Gastrointestinal Tract Microbiome Research Articles

A phase 1b study to evaluate the efficacy, safety, and pharmacokinetics of an investigational microbiome therapeutic, SER-155, in adults undergoing hematopoietic stem cell transplantation.

TPS7080 Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a rationally designed investigational cultivated microbiome therapeutic, hypothesized to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study evaluating the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods: This study will enroll approximately 70 subjects ≥18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo. A variety of conditioning regimens, donor types, and GVHD-prophylaxis regimens are included. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, participants in both cohorts receive 2 treatment courses (one before and one after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, plus a conditional 3rd treatment course if the subject receives antibiotics. Safety outcomes are followed through 52 weeks post HCT. The primary endpoint is the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Results: Cohort 1 enrollment is complete, with 13 participants receiving SER-155. In December 2022, the Data and Safety Monitoring Committee supported continuation to Cohort 2 enrollment following review of safety data from Cohort 1. Enrollment in Cohort 2 is underway. Conclusions: This Phase 1b study is designed to assess the safety, and clinical efficacy of SER-155 in allogeneic HCT, expanding the clinical experience of microbiome- directed interventions in allogeneic HCT recipients. Clinical trial information: NCT04995653 .

Evidence of a divided nutritive function in rainbow Trout (Oncorhynchus mykiss) midgut and hindgut microbiomes by whole shotgun metagenomic approach

The nutritive role and ecology of gut-dwelling microbes in rainbow trout remain enigmatic. To improve our understanding of the rainbow trout gastrointestinal tract (GIT) microbiome, we performed whole shotgun metagenomic analyses on the assembled contigs from luminal contents from both mid- and hind-GIT regions for taxonomic and functional classifications of fish-fed animal and plant protein dietary sources. Our study revealed that trout respond well to the two diets containing animal and plant protein sources when supplemented with essential amino acids to meet the requirements of the fish. Microbes present were predominantly bacteria (89.9%) and mainly of the phyla Tenericutes, Firmicutes, Fusobacteria, and Proteobacteria. Eukaryotic (8.8%) microbes were mainly from phyla Ascomycota and Basidiomycota, while Archaea (<1%) were also present and predominantly from the phylum Euryarchaeota. Comparisons of genus-level classifications and functional profiles revealed compositional differences in these GIT locations that appear modulated by differences in the dietary treatments. The functional analysis provided evidence of amino acid biosynthesis/catabolism and methane production in the mid-GIT, while in the hind-GIT, proteolytic hydrolysis and butyrate metabolism were expressed in the trout fed with plant protein diet. The animal protein-based diet provided metabolites for microbial protein fermentation in the hind-GIT. Our report highlights and identifies the potential nutritive contributions of GIT microbes to trout and a potentially crucial functional division along the GIT. Finally, the plant-based diet enhanced amino acid catabolism in the midgut section, while the hindgut section supports evidence of methanogen fermentation.

Unveiling the Human Gastrointestinal Tract Microbiome: The Past, Present, and Future of Metagenomics

Over 1014 symbiotic microorganisms are present in a healthy human body and are responsible for the synthesis of vital vitamins and amino acids, mediating cellular pathways and supporting immunity. However, the deregulation of microbial dynamics can provoke diverse human diseases such as diabetes, human cancers, cardiovascular diseases, and neurological disorders. The human gastrointestinal tract constitutes a hospitable environment in which a plethora of microbes, including diverse species of archaea, bacteria, fungi, and microeukaryotes as well as viruses, inhabit. In particular, the gut microbiome is the largest microbiome community in the human body and has drawn for decades the attention of scientists for its significance in medical microbiology. Revolutions in sequencing techniques, including 16S rRNA and ITS amplicon sequencing and whole genome sequencing, facilitate the detection of microbiomes and have opened new vistas in the study of human microbiota. Especially, the flourishing fields of metagenomics and metatranscriptomics aim to detect all genomes and transcriptomes that are retrieved from environmental and human samples. The present review highlights the complexity of the gastrointestinal tract microbiome and deciphers its implication not only in cellular homeostasis but also in human diseases. Finally, a thorough description of the widely used microbiome detection methods is discussed.

Trophic level and proteobacteria abundance drive antibiotic resistance levels in fish from coastal New England

BackgroundThe natural marine environment represents a vast reservoir of antimicrobial resistant bacteria. The wildlife that inhabits this environment plays an important role as the host to these bacteria and in the dissemination of resistance. The relationship between host diet, phylogeny, and trophic level and the microbiome/resistome in marine fish is not fully understood. To further explore this relationship, we utilize shotgun metagenomic sequencing to define the gastrointestinal tract microbiomes of seven different marine vertebrates collected in coastal New England waters.ResultsWe identify inter and intraspecies differences in the gut microbiota of these wild marine fish populations. Furthermore, we find an association between antibiotic resistance genes and host dietary guild, which suggests that higher trophic level organisms have a greater abundance of resistance genes. Additionally, we demonstrate that antibiotic resistance gene burden is positively correlated with Proteobacteria abundance in the microbiome. Lastly, we identify dietary signatures within the gut of these fish and find evidence of possible dietary selection for bacteria with specific carbohydrate utilization potential.ConclusionsThis work establishes a link between host lifestyle/dietary guild, and microbiome composition and the abundance of antibiotic resistance genes within the gastrointestinal tract of marine organisms. We expand the current understanding of marine organism-associated microbial communities and their role as reservoirs of antimicrobial resistance genes.

Gut Microbiome Proteomics in Food Allergies.

Food allergies (FA) have dramatically increased in recent years, particularly in developed countries. It is currently well-established that food tolerance requires the strict maintenance of a specific microbial consortium in the gastrointestinal (GI) tract microbiome as alterations in the gut microbiota can lead to dysbiosis, causing inflammation and pathogenic intestinal conditions that result in the development of FA. Although there is currently not enough knowledge to fully understand how the interactions between gut microbiota, host responses and the environment cause food allergies, recent advances in '-omics' technologies (i.e., proteomics, genomics, metabolomics) and in approaches involving systems biology suggest future headways that would finally allow the scientific understanding of the relationship between gut microbiome and FA. This review summarizes the current knowledge in the field of FA and insights into the future advances that will be achieved by applying proteomic techniques to study the GI tract microbiome in the field of FA and their medical treatment. Metaproteomics, a proteomics experimental approach of great interest in the study of GI tract microbiota, aims to analyze and identify all the proteins in complex environmental microbial communities; with shotgun proteomics, which uses liquid chromatography (LC) for separation and tandem mass spectrometry (MS/MS) for analysis, as it is the most promising technique in this field.

The gastrointestinal microbiome in dairy cattle is constrained by the deterministic driver of the region and the modified effect of diet

BackgroundDairy cattle (Bos taurus), especially Holstein cows, which are the highest-producing dairy animals and are widely bred to provide milk products to humans, rely critically on their associated gastrointestinal tract (GIT) microbiota to digest plant feed. However, the region-specific taxonomic composition and function of the GIT microbiome in dairy cattle and the mechanistic basis for the diet-induced effects remain to be elucidated. ResultsWe collected 120 digesta samples from 10 GIT regions of 12 Holstein cows fed forage- and grain-based diets and characterized their GIT microbiome via functional shotgun metagenomics and the resolution of metagenome-assembled genomes. Our results demonstrated that the GIT microbiome was mainly partitioned into three distinct clusters, four-chambered stomach, small intestine, and large intestine. Moreover, we found that the four-chambered stomach microbiome with the highest diversity had a strong ability to degrade recalcitrant polysaccharide substrates, underpinned by the prevalence of potential cellulosome-­producing and plant-derived polysaccharide utilization loci-encoding consortia. In contrast, the post-gastric intestinal microbiome orchestrated alternative fermentation pathways to adapt to nutrient availability and energy acquisition. Diet shifts selectively modified the metabolic cascades of the microbiome in specific GIT regions, evidenced by the loss of fiber-degrading taxa and increased hydrogen sinks in propionate after grain introduction.ConclusionsOur findings provide new insights into GIT microbial organization and function in dairy cattle by GIT regions and diet regimes, which offers clues for improving animal production and health in the future.4ZJAH2fLvvvrZAThHy4aExVideo

Altered gastrointestinal tract structure and microbiome following cerebral malaria infection.

Cerebral malaria (CM) is the most severe form of malaria with the highest mortality rate and can result in life-long neurological deficits and ongoing comorbidities. Factors contributing to severity of infection and development of CM are not fully elucidated. Recent studies have indicated a key role of the gut microbiome in a range of health conditions that affect the brain, but limited microbiome research has been conducted in the context of malaria. To address this knowledge gap, the impact of CM on the gut microbiome was investigated in mice. C57BL/6J mice were infected with Plasmodium berghei ANKA (PbA) parasites and compared to non-infected controls. Microbial DNA from faecal pellets collected daily for 6-days post-infection were extracted, and microbiome comparisons conducted using 16S rRNA profiling. We identified significant differences in the composition of bacterial communities between the infected and the non-infected groups, including a higher abundance of the genera Akkermansia, Alistipes and Alloprevotella in PbA-infected mice. Furthermore, intestinal samples were collected post-cull for morphological analysis. We determined that the caecal weight was significantly lower, and the small intestine wassignificantly longer in PbA-infected mice than in the non-infected controls. We concluded that changes in microbial community composition were primarily driven by the infection protocol and, to a lesser extent, by the time of infection. Our findings pave the way for a new area of research and novel intervention strategies to modulate the severity of cerebral malaria disease.

Integrated multi-omics of the gastrointestinal microbiome and ruminant host reveals metabolic adaptation underlying early life development

BackgroundThe gastrointestinal tract (GIT) microbiome of ruminants and its metabolic repercussions vastly influence host metabolism and growth. However, a complete understanding of the bidirectional interactions that occur across the host-microbiome axis remains elusive, particularly during the critical development stages at early life. Here, we present an integrative multi-omics approach that simultaneously resolved the taxonomic and functional attributes of microbiota from five GIT regions as well as the metabolic features of the liver, muscle, urine, and serum in sika deer (Cervus nippon) across three key early life stages.ResultsWithin the host, analysis of metabolites over time in serum, urine, and muscle (longissimus lumborum) showed that changes in the fatty acid profile were concurrent with gains in body weight. Additional host transcriptomic and metabolomic analysis revealed that fatty acid β-oxidation and metabolism of tryptophan and branched chain amino acids play important roles in regulating hepatic metabolism. Across the varying regions of the GIT, we demonstrated that a complex and variable community of bacteria, viruses, and archaea colonized the GIT soon after birth, whereas microbial succession was driven by the cooperative networks of hub populations. Furthermore, GIT volatile fatty acid concentrations were marked by increased microbial metabolic pathway abundances linked to mannose (rumen) and amino acids (colon) metabolism. Significant functional shifts were also revealed across varying GIT tissues, which were dominated by host fatty acid metabolism associated with reactive oxygen species in the rumen epithelium, and the intensive immune response in both small and large intestine. Finally, we reveal a possible contributing role of necroptosis and apoptosis in enhancing ileum and colon epithelium development, respectively.ConclusionsOur findings provide a comprehensive view for the involved mechanisms in the context of GIT microbiome and ruminant metabolic growth at early life.5sdAQaaw9Xaw7sGvUGm-9aVideo

Detection of Colistin Sulfate on Piglet Gastrointestinal Tract Microbiome Alterations.

The gut microbiome exerts important functions on host health maintenance, whereas excessive antibiotic use may cause gut flora dysfunction resulting in serious disease and dysbiosis. Colistin is a broad-spectrum antibiotic with serious resistance phenomena. However, it is unclear whether colistin alters the gastrointestinal tract microbiome in piglets. In this study, 16s rDNA-based metagenome analyses were used to assess the effects of colistin on the modification of the piglet microbiome in the stomach, duodenum, jejunum, cecum, and feces. Both α- and β-diversity indices showed that colistin modified microbiome composition in these gastrointestinal areas. In addition, colistin influenced microbiome composition at the phylum and genus levels. At the species level, colistin upregulated Mycoplasma hyorhinis, Chlamydia trachomatis, Lactobacillus agilis, Weissella paramesenteroides, and Lactobacillus salivarius abundance, but downregulated Actinobacillus indolicus, Campylobacter fetus, Glaesserella parasuis, Moraxella pluranimalium, Veillonella caviae, Neisseria dentiae, and Prevotella disiens abundance in stomachs. Colistin-fed piglets showed an increased abundance of Lactobacillus mucosae, Megasphaera elsdenii DSM 20460, Fibrobacter intestinalis, and Unidentified rumen bacterium 12-7, but Megamonas funiformis, Uncultured Enterobacteriaceae bacterium, Actinobacillus porcinus, Uncultured Bacteroidales bacterium, and Uncultured Clostridiaceae bacterium abundance was decreased in the cecum. In feces, colistin promoted Mucispirillum schaedleri, Treponema berlinense, Veillonella magna, Veillonella caviae, and Actinobacillus porcinus abundance when compared with controls. Taken together, colistin modified the microbiome composition of gastrointestinal areas in piglets. This study provides new clinical rationalization strategies for colistin on the maintenance of animal gut balance and human public health.

Evolutionary aspects of gastrointestinal tract microbiome-host interaction underlying gastrointestinal barrier integrity

In the host sustenance and homeostasis, the microbiome is a key component in the functional system. Throughout ontogenetic development, microbiome including that of the gastrointestinal tract (GIT) is the vital factor that ensures not only host functioning, but also its interaction with environment. To uncover the mechanisms underlying GIT microbiome showing a decisive influence on host organism, a systematic approach is needed, because diverse microorganisms are predominantly localized in different parts of the GIT. Recently, a new interdisciplinary direction of science, nanobioinformatics that has been extensively developed considers gene networks as the major object of study representing a coordinated group of genes that functionally account for formation and phenotypic disclosure of various host traits. Here, an important place should be provided to the genetically determined level of the gastrointestinal tract microbiome, its interaction at the level of the host food systems. There have been increasing evidence indicating that the microbiome is directly involved in the pathogenesis of host diseases showing a multi-layered interaction with host metabolic and immune systems. At the same time, the microbial community is unevenly distributed throughout the gastrointestinal tract, and its different portions are variously active while interacting with the host immune system. The architecture of interaction between the microbiome and host cells is extremely complex, and the interaction of individual cells, at the same time, varies greatly. Bacteria colonizing the crypts of the small intestine regulate enterocyte proliferation by affecting DNA replication and gene expression, while bacteria at the tip of the intestinal villi mediate gene expression responsible for metabolism and immune response. Enterocytes and Paneth cells, in turn, regulate the vital activity of the community of microorganisms through the production of polysaccharides (carbohydrates) and antibacterial factors on their surface. Thus, the integrity of the gastrointestinal barrier (GIB) is maintained, which protects the body from infections and inflammation, while violation of its integrity leads to a number of diseases. It has been shown that depending on the dominance of certain types of bacteria the microbiome can maintain or disrupt GIB integrity. The structural and functional GIB integrity is important for body homeostasis. To date, at least 50 proteins have been characterized as being involved in the structural and functional integrability of tight junctions between gastrointestinal tract epithelial cells. The current review comprehensively discusses such issues and presents original research carried out at various facilities of translational biomedicine.

A Phase 1b Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of an Investigational Microbiome Therapeutic, SER-155, in Adults Undergoing Hematopoietic Stem Cell Transplantation

Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT that is currently enrolling at 4 sites. Study Design and Methods: This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table 1; Figure 1). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. In April 2022, the SER-155 Data and Safety Monitoring Committee met as part of a planned review of available safety data from Cohort 1 and supported continuation of Cohort 1 enrollment. Summary: In this Phase 1b study, the feasibility, safety, and clinical efficacy of SER-155 is being assessed in the setting of allogeneic HCT. This trial will add to the expanding clinical experience of microbiome-directed interventions in allogeneic HCT recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The gastrointestinal microbiome of browsing goats (Capra hircus).

Despite the growing interest in the ruminants’ gastrointestinal tract (GIT) microbiomes’ ability to degrade plant materials by animal husbandry and industrial sectors, only a few studies addressed browsing ruminants. The present work describes the taxonomic and functional profile of the bacterial and archaeal communities from five different gastrointestinal sections (rumen, omasum-abomasum, jejunum, cecum and colon) of browsing Capra hircus, by metabarcoding using 16S rRNA genes hypervariable regions. The bacterial communities across the GITs are mainly composed of Bacillota and Bacteroidota. Prevotella was the leading bacterial group found in the stomachs, Romboutsia in the jejuna, and Rikenellaceae_RC9_gut_group, Bacteroides, UCG-010_ge, UCG-005, and Alistipes in large intestines. The archaeal communities in the stomachs and jejuna revealed to be mainly composed of Methanobrevibacter, while in the large intestines its dominance is shared with Methanocorpusculum. Across the GITs, the main metabolic functions were related to carbohydrate, amino acid, and energy metabolisms. Significant differences in the composition and potential biological functions of the bacterial communities were observed among stomachs, jejuna and large intestines. In contrast, significant differences were observed among stomachs and jejuna verse large intestines for archaeal communities. Overall different regions of the GIT are occupied by different microbial communities performing distinct biological functions. A high variety of glycoside hydrolases (GHs) indispensable for degrading plant cell wall materials were predicted to be present in all the GIT sections.

Compositional Dynamics of Gastrointestinal Tract Microbiomes Associated with Dietary Transition and Feeding Cessation in Lake Sturgeon Larvae.

Compromised nutritional conditions associated with dietary transitions and feeding cessation in the wild and during fish aquaculture operations are common and can impact growth and survival. These effects are especially prevalent during early ontogenetic stages. We quantified phenotypic and GI tract microbial community responses with an emphasis on protease-producing bacteria of lake sturgeon (Acipenser fulvescens) larvae, a species of aquacultural and conservational importance. To quantify responses associated with experimental food transition and feeding cessation, we performed a 36-day feeding experiment using two treatments: control and diet transition. However, larvae in the diet transition treatment failed to undergo transition and ceased feeding. Larvae in the diet transition treatment exhibited lower growth (total length and body weight) and survival than control larvae. Treatment had a greater effect than ontogenetic changes on taxonomic composition and diversity of the GI tract microbial community. Proteobacteria dominated the GI tract microbial community of the diet transition larvae whereas Firmicutes dominated the GI tracts of control larvae. Most of the 98 identified protease-producing isolates in both treatments were from genera Pseudomonas and Aeromonas: taxonomic groups that include known fish pathogens. Overall, failing to transition diets affected responses in growth and GI tract microbiome composition and diversity, with the later dysbiosis being an indicator of morbidity and mortality in larval lake sturgeon. Thus, microbiological interrogations can characterize responses to dietary regimes. The results can inform fish culturalists and microbiologists of the importance of dietary practices consistent with the establishment and maintenance of healthy GI tract microbiota and optimal growth during early ontogeny.

Biological aspects of phage therapy versus antibiotics against Salmonella enterica serovar Typhimurium infection of chickens.

Phage therapy is a promising alternative treatment of bacterial infections in human and animals. Nevertheless, despite the appearance of many bacterial strains resistant to antibiotics, these drugs still remain important therapeutics used in human and veterinary medicine. Although experimental phage therapy of infections caused by Salmonella enterica was described previously by many groups, those studies focused solely on effects caused by bacteriophages. Here, we compared the use of phage therapy (employing a cocktail composed of two previously isolated and characterized bacteriophages, vB_SenM-2 and vB_Sen-TO17) and antibiotics (enrofloxacin and colistin) in chickens infected experimentally with S. enterica serovar Typhimurium. We found that the efficacies of both types of therapies (i.e. the use of antibiotics and phage cocktail) were high and very similar to one another when the treatment was applied shortly (one day) after the infection. Under these conditions, S. Typhimurium was quickly eliminated from the gastrointestinal tract (GIT), to the amount not detectable by the used methods. However, later treatment (2 or 4 days after detection of S. Typhimurium in chicken feces) with the phage cocktail was significantly less effective. Bacteriophages remained in the GIT for up to 2-3 weeks, and then were absent in feces and cloaca swabs. Interestingly, both phages could be found in various organs of chickens though with a relatively low abundance. No development of resistance of S. Typhimurium to phages or antibiotics was detected during the experiment. Importantly, although antibiotics significantly changed the GIT microbiome of chickens in a long-term manner, analogous changes caused by phages were transient, and the microbiome normalized a few weeks after the treatment. In conclusion, phage therapy against S. Typhimurium infection in chickens appeared as effective as antibiotic therapy (with either enrofloxacin or colistin), and less invasive than the use the antibiotics as fewer changes in the microbiome were observed.

Comparative genomics of Leuconostoc lactis strains isolated from human gastrointestinal system and fermented foods microbiomes

BackgroundLeuconostoc lactis forms a crucial member of the genus Leuconostoc and has been widely used in the fermentation industry to convert raw material into acidified and flavored products in dairy and plant-based food systems. Since the ecological niches that strains of Ln. lactis being isolated from were truly diverse such as the human gut, dairy, and plant environments, comparative genome analysis studies are needed to better understand the strain differences from a metabolic adaptation point of view across diverse sources of origin. We compared eight Ln. lactis strains of 1.2.28, aa_0143, BIOML-A1, CBA3625, LN19, LN24, WIKIM21, and WiKim40 using bioinformatics to elucidate genomic level characteristics of each strain for better utilization of this species in a broad range of applications in food industry.ResultsPhylogenomic analysis of twenty-nine Ln. lactis strains resulted in nine clades. Whole-genome sequence analysis was performed on eight Ln. lactis strains representing human gastrointestinal tract and fermented foods microbiomes. The findings of the present study are based on comparative genome analysis against the reference Ln. lactis CBA3625 genome. Overall, a ~ 41% of all CDS were conserved between all strains. When the coding sequences were assigned to a function, mobile genetic elements, mainly insertion sequences were carried by all eight strains. All strains except LN24 and WiKim40 harbor at least one intact putative prophage region, and two of the strains contained CRISPR-Cas system. All strains encoded Lactococcin 972 bacteriocin biosynthesis gene clusters except for CBA3625.ConclusionsThe findings in the present study put forth new perspectives on genomics of Ln. lactis via complete genome sequence based comparative analysis and further determination of genomic characteristics. The outcomes of this work could potentially pave the way for developing elements for future strain engineering applications.

Gastrointestinal Tract Microbiome Effect and Role in Disease Development.

In recent years, it has been shown that gastrointestinal microflora has a substantial impact on the development of a large number of chronic diseases. The imbalance in the number or type of microbes in the gastrointestinal tract can lead to diseases and conditions, including autism spectrum disorder, celiac disease, Crohn’s disease, diabetes, and small bowel cancers. This can occur as a result of genetics, alcohol, tobacco, chemotherapeutics, cytostatics, as well as antibiotic overuse. Due to this, essential taxa can be lost, and the host’s metabolism can be severely affected. A less known condition called small intestine bacterial overgrowth (SIBO) can be seen in patients who suffer from hypochlorhydria and small intestine cancers. It is characterized as a state in which the bacterial population in the small intestine exceeds 105–106 organisms/mL. The latest examination methods such as double-balloon enteroscopy and wireless capsule endoscopy have the potential to increase the accuracy and precision of diagnosis and provide better patient care. This review paper aims to summarize the effect of the gastrointestinal environment on chronic disease severity and the development of cancers.

Resistome Analysis of Global Livestock and Soil Microbiomes.

Antimicrobial resistance (AMR) is a serious threat to public health globally; it is estimated that AMR bacteria caused 1.27 million deaths in 2019, and this is set to rise to 10 million deaths annually. Agricultural and soil environments act as antimicrobial resistance gene (ARG) reservoirs, operating as a link between different ecosystems and enabling the mixing and dissemination of resistance genes. Due to the close interactions between humans and agricultural environments, these AMR gene reservoirs are a major risk to both human and animal health. In this study, we aimed to identify the resistance gene reservoirs present in four microbiomes: poultry, ruminant, swine gastrointestinal (GI) tracts coupled with those from soil. This large study brings together every poultry, swine, ruminant, and soil shotgun metagenomic sequence available on the NCBI sequence read archive for the first time. We use the ResFinder database to identify acquired antimicrobial resistance genes in over 5,800 metagenomes. ARGs were diverse and widespread within the metagenomes, with 235, 101, 167, and 182 different resistance genes identified in the poultry, ruminant, swine, and soil microbiomes, respectively. The tetracycline resistance genes were the most widespread in the livestock GI microbiomes, including tet(W)_1, tet(Q)_1, tet(O)_1, and tet(44)_1. The tet(W)_1 resistance gene was found in 99% of livestock GI tract microbiomes, while tet(Q)_1 was identified in 93%, tet(O)_1 in 82%, and finally tet(44)_1 in 69%. Metatranscriptomic analysis confirmed these genes were “real” and expressed in one or more of the livestock GI tract microbiomes, with tet(40)_1 and tet(O)_1 expressed in all three livestock microbiomes. In soil, the most abundant ARG was the oleandomycin resistance gene, ole(B)_1. A total of 55 resistance genes were shared by the four microbiomes, with 11 ARGs actively expressed in two or more microbiomes. By using all available metagenomes we were able to mine a large number of samples and describe resistomes in 37 countries. This study provides a global insight into the diverse and abundant antimicrobial resistance gene reservoirs present in both livestock and soil microbiomes.

Do gastrointestinal microbiomes play a role in bats' unique viral hosting capacity?

Bats are reservoirs for zoonotic viruses, which they tolerate without experiencing disease. Research focused on deciphering mechanisms of virus tolerance in bats has rarely considered the influence of their gastrointestinal tract (GIT) microbiome. In mammals, GIT microbiomes influence infections through their effect on host physiology, immunity, nutrition, and behavior. Bat GIT microbiomes more closely resemble the Proteobacteria-dominated GIT microbiomes of birds than those of other mammals. As an adaptation to flight, bats have rapid GIT transit times which may reduce the stability of their microbiome, constrain nutrient uptake, and affect pathogen exposure and evolution of tolerance mechanisms. Experimental and longitudinal studies are needed to understand the function of bats' GIT microbiomes and their role in modulating viral infection dynamics.

Gut Microbiota and Cardiovascular Disease: Symbiosis Versus Dysbiosis.

The gut microbiome interacts with host physiology through various mechanisms, including the cardiovascular (CV) system. A healthy microbiome has the ability to process and digest complex carbohydrates into short-chain fatty acids (SCFA). These SCFA function as signaling molecules, immune-modulating molecules, and energy sources. However, when the microbiome is altered, it produces gut dysbiosis with overgrowth of certain bacteria that may lead to overproduction of trimethylamine-N-oxide (TMAO) from the metabolism of phosphatidylcholine, choline, and carnitine; dysbiosis also leads to increased intestinal permeability allowing the microbiome-derived lipopolysaccharide (LPS), a bacterial endotoxin, to enter the blood circulation, triggering inflammatory responses. An altered gastrointestinal (GI) tract environment and microbiome- derived metabolites are associated with CV events. Disrupted content and function of the microbiome leading to elevated TMAO and LPS levels, altered bile acid metabolism pathways, and SCFA production are associated with an increased risk of CV diseases (CVD), including atherosclerosis, myocardial infarction, thrombosis, arrhythmias, and stroke. Therapeutic interventions that may favorably influence a dysbiotic GI tract profile and promote a healthy microbiome may benefit the CV system and lead to a reduction of CVD incidence in certain situations. These issues are herein reviewed with a focus on the spectrum of microbiota-related CVD, the mechanisms involved, and the potential use of microbiome modification as a possible therapeutic intervention.

A phase 1b study to evaluate safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing hematopoietic stem cell transplantation to reduce the risk of infection and graft versus host disease (NCT04995653).

TPS7074 Background:In patients undergoing allogeneic hematopoietic stem cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a cultivated investigational microbiome therapeutic rationally designed to improve clinical outcomes in patients undergoing HCT by restoring colonization resistance to pathobionts, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods:This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis of any etiology or active inflammatory bowel disease or total colectomy, transplant using umbilical cord blood or ex vivo T-cell therapy, receipt of fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Clinical trial information: NCT04995653. [Table: see text]