Martin-Nuez GM, Cornejo-Pareja I, Clemente-Postigo M, Tinahones FJ. Fecal pellets were suspended in the assay buffer provided at a concentration of 1 mg/10 l and centrifuged at 13,000 g for 10 minutes at room temperature to remove insoluble material. Walser M, Bodenlos LJ. Herein, recent evidences supporting the role of gut microbiome in obesity and the current therapies designed to engineer gut microbiome for treatment of obesity will be reviewed. PMC A commercial CO2 source (Airgas) was used as the standard. An official website of the United States government. By taking advantage of the minimal urease activity in ASF, we provide evidence that reprogramming the gut microbiota can lead to lower fecal ammonia levels and mitigate the morbidity and mortality associated with liver damage. The human gut microbiome is a diverse and individualised aggregate of trillions of archaea, fungi, yeasts, viruses, bacteriophages and predominantly bacteria from four main bacterial phyla: Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes.Gaining insight into these microbes has allowed for a deeper understanding of disease onset and progression, and consequently the . Rows indicate bacterial lineages as annotated on the left. Epub 2018 Dec 16. Studies have shown that the ecological dynamics of the. 2021 Nov 1;4(1):1246. doi: 10.1038/s42003-021-02784-w. Nutrients. and transmitted securely. A. As the mouse navigated the maze, each arm entry was noted. By understanding and incorporating the effects of individual dietary components on microbial metabolic output and host physiology, we examine the potential for diet-based therapies for autoimmune disease prevention and treatment. While promising, studies of probiotic therapies in humans described to date have suffered from methodological limitations, did not document long-term effects, and showed consistently minimal effects on outcome, motivating efforts to engineer more resilient and effective bacterial communities. 8600 Rockville Pike Over the last decade, gut microbiome has emerged as an important contributor to the pathogenesis of obesity. Over the last decade, gut microbiome has emerged as an important contributor to the pathogenesis . The new community persisted over the long term, as ASF-transplanted mice showed low fecal ammonia levels for over 1 year in a specific pathogenfree (SPF) housing facility (data not shown). The https:// ensures that you are connecting to the Over time, the Parabacteroides and environmental Firmicutes established a new steady state approximating the composition of conventional microbiota in humans and mice (40, 41, 49), possibly involving a syntrophic relationship between these lineages (50). In each of these 3 groups, Parabacteroides (ASF519) remained the dominant taxon. State-of-art knowledge is presented here on biomaterial technologies that facilitate the study, analysis, and manipulation of the gut microbiome, including intestinal organoids, guton-chip models, hydrogels for spatial mapping of gut microbiome compositions, microbiome biosensors, and oral bacteria delivery systems. At the end of the timed trial (8 minutes), total arm entries were summed and spontaneous alternations determined by the following formula: percentage of spontaneous alternations = [(number of alternations)/(total arm entries 2)] 100. Studying the Microbiome. Penn Medicine researchers have singled out a bacterial enzyme behind an imbalance in the gut microbiome linked to Crohn's disease. Mucispirillum schaedleri (ASF457) and Ruminococcaceae (ASF500) also appeared early on. Hildebrandt MA, et al. Alexander T, Thomas K, Cherian A. This 'microbiome gene therapy' approach offers a number of advantages. The measurement of isotopic abundance in [13C]urea in plasma involves the elimination of CO2 from the sample and the subsequent conversion of urea to CO2 with commercially available urease (59). A major cause of morbidity and mortality associated with acute liver injury is the development of HE. Systemic ammonia levels are elevated in patients with liver injury, chronic liver disease, or urea cycle defects, whose hepatic abnormalities prevent the normal processing of ammonia delivered to the liver from the intestinal tract. Holecek M. Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy. doi: 10.1016/j.heliyon.2022.e10911. Crit Rev Food Sci Nutr. Persistence of the transplanted ASF community was quantified using segmental regression, plotting time against the proportion of ASF in each sample (Figure 3A). Online ahead of print. Gut-brain-axis harbingered the birth of a new tool, since the reporting of influence of gut microbiome (GM) on the brain. Actual Study Start Date : October 11, 2017. nov. and Parabacteroides merdae comb. The food we eat, medications, exercise, sleep and stress all affect the gut microbiome and can cause it to become disrupted, leading to many diseases such as obesity, gut problems and even Alzheimer's. DNA bar coding and pyrosequencing to identify rare HIV drug resistance mutations. Parabacteroides (ASF519) was the predominant lineage present in pellets. PEG was used in our gut-cleansing protocol, because the use of a purgative will likely be necessary to reduce bacterial load in the human intestinal tract due to high biomass. official website and that any information you provide is encrypted The .gov means its official. University of Pennsylvania School of Medicine. Endocrinol. The application of modulatory, additive, or subtractive gene modifications will allow unprecedented insight into host-microbiome associations and promote the development of microbiome-based therapeutics. No urease genes were identified in the predominant Parabacteroides ASF519. 2021 Dec 4;11(12):1830. doi: 10.3390/biom11121830. A low-carbohydrate, high-fat ketogenic diet (KD) can help to treat refractory epilepsy, a condition that affects . Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota in humans and mice. Microbiome engineering seeks to alter the composition or activity of complex microbial populations, including the one inhabiting the human gut. Bethesda, MD 20894, Web Policies sharing sensitive information, make sure youre on a federal Rev. Nat. Official Title: Engineering Gut Microbiome to Target Breast Cancer. It was certainly one of the main reasons for me and for many of my colleagues, why we decided to study molecular biology. The 80%90% survival rates were similar between the 2 groups at the lower TAA dose (Supplemental Figure 3B). Moeller (2021) Genome Biology and Evolution 13 evab156 Herein, recent evidences supporting the role of gut microbiome in obesity and the current therapies designed to engineer gut microbiome for treatment of obesity will be reviewed. government site. In fact, the Penn and CHOP team are currently conducting a therapeutic clinical study in patients with refractory Crohn's disease using a strategy based on data from this study that focuses on deeply altering the gut microbiota. Progression of time is indicated by a gray arrow. Please enable it to take advantage of the complete set of features! "The outcomes of this study and the analysis of collected biospecimens will be an important first step in building a technology platform to engineer a beneficial composition of the gut microbiota for the treatment of inflammatory bowel diseases," Wu said. The ASF community did not fully exclude other taxa. sunzhihong78@163.com. Micro-organisms are present in great numbers within and upon the human body, throughout the environment, and are critical for industrial biomanufacturing. The development and testing of novel hypotheses integrating the molecular, ecological, and evolutionary dynamics within complex environments such as the gut during surgical injury hold real promise for accelerating our . (A) Urease activity in the feces of a conventionally housed mouse versus a mouse treated with ABX and a mouse colonized with ASF. Hampel H, Bynum G, Zamora E, El-Serag H. Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. An imbalance in the gut microbiome -- more "bad" bacteria than "good" -- is known as dysbiosis, which is caused by environmental stressors, such as intestinal inflammation, antibiotics, or diet. Summary: The gut microbiome is able to communicate with the central nervous system via the gut-brain axis. In the low-dose TAA acute liver injury model, mice were given a single dose of TAA at 300 mg/kg by i.p. A possible lack of urease genes in many of the Clostridium taxa that accumulated after transplantation may explain the persistently reduced urease activity, although we cannot exclude other mechanisms, since the regulation of urease enzymatic activity is known to be complex (6). Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. "Because it's a single enzyme that is involved in this process, it might be a targetable solution," said the study's senior author, Gary D. Wu, MD, associate chief for research in the division of Gastroenterology at the Perelman School of Medicine at the University of Pennsylvania. Microbiome engineering holds great promise because of advances in the field of synthetic biology, which strives to create and rewire biological organisms so they perform desired tasks.. 2018 Jan 8;360:j5145. As in humans, bacteria belonging to the Bacteroides genus were dominant taxa in conventionally housed mice (24, 25). Lemon KP, Armitage GC, Relman DA, Fischbach MA. eCollection 2021. Mice in the high-dose TAA acute liver injury model were given a single i.p. Willing BP, Vacharaksa A, Croxen M, Thanachayanont T, Finlay BB. In a series of human and mouse studies, the researchers discovered that a type of "bad" bacteria known as Proteobacteria feeding on urea, a waste product that can end up back in the colon, played an important role in the development of dysbiosis. Modulating the gut microenvironment as a treatment strategy for irritable bowel syndrome: a narrative review, Microbial lactate utilisation and the stability of the gut microbiome, Involvement of microbiota and short-chain fatty acids on non-alcoholic steatohepatitis when induced by feeding a hypercaloric diet rich in saturated fat and fructose, Higher total faecal short-chain fatty acid concentrations correlate with increasing proportions of butyrate and decreasing proportions of branched-chain fatty acids across multiple human studies, The microbiome in adult acute appendicitis. The Y maze test was conducted to assess the rodents memory and spatial learning (60). Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function. This finding was also seen in the setting of chronic liver injury in mice transplanted 3 weeks prior to the chronic delivery of TAA at low, escalating doses for 7 weeks (Figure 6B). government site. Antibiotics (ABX) traditionally used to treat HE, including aminoglycosides and metronidazole, are limited by side effects and concerns for safety including ototoxicity, nephrotoxicity, and peripheral neuropathy (9, 10). There is evidence that the consumption of commercial food products for children is highly prevalent in the world, surpassing the consumption of homemade food We need to act now to limit increasing global temperatures by reducing greenhouse gas emissions to meet global targets set out in the Paris Agreement. 3Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Go to My account > My alerts to manage your alert preferences. In January 2019, the Wang Lab at Columbia University developed one such platform called Metagenomic Alteration of Gut Microbiome by In situ Conjugation (MAGIC) to genetically manipulate complex microbial communities in their native habitat. Dollive S, et al. DNA was isolated from stool as previously described (46, 55). In this Perspective, we consolidate knowledge on diet-microbiome interactions in local inflammation, gut microbiota imbalance and host immune dysregulation. Adv Nutr. Obesity is a complex, multifactorial disease that is increasing in prevalence despite extensive research and efforts to curb it. Epub 2020 Mar 10. While the field of microbiome research is still in its infancy, growing engineering efforts are emerging to enable new studies in the microbiome and to rapidly translate these findings to microbiome-based interventions. doi:10.1172/JCI79214. The inception of the Human Microbiome Project (HMP) 8 has greatly advanced the metagenomics characterization of the microbiota in the human body, particularly those of gut, oral, skin, urogenital and lung/nasal origin, hence the HMP has facilitated identification of factors that differentiate healthy and diseased microbiota. Introduction. Careers. That led the researchers to track nitrogen metabolism activity in the mouse models to help reveal mechanisms that might be targets for the treatment of disease. Members of the Bacteroidetes phylum did not recolonize after ASF transplantation, suggesting that ASF519, a member of the closely related Parabacteroides genus, may have occupied niches available to this group. Recent evidences supporting the role of gut microbiome in obesity and the current therapies designed to engineer gut microbiome for treatment of obesity will be reviewed. (2017, November 15). An individual's microbiome is quite stable over time, but there is variability at the extremes of age and among different individuals. 2020 Jun;35(3):406-416. doi: 10.1002/ncp.10489. The gut microbiome has important effects on human health, but its significance to the human aging process is unclear, the authors noted. The application of modulatory, additive, or subtractive gene modifications will allow unprecedented insight into host-microbiome associations and promote the development of microbiome-based therapeutics. Collaboration NCDRF, Lancet 2016, 387, 1377. Segmented regression analysis showed 2 phases, indicating a slow decline in the ASF proportion up to about day 30, followed by establishment of a new steady state consisting of approximately 40% ASF lineages. Epub 2020 Apr 22. Analysis of the Relationship between Gut Flora Levels in Childhood Obese Population and Normal Healthy Population Based on Machine Learning. Increasing evidence suggests that the gut microbiome lies at the core of many age-associated changes, including immune system dysregulation and susceptibility to diseases. HHS Vulnerability Disclosure, Help Clipboard, Search History, and several other advanced features are temporarily unavailable. Have any problems using the site? Hecht GA, et al. Microbiome manipulation, then, creates a staggering number of exciting potential medical applications. In this module, we will dive into the fundamentals of how we study the human microbiome. Two ASF members contained urease genes, ASF492 and ASF361, but both were minor members of the community after transplantation (Figure 2). Rev. | Find, read and cite all the research . Mechanistic and therapeutic opportunities to preserve the microbiome and constrain the pathobiome: toward ecosystem engineering as a strategy for sepsis prevention. Riordan SM, Williams R. Treatment of hepatic encephalopathy. To investigate the role of nitrogen metabolism in dysbiosis, the researchers performed a metabolomic analysis characterizing small molecules in fecal samples from 90 patients with Crohn's disease from the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiota Composition (PLEASE) study and 26 healthy children. Clipboard, Search History, and several other advanced features are temporarily unavailable. The air was purged into a trap containing 2.5 ml of 0.2 M benzethonium hydroxide in methanol (catalog 82156; Sigma-Aldrich), and 14CO2 activity was quantified by liquid scintillation counting. To exclude the possibility that ASF transplantation directly reduced liver injury, we measured plasma alanine aminotransferase (ALT) and quantified histologic evidence of hepatocyte necrosis (Supplementary Figure 4, A and B). while in previous years much of the work on gut-brain communication concentrated on digestive function and satiety (1), recent research has taken a look at cognitive, psychological and neurological effects of gut-to-brain / brain-to-gut communication. Obesity is a complex, multifactorial disease that is increasing in prevalence despite extensive research and efforts to curb it. First, by editing species that already have established long-term colonization, the genetically altered bacteria will likely be retained in the gut for much longer than exogenously dosed bacteria, possibly achieving stable engraftment. 1Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Microbial modulation of the gut microbiome for treating autoimmune diseases. The groups studied are indicated at the top of the heatmap and include (from the left) conventional mice that were gavaged with ASF stool without preparation (Conventional + ASF gavage); mice that were ASF colonized from birth, then transferred to a nonsterile SPF facility (ASF-colonized); mice that were germ-free, then gavaged with ASF (Germ-free + ASF gavage); and conventional mice that were prepared with ABX and PEG treatment, then gavaged with ASF (Prepared host + ASF gavage). Testing. The gut microbiome It is composed of a complex ecosystem (microbiota) composed of 10*12 to 10*14, i.e. Rifaximin treatment in hepatic encephalopathy. Industrialized Foods Why can it be a risky option in food introduction? official website and that any information you provide is encrypted Over a 4-week monitoring period, ASF was partially displaced by selective colonization with environmental Firmicutes, reaching a new steady state, but fecal ammonia levels remained low. We found that ASF is low in urease activity, making it useful for the studies of metabolic engineering described here. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Herein, we review the evidence that . Front Endocrinol (Lausanne). Faust K, et al. The emerging field of microbiome engineering is in its infancy and faces several challenges . -. Figure 3: Possible mechanisms by which metabolites produced by the gut microbiota could influence the development or progression of metastasis.Potential sites of interaction include: 1) establishment of a premetastatic niche that is favorable to the growth of the metastatic cancer cells, 2) triggering a break from dormancy, 3) promotion of an interaction between the tumor and the . With an estimated 100 trillion microorganisms, the gut is an extraordinarily complex system of microbe-microbe and microbe-host interactions. Bethesda, MD 20894, Web Policies Incorporation of urea and ammonia nitrogen into ileal and fecal microbial proteins and plasma free amino acids in normal men and ileostomates. Gut Microbiome. Lozupone C, Knight R. UniFrac: a new phylogenetic method for comparing microbial communities. The human gut phageome: origins and roles in the human gut microbiome. Gut Microbiome in Ketogenic Diet Protects against Epileptic Seizures. The urease-positive E. coli also exacerbated colitis in the mice. Effect of three antibacterial drugs in lowering blood & stool ammonia production in hepatic encephalopathy. HHS Vulnerability Disclosure, Help -, Bach, J. F. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. No high-quality read pairs mapped concordantly to strain ASF360. Bass N, et al. Future mental health therapies may involve manipulating the bacteria in the gut microbiome. The 16S rRNA gene copy number was reduced by approximately 4 logs within 72 hours of oral ABX initiation (P < 0.0001 for days 0, 1, and 2 compared with the mean of days 515), then returned to baseline 5 days after discontinuing ABX (Figure 1C; P = 0.36 for comparison of ABX versus control at day 21), paralleling previous studies (22, 23). In this experiment, mice were allowed to habituate to the testing room, where there were no overt visual cues, for 30 minutes prior to testing. Transplantation of ASF into prepared hosts led to a reduction in fecal urease activity lasting for at least 80 days (Figure 5C). eCollection 2022. Engineering the Gut Microbiome for Treatment of Obesity: A Review of Current Understanding and Progress Obesity is a complex, multifactorial disease that is increasing in prevalence despite extensive research and efforts to curb it. Lau RI, Zhang F, Liu Q, Su Q, Chan FKL, Ng SC. 2018 Oct;12(10):985-996. doi: 10.1080/17474124.2018.1517044. Immunol. University of Pennsylvania School of Medicine. Diversity of the human intestinal microbial flora. Gut microbiome and aging nexus and underlying mechanism . n = 10 for ASF-colonized. Fasting induced substantial and significant changes in the microbiome and immune cells. An imbalance of gut bacteria has been associated with mental health disorders, including depression, anxiety and schizophrenia. Here, we engineered murine gut microbiota to reduce urease activity. 2019, 15, 288. Nevertheless, the reduction in fecal ammonia levels compared with those at baseline remained significant for several months, even in mice on a nonirradiated diet (Figure 5D). Researchers previously showed pretreating mice with antibiotics (vancomycin and neomycin) and polyethylene glycol (PEG), an intestinal purging agent used by patients in preparation for a colonoscopy, significantly reduced the bacterial load enough to create an opportunity for a newly introduced bacterial community to establish themselves. The engineered gut community was tested in thioacetamide (TAA) models of acute and chronic liver injury (Figure 1A), in which we demonstrate that it reduced fecal ammonia levels, mortality, and neurobehavioral deficits. Clin Exp Immunol. MeSH "This award affirms the incredible ingenuity in Tagbo's research. Here we devised an approach, metagenomic alteration of gut microbiome by in situ conjugation (MAGIC), to genetically modify gut microbiota in their native habitat by engineering the. Fecal ammonia levels were reduced in mice transplanted with ASF compared with those with normal microbiota (Supplemental Figure 3C). Shotgun metagenomic data were collected using the TruSeq library preparation method and a HiSeq instrument (both from Illumina). www.sciencedaily.com/releases/2017/11/171115144142.htm (accessed November 7, 2022). After approximately 2 months under nonsterile conditions, ASF519 remained the dominant taxon, and non-ASF taxa accounted for almost half of the sequence reads. Immunol. Simple Energy Balance or Microbiome for Childhood Obesity Prevention? Or view hourly updated newsfeeds in your RSS reader: Keep up to date with the latest news from ScienceDaily via social networks: Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Sakamoto M, Benno Y. Reclassification of Bacteroides distasonis, Bacteroides goldsteinii and Bacteroides merdae as Parabacteroides distasonis gen. nov., comb. Epub 2022 Feb 14. 6 Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China. The novel community assembled after 30 days had low urease activity, even though new lineages became established in addition to ASF (Figure 2). Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Several Firmicutes lineages did colonize over time, including lineages annotated as Oscillibacter, Clostridium, and other Firmicutes (mostly of the order Clostridiales). Miranda AS, et al. Nicaise C, et al. 2022 Oct 3;8(10):e10911. ASF is acknowledged to be an innocuous bacterial consortium in mice with beneficial effects on immune tolerance (18). Fecal pellets were collected for bacterial taxonomic and biochemical analyses at the time points indicated in the figures (Figure 1C, Figures 24, Figure 5, A, C, and D, Supplemental Figure 1, Supplemental Figure 2, and Supplemental Figure 3, A and C). Compared with control mice, prepared/ASF mice demonstrated markedly reduced mortality rates that were maintained over the 7-week period during which hepatic fibrosis developed in both groups (refs. Over time, ASF has been maintained in laboratory mice by fecal-oral transmission associated with cohousing in gnotobiotic isolators. da Silva TF, Casarotti SN, de Oliveira GLV, Penna ALB. Control of acute, chronic, and constitutive hyperammonemia by wild-type and genetically engineered Lactobacillus plantarum in rodents. Microbiome manipulation, then, creates a staggering number of exciting potential medical applications. The overall aim is to explore how the mammalian gut microbiome shapes and is shaped by social behaviour, using house mice as a model system. Fischer J, Baldessarini R. False neurotransmitters and hepatic failure. 2015, 11, 465. Zhao H, Wang H, Lu Z, Xu S. Intestinal microflora in patients with liver cirrhosis. Similar results were obtained with pellets from mice treated with oral ABX that reduced the bacterial load by 10,000-fold (Figure 5A). 2Division of Gastroenterology, Hepatology, and Nutrition, The Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. Urea metabolism in man. It was a new technology, exciting and mysterious, just like in one of those Sci-Fi movies. Before Rice Bioengineering researchers are applying advances in Cellular and Molecular Engineering and Synthetic Biology to engineer gut bacteria that diagnose and treat . -, Markle, J. G. M. et al. Crohn's disease is an inflammatory bowel disease that affects nearly one million children and adults in the United States. Before The communities were again dominated by ASF519. These groups were then compared with (a) germ-free mice gavaged with ASF (referred to herein as germ-free/ASF mice); and (b) conventional mice pretreated with ABX and PEG and gavaged with ASF (referred to herein as prepared/ASF mice) (Figure 2, Germ-free + ASF gavage and Prepared host + ASF gavage). 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