microbiota, promoting colon repair and the recovery of gastrointestinal function. These alterations are accompanied by the relief of depressive-like behaviors through a process modulated by the neuronal network and the regulation of inflammation by the gut-brain axis.