Engineering the gut microbiota to treat chronic diseases.
Ontology highlight
ABSTRACT:
SUBMITTER: Dosoky NS
PROVIDER: S-EPMC7484268 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.
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Project description:The gut epithelium's large surface area, its direct exposure to ingested nutrients, its vast stem cell population and its immunotolerogenic environment make it an excellent candidate for therapeutic cells to treat diabetes. Thus, several attempts have been made to coax immature gut cells to differentiate into insulin-producing cells by altering the expression patterns of specific transcription factors. Furthermore, because of similarities in enteroendocrine and pancreatic endocrine cell differentiation pathways, other approaches have used genetically engineered enteroendocrine cells to produce insulin in addition to their endogenous secreted hormones. Several studies support the utility of both of these approaches for the treatment of diabetes. Converting a patient's own gut cells into meal-regulated insulin factories in a safe and immunotolerogenic environment is an attractive approach to treat and potentially cure diabetes. Here, we review work on these approaches and indicate where we feel further advancements are required.
| S-EPMC4854511 | biostudies-other
Project description:The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.
| S-EPMC8111113 | biostudies-literature
Project description:Background: Chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD) are prevalent in China. According to traditional Chinese medicine (TCM) theory, damp-heat (DH) syndrome is common in chronic liver disease. However, the biological characteristics related to quantitative diagnosis remain to be determined. This study aimed to identify the consistent alterations in the gut microbiota associated with DH syndrome in patients with CHB or NAFLD. Methods: A total of 405 individuals were recruited, of which 146 were participants who met the consistent TCM diagnosis by three senior TCM physicians and were typical syndromes. All participants were required to provide fresh stool and serum samples. The gut microbiota was assessed by fecal 16S rRNA gene sequencing, and the serum metabolite profiles of participants were quantified by an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system. DH syndrome-related bacteria taxa were identified based on the 146 individuals with typical syndromes and validated in all 405 volunteers. Results: The results showed that CHB and NAFLD patients with typical TCM DH syndrome had consistently elevated serum total bile acid (TBA) levels. Significant alterations in microbial community were observed according to TCM syndromes identification. A total of 870 microbial operational taxonomic units and 21 serum metabolites showed the same variation trends in both the CHB and NAFLD DH syndrome groups. The functional analysis predicts consistent dysregulation of bile acid metabolism. Five genera (Agathobacter, Dorea, Lachnospiraceae_NC2004_group, Subdoligranulum, and unclassified_c__Clostridia) significantly decreased in abundance in patients with DH syndrome. We utilize these five genera combined with TBA to construct a random forest classifier model to predict TCM diagnosis. The diagnostic receiver-operator characteristic (ROC) areas for DH syndrome were 0.818 and 0.791 in internal tenfold cross-validation and the test set based on all 405 individuals, respectively. Conclusion: There are common signatures of gut microbiota associated with DH syndrome in patients with different chronic liver diseases. Serum TBA combined with DH-related genera provides a good diagnostic potential for DH syndrome in chronic liver disease.
| S-EPMC9712756 | biostudies-literature
Project description:Gut microbiota is a community of microorganisms that reside in the gastrointestinal tract. An increasing number of studies has demonstrated that the gut-liver axis plays a critical role in liver homeostasis. Dysbiosis of gut microbiota can cause liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Preclinical and clinical investigations have substantiated that the metabolites and other molecules derived from gut microbiota and diet interaction function as mediators to cause liver fibrosis, cirrhosis, and final cancer. This effect has been demonstrated to be associated with dysregulation of intrahepatic immunity and liver metabolism. Targeting these findings have led to the development of novel preventive and therapeutic strategies. Here, we review the cellular and molecular mechanisms underlying gut microbiota-mediated impact on liver disease. We also summarize the advancement of gut microbiota-based therapeutic strategies in the control of liver diseases.
| S-EPMC7789060 | biostudies-literature
Project description:Gut dysbiosis is regarded as a pathogenetic factor of nonalcoholic fatty liver disease (NAFLD), but its role in NAFLD persistence is unknown. We investigated the influence of the gut microbiota on persistent NAFLD. This cohort study included 766 subjects with 16S ribosomal RNA (rRNA) gene sequencing data from fecal samples at baseline who underwent repeated health check-up examinations. Fatty liver was determined using ultrasound at baseline and follow-up. Participants were categorized into four groups: none (control), developed, regressed, or persistent NAFLD. The persistent NAFLD group had lower richness compared with the control group. Significant differences were also found in both non-phylogenic and phylogenic beta diversity measures according to NAFLD persistence. Pairwise comparisons indicated that taxa abundance mainly differed between the control and persistent NAFLD groups. A relative high abundance of Fusobacteria and low abundance of genera Oscillospira and Ruminococcus of the family Ruminococcaceae and genus Coprococcus of the family Lachnospiraceae were found in the persistent NAFLD group. Based on the functional predictions, pathways related to primary and secondary bile acid biosynthesis were highly detected in the persistent NAFLD group compared with the control group. These findings support that the composition of the gut microbiome associated with dysregulation of bile acid biosynthetic pathways may contribute to the persistence of NAFLD. This is the first cohort study to demonstrate the influence of microbiota on persistent NAFLD. Our findings may help identify potential targets for therapeutic intervention in NAFLD.
| S-EPMC6722749 | biostudies-literature
Project description:BackgroundNeurological diseases are difficult to diagnose in time, and there is currently a lack of effective predictive methods. Previous studies have indicated that a variety of neurological diseases cause changes in the gut microbiota. Alpha diversity is a major indicator to describe the diversity of the gut microbiota. At present, the relationship between neurological diseases and the alpha diversity of the gut microbiota remains unclear.MethodsWe performed a systematic literature search of Pubmed and Bioproject databases up to January 2021. Six indices were used to measure alpha diversity, including community richness (observed species, Chao1 and ACE), community diversity (Shannon, Simpson), and phylogenetic diversity (PD). Random-effects meta-analyses on the standardized mean difference (SMD) were carried out on the alpha diversity indices. Subgroup analyses were performed to explore the sources of interstudy heterogeneity. Meta-analysis was performed on articles by matching the age, sex, and body mass index (BMI) of the disease group with the control group. Meanwhile, subgroup analysis was performed to control the variability of the sequencing region, platform, geographical region, instrument, and diseases. The area under the curve (AUC) value of the receiver operating characteristic (ROC) curve was calculated to assess the prediction effectiveness of the microbial alpha diversity indices.ResultsWe conducted a meta-analysis of 24 published studies on 16S rRNA gene amplified sequencing of the gut microbiota and neurological diseases from the Pubmed and Bioproject database (patients, n = 1,469; controls, n = 1,289). The pooled estimate demonstrated that there was no significant difference in the alpha diversity between patients and controls (P < 0.05). Alpha diversity decreased only in Parkinson's disease patients, while it increased in anorexia nervosa patients compared to controls. After adjusting for age, sex, BMI, and geographical region, none of the alpha diversity was associated with neurological diseases. In terms of Illumina HiSeq 2000 and the V3-V5 sequencing region, the results showed that alpha diversity increased significantly in comparison with the controls, while decreased in Illumina HiSeq 2500. ROC curves suggested that alpha diversity could be used as a biomarker to predict the AD (Simpson, AUC= 0.769, P = 0.0001), MS (observed species, AUC= 0.737, P = 0.001), schizophrenia (Chao1, AUC = 0.739, P = 0.002).ConclusionsOur review summarized the relationship between alpha diversity of the gut microbiota and neurological diseases. The alpha diversity of gut microbiota could be a promising predictor for AD, schizophrenia, and MS, but not for all neurological diseases.
| S-EPMC9274120 | biostudies-literature
Project description:Purpose: To explore whether chronic alcohol consumption affects sperm quality by inducing changes in the gut microbiota.
2022-12-21 | GSE192522 | GEO
Project description:BackgroundOcular neovascularization is a hallmark of retinal diseases including neovascular age-related macular degeneration and diabetic retinopathy, two leading causes of blindness in adults. Neovascularization is driven by the interaction of soluble vascular endothelial growth factor (VEGF) ligands with transmembrane VEGF receptors (VEGFR), and inhibition of the VEGF pathway has shown tremendous clinical promise. However, anti-VEGF therapies require invasive intravitreal injections at frequent intervals and high doses, and many patients show incomplete responses to current drugs due to the lack of sustained VEGF signaling suppression.MethodsWe synthesized insights from structural biology with molecular engineering technologies to engineer an anti-VEGF antagonist protein. Starting from the clinically approved decoy receptor protein aflibercept, we strategically designed a yeast-displayed mutagenic library of variants and isolated clones with superior VEGF affinity compared to the clinical drug. Our lead engineered protein was expressed in the choroidal space of rat eyes via nonviral gene delivery.ResultsUsing a structure-informed directed evolution approach, we identified multiple promising anti-VEGF antagonist proteins with improved target affinity. Improvements were primarily mediated through reduction in dissociation rate, and structurally significant convergent sequence mutations were identified. Nonviral gene transfer of our engineered antagonist protein demonstrated robust and durable expression in the choroid of treated rats one month post-injection.ConclusionsWe engineered a novel anti-VEGF protein as a new weapon against retinal diseases and demonstrated safe and noninvasive ocular delivery in rats. Furthermore, our structure-guided design approach presents a general strategy for discovery of targeted protein drugs for a vast array of applications.
| S-EPMC7596137 | biostudies-literature
Project description:Background: Chronic constipation, including functional constipation and constipation-type irritable bowel syndrome, is a prevalent, multifactorial gastrointestinal disorder, and its etiology and pathophysiology remain poorly understood. Recently studies using 16S rRNA-based microbiota profiling have demonstrated dysbiosis of gut microbiota in chronic constipation. Aims: To provide an overview of recent studies for microbiota in chronic constipation and treatments for chronic constipation using probiotics, prebiotics, synbiotics, antibiotics and fecal microbiota transplantation (FMT). Methods: PubMed searches were performed up to 1 August 2018 using keywords: "IBS," "IBS-C," "irritable bowel syndrome," "irritable bowel syndrome with constipation," "functional constipation," "chronic constipation" in combination with "gut microbiota," "dysbiosis," "gut microflora" for microbiota in chronic constipation, and in combination with "probiotics," "prebiotics," "synbiotics," "antibiotics," and "fecal microbiota transplantation." Results: The findings of gut microbiota in functional constipation are inconsistent, and currently no consensus exists. Although no clear consensus exists, compared with healthy subjects, IBS-C patients have a lower level of Actinobacteria, including Bifidobacteria, in their fecal samples and a higher level of Bacteroidetes in their mucosa. In most randomized controlled and parallel-group trials, probiotics, prebiotics, synbiotics, antibiotics, and FMT therapy for chronic constipation were effective with few side effects. However, there are many studies in a small number and the types of probiotics are different, it is difficult to evaluate the effect. Conclusions: Evidence indicates that dysbiosis of gut microbiota may contribute to functional constipation and constipation-type irritable bowel syndrome. Targeting treatments for the dysbiosis of constipation by probiotics, prebiotics, synbiotics, antibiotics, and FMT may be a new option, especially for refractory constipation to conventional therapies.
| S-EPMC6379309 | biostudies-literature