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Characterization of microbial community metabolic output is crucial to understanding their functions. Construction of genome-scale metabolic models from metagenome-assembled genomes (MAG) has enabled prediction of metabolite production by microbial communities, yet little is known about their accuracy. Here, we examined the performance of two approaches for metabolite prediction from metagenomes, one that is MAG-guided and another that is taxonomic reference-guided. We applied both on shotgun metagenomics data from human and environmental samples, and validated findings in the human samples using untargeted metabolomics. We found that in human samples, where taxonomic profiling is optimized and reference genomes are readily available, when number of input taxa was normalized, the reference-guided approach predicted more metabolites than the MAG-guided approach. The two approaches showed significant overlap but each identified metabolites not predicted in the other. Pathway enrichment analyses identified significant differences in inferences derived from data based on the approach, highlighting the need for caution in interpretation. In environmental samples, when the number of input taxa was normalized, the reference-guided approach predicted more metabolites than the MAG-guided approach for total metabolites in both sample types and non-redundant metabolites in seawater samples. Nonetheless, as was observed for the human samples, the approaches overlapped substantially but also predicted metabolites not observed in the other. Our findings report on utility of a complementary input to genome-scale metabolic model construction that is less computationally intensive forgoing MAG assembly and refinement, and that can be applied on shallow shotgun sequencing where MAGs cannot be generated.IMPORTANCELittle is known about the accuracy of genome-scale metabolic models (GEMs) of microbial communities despite their influence on inferring community metabolic outputs and culture conditions. The performance of GEMs for metabolite prediction from metagenomes was assessed by applying two approaches on shotgun metagenomics data from human and environmental samples, and validating findings in the human samples using untargeted metabolomics. The performance of the approach was found to be dependent on sample type, but collectively, the reference-guided approach predicted more metabolites than the MAG-guided approach. Despite the differences, the predictions from the approaches overlapped substantially but each identified metabolites not predicted in the other. We found significant differences in biological inferences based on the approach, with some examples of uniquely enriched pathways in one group being invalidated when using the alternative approach, highlighting the need for caution in interpretation of GEMs.
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ABSTRACT: Desai, I, Wewege, MA, Jones, MD, Clifford, BK, Pandit, A, Kaakoush, NO, Simar, D, and Hagstrom, AD. The effect of creatine supplementation on resistance training-based changes to body composition: A systematic review and meta-analysis. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this review was to determine the added effect of creatine supplementation on changes in body composition with resistance training in adults younger than 50 years. The review protocol was preregistered on the Open Science Framework (osf.io/x48a6/). Our primary outcome was lean body mass (LBM); secondary outcomes were body fat percentage (%) and body fat mass (kg). We performed a random-effects meta-analysis in R using the metafor package. Subgroup analyses were conducted to examine the effects of training status and use of a carbohydrate drink with creatine. We conducted a meta-regression to examine the moderating effect of total training volume. Statistical significance was set at p < 0.05. One thousand six hundred ninety-four records were screened, and 67 full-text articles were assessed for eligibility. Twelve studies were included in the meta-analysis. Fifty-two percentages of the studies had low risk, 41% some concerns, and 7% high risk of bias. Compared with resistance training (RT) alone, creatine supplementation increased LBM by 1.14 kg (95% CI 0.69 to 1.59), and reduced body fat percentage by -0.88% (95% CI -1.66 to -0.11) and body fat mass by -0.73 kg (95% CI -1.34 to -0.11). There were no differences between training status or carbohydrate subgroups. Training volume was not associated with effect size in all outcomes; 7 g or 0.3 g/kg of body mass of creatine per day is likely to increase LBM by 1 kg and reduce fat mass by 0.7 kg more than RT alone. Concurrent carbohydrate ingestion did not enhance the hypertrophy benefits of creatine.
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Host molecular responses to fecal microbiota transplantation (FMT) in ulcerative colitis are not well understood. Here, we profile the human colonic mucosal transcriptome prior to and following FMT or placebo to identify molecules regulated during disease remission. FMT alters the transcriptome above the effect of placebo (n = 75 vs 3 genes, q < 0.05), including modulation of structural, metabolic and inflammatory pathways. This response is attributed to responders with no consistency observed in non-responders. Regulated pathways in responders include tight junctions, calcium signalling and xenobiotic metabolism. Genes significantly regulated longitudinally in responders post-FMT could discriminate them from responders and non-responders at baseline and non-responders post-FMT, with GBP5 and IRF4 downregulation being associated with remission. Female mice with a deletion of GBP5 are more resistant to developing colitis than their wild-type littermates, showing higher colonic IRF4 phosphorylation. The colonic mucosal response discriminates UC remission following FMT, with GBP5 playing a detrimental role in colitis.
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Colitis Ulcerosa , Trasplante de Microbiota Fecal , Animales , Femenino , Humanos , Ratones , Heces , Proteínas de Unión al GTP , Mucosa Intestinal , Resultado del TratamientoRESUMEN
The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer. Mechanistically, Ku70 translocates from the nucleus into the cytoplasm where it binds to cytosolic DNA and interacts with the GTPase Ras and the kinase Raf, forming a tripartite protein complex and docking at Rab5+Rab7+ early-late endosomes. This Ku70-Ras-Raf signalosome activates the MEK-ERK pathways, leading to impaired activation of cell cycle proteins Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. We also identified the domains of Ku70, Ras, and Raf involved in activating the Ku70 signaling pathway. Therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer.
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Neoplasias , Transducción de Señal , Animales , Humanos , Ratones , Proliferación Celular , ADN , Sistema de Señalización de MAP Quinasas , Neoplasias/genéticaRESUMEN
Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.
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SCOPE: The effects of diet cycling on cognition and fecal microbiota are not well understood. METHOD AND RESULTS: Adult male Sprague-Dawley rats were cycled between a high-fat, high-sugar "cafeteria" diet (Caf) and regular chow. The impairment in place recognition memory produced by 16 days of Caf diet was reduced by switching to chow for 11 but not 4 days. Next, rats received 16 days of Caf diet in 2, 4, 8, or 16-day cycles, each separated by 4-day chow cycles. Place recognition memory declined from baseline in all groups and was impaired in the 16- versus 2-day group. Finally, rats received 24 days of Caf diet continuously or in 3-day cycles separated by 2- or 4-day chow cycles. Any Caf diet access impaired cognition and increased adiposity relative to controls, without altering hippocampal gene expression. Place recognition and adiposity were the strongest predictors of global microbiota composition. Overall, diets with higher Caf > chow ratios produced greater spatial memory impairments and larger shifts in gut microbiota species richness and beta diversity. CONCLUSION: Results suggest that diet-induced cognitive deficits worsen in proportion to unhealthy diet exposure, and that shifting to a healthy chow for at least a week is required for recovery under the conditions tested here.
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Dieta , Microbioma Gastrointestinal , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Obesidad/etiología , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , CogniciónRESUMEN
Inflammasome signaling is a central pillar of innate immunity triggering inflammation and cell death in response to microbes and danger signals. Here, we show that two virulence factors from the human bacterial pathogen Clostridium perfringens are nonredundant activators of the NLRP3 inflammasome in mice and humans. C. perfringens lecithinase (also known as phospolipase C) and C. perfringens perfringolysin O induce distinct mechanisms of activation. Lecithinase enters LAMP1+ vesicular structures and induces lysosomal membrane destabilization. Furthermore, lecithinase induces the release of the inflammasome-dependent cytokines IL-1ß and IL-18, and the induction of cell death independently of the pore-forming proteins gasdermin D, MLKL and the cell death effector protein ninjurin-1 or NINJ1. We also show that lecithinase triggers inflammation via the NLRP3 inflammasome in vivo and that pharmacological blockade of NLRP3 using MCC950 partially prevents lecithinase-induced lethality. Together, these findings reveal that lecithinase activates an alternative pathway to induce inflammation during C. perfringens infection and that this mode of action can be similarly exploited for sensing by a single inflammasome.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Clostridium perfringens/metabolismo , Factores de Virulencia , Inflamación , Interleucina-1beta/metabolismo , Factores de Crecimiento Nervioso , Moléculas de Adhesión Celular NeuronalRESUMEN
BACKGROUND: Systemic inflammation has been clearly linked to poorer health outcomes from cancer diagnosis through to survivorship. There is accumulating evidence that exercise can reduce inflammation. However, the optimal intensity of exercise to reduce systemic inflammation is unknown. AIMS: The aim of this randomised crossover study was to identify the difference between high- and low-intensity aerobic exercise on the inflammatory profile of cancer survivors after a single exercise session (acute) and a short training period (six sessions over 2 weeks). METHOD: Participants (n = 20) were randomised to either low- or high-intensity exercise. They underwent 2 weeks of stationary cycling at their assigned intensity and then underwent a 6-week washout period of no exercise before returning to complete 2 weeks of exercise at the remaining intensity. RESULTS: Twenty participants with a mean age of 56.4 (±9.4) years were enrolled and completed the intervention. There was no effect of exercise intensity after a single exercise session. After 2 weeks of training, there was a significant effect of intensity on chemokines CCL2 (mean difference ± SEM; 13.2 pg/mL ± 5.0, p = .04) and CXCL12 (150.3 pg/mL ± 51.8, p = .02), where CCL2 was decreased after low-intensity exercise and CXCL12 decreased after high-intensity exercise. DISCUSSION: Our data suggest that while exercise intensity may impact different cell types in the circulation, both low- and high-intensity exercise can positively modulate inflammatory markers. CONCLUSION: The potential to scale up low-intensity exercise over time is likely to be more broadly applicable and achievable for cancer survivor cohorts while still eliciting beneficial effects on systemic inflammation.
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Supervivientes de Cáncer , Neoplasias , Humanos , Persona de Mediana Edad , Estudios Cruzados , Calidad de Vida , Ejercicio Físico , Inflamación , Neoplasias/terapiaRESUMEN
The negative impact of irradiation or diet on the metabolic and immune profiles of cancer survivors have been previously demonstrated. The gut microbiota plays a critical role in regulating these functions and is highly sensitive to cancer therapies. The aim of this study was to investigate the effect of irradiation and diet on the gut microbiota and metabolic or immune functions. We exposed C57Bl/6J mice to a single dose of 6 Gy radiation and after 5 weeks, fed them a chow or high-fat diet (HFD) for 12 weeks. We characterised their faecal microbiota, metabolic (whole body and adipose tissue) functions, and systemic (multiplex cytokine, chemokine assay, and immune cell profiling) and adipose tissue inflammatory profiles (immune cell profiling). At the end of the study, we observed a compounding effect of irradiation and diet on the metabolic and immune profiles of adipose tissue, with exposed mice fed a HFD displaying a greater inflammatory signature and impaired metabolism. Mice fed a HFD also showed altered microbiota, irrespective of irradiation status. An altered diet may exacerbate the detrimental effects of irradiation on both the metabolic and inflammatory profiles. This could have implications for the diagnosis and prevention of metabolic complications in cancer survivors exposed to radiation.
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Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Disbiosis/metabolismo , Citocinas/farmacología , Inmunidad , Ratones Endogámicos C57BLRESUMEN
Moraxella catarrhalis is an important human respiratory pathogen and a major causative agent of otitis media and chronic obstructive pulmonary disease. Toll-like receptors contribute to, but cannot fully account for, the complexity of the immune response seen in M. catarrhalis infection. Using primary mouse bone marrow-derived macrophages to examine the host response to M. catarrhalis infection, our global transcriptomic and targeted cytokine analyses revealed activation of immune signalling pathways by both membrane-bound and cytosolic pattern-recognition receptors. We show that M. catarrhalis and its outer membrane vesicles or lipooligosaccharide (LOS) can activate the cytosolic innate immune sensor caspase-4/11, gasdermin-D-dependent pyroptosis, and the NLRP3 inflammasome in human and mouse macrophages. This pathway is initiated by type I interferon signalling and guanylate-binding proteins (GBPs). We also show that inflammasomes and GBPs, particularly GBP2, are required for the host defence against M. catarrhalis in mice. Overall, our results reveal an essential role for the interferon-inflammasome axis in cytosolic recognition and immunity against M. catarrhalis, providing new molecular targets that may be used to mitigate pathological inflammation triggered by this pathogen.
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Caspasas , Inflamasomas , Ratones , Humanos , Animales , Caspasas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Moraxella catarrhalis/metabolismo , Proteínas Portadoras , Inmunidad InnataRESUMEN
The pathogenesis of human leukocyte antigen (HLA)-B27-associated diseases such as acute anterior uveitis (AAU) and ankylosing spondylitis (AS) remains poorly understood, though Gram-negative bacteria and subclinical bowel inflammation are strongly implicated. Accumulating evidence from animal models and clinical studies supports several hypotheses, including HLA-B27-dependent dysbiosis, altered intestinal permeability, and molecular mimicry. However, the existing literature is hampered by inadequate studies designed to establish causation or uncover the role of viruses and fungi. Moreover, the unique disease model afforded by AAU to study the gut microbiota has been neglected. This review critically evaluates the current literature and prevailing hypotheses on the link between the gut microbiota and HLA-B27-associated disease. We propose a new potential role for HLA-B27-driven altered antibody responses to gut microbiota in disease pathogenesis and outline recommendations for future well-controlled human studies, focusing on AAU.
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Microbioma Gastrointestinal , Microbiota , Espondilitis Anquilosante , Uveítis Anterior , Animales , Humanos , Antígeno HLA-B27/genética , Uveítis Anterior/complicaciones , Uveítis Anterior/patología , Espondilitis Anquilosante/complicaciones , Enfermedad AgudaRESUMEN
SCOPE: Maternal obesity increases the risk of health complications in children, highlighting the need for effective interventions. A rat model of maternal obesity to examine whether a diet switch intervention could reverse the adverse effects of an unhealthy postweaning diet is used. METHODS AND RESULTS: Male and female offspring born to dams fed standard chow or a high-fat, high-sugar "cafeteria" (Caf) diet are weaned onto chow or Caf diets until 22 weeks of age, when Caf-fed groups are switched to chow for 5 weeks. Adiposity, gut microbiota composition, and place recognition memory are assessed before and after the switch. Body weight and adiposity fall in switched groups but remain significantly higher than chow-fed controls. Nonetheless, the diet switch improves a deficit in place recognition memory observed in Caf-fed groups, increases gut microbiota species richness, and alters ß diversity. Modeling indicate that adiposity most strongly predicts gut microbiota composition before and after the switch. CONCLUSION: Maternal obesity does not alter the effects of switching diet on metabolic, microbial, or cognitive measures. Thus, a healthy diet intervention lead to major shifts in body weight, adiposity, place recognition memory, and gut microbiota composition, with beneficial effects preserved in offspring born to obese dams.
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Microbioma Gastrointestinal , Obesidad Materna , Ratas , Femenino , Animales , Masculino , Embarazo , Humanos , Azúcares , Dieta Saludable , Obesidad Materna/complicaciones , Obesidad/etiología , Obesidad/metabolismo , Peso Corporal , Dieta Alta en Grasa/efectos adversos , CogniciónRESUMEN
Little is known of the relationships among paediatric upper gastrointestinal microbiotas, and the impact of medication use and disease on their diversity. Here, we investigated the diversity of three microbiotas in the upper gastrointestinal tract of paediatric patients in relation to each other and to host factors. Oral, oesophageal and gastric microbiotas from a prospective paediatric cohort (n=54) were profiled using the 16S rRNA gene and ITS2 amplicon sequencing. 16S rRNA gene amplicon sequencing of oesophageal biopsies from a retrospective paediatric cohort (n=96) and shotgun metagenomics data from oesophageal brushings (n=88) were employed for genomic signature validation. Bacterial diversity and composition showed substantial differences across oral, oesophageal and gastric fluid samples that were not replicated for fungi, and the presence of reflux led to increased homogeneity in the bacterial component of these three microbiotas. The oral and oesophageal microbiotas were associated with age, sex, history of oesophageal atresia and presence of oesophageal metaplasia, with the latter characterized by Prevotella enrichment. Proton pump inhibitor use was associated with increased oral bacterial richness in the gastric fluid, and this correlated with increased levels of gastric pro-inflammatory cytokines. Profiling of oesophageal biopsies from a retrospective paediatric cohort confirmed an increased Prevotella prevalence in samples with metaplasia. Analysis of metagenome-derived oesophageal Prevotella melaninogenica genomes identified strain-specific features that were significantly increased in prevalence in samples with metaplasia. Prevotella enrichment is a signature associated with paediatric oesophageal metaplasia, and proton pump inhibitor use substantially alters the paediatric gastric microenvironment.
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Esofagitis Péptica , Microbioma Gastrointestinal , Microbiota , Tracto Gastrointestinal Superior , Bacterias/genética , Niño , Citocinas , Esofagitis Péptica/tratamiento farmacológico , Humanos , Metaplasia/tratamiento farmacológico , Microbiota/genética , Estudios Prospectivos , Inhibidores de la Bomba de Protones/uso terapéutico , ARN Ribosómico 16S/genética , Estudios RetrospectivosRESUMEN
Fecal microbiota transplantation (FMT) is a promising therapeutic approach for microbiota-associated pathologies, but our understanding of the post-FMT microbiome assembly process and its ecological and clinical determinants is incomplete. Here we perform a comprehensive fecal metagenome analysis of 14 FMT trials, involving five pathologies and >250 individuals, and determine the origins of strains in patients after FMT. Independently of the underlying clinical condition, conspecific coexistence of donor and recipient strains after FMT is uncommon and donor strain engraftment is strongly positively correlated with pre-FMT recipient microbiota dysbiosis. Donor strain engraftment was enhanced through antibiotic pretreatment and bowel lavage and dependent on donor and recipient É-diversity; strains from relatively abundant species were more likely and from predicted oral, oxygen-tolerant, and gram-positive species less likely to engraft. We introduce a general mechanistic framework for post-FMT microbiome assembly in alignment with ecological theory, which can guide development of optimized, more targeted, and personalized FMT therapies.
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Infecciones por Clostridium , Microbioma Gastrointestinal , Infecciones por Clostridium/terapia , Disbiosis/terapia , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/genética , Humanos , MetagenómicaRESUMEN
OBJECTIVE: Faecal microbiota transplantation (FMT) has variable efficacy in treating UC. Recently, oral lyophilised FMT was found to induce remission in patients with UC, with one donor having 100% efficacy compared with a second donor (36% efficacy). We characterised differences in the gut microbiota of these two donors with the aim of improving FMT donor selection. DESIGN: Faecal samples from the two donors were collected over a period of 44 (donor 1) or 70 (donor 2) weeks. The microbiome and metabolome were profiled using shotgun metagenomics and untargeted metabolomics RESULTS: Gut microbiome long-term stability was highly evident in the effective donor. Donor microbiota species evenness was a robust feature associated with clinical efficacy across two clinical trials of FMT in UC, leading to increased donor species engraftment in patients. Alpha diversity and beta diversity of donor gut microbiotas significantly differed. 90 bacterial species and one archaeon were differentially abundant between donors, 44 of which were >0.1% in relative abundance. 17/44 species were enriched in the effective donor, 11 of which (64.7%) were assembled into high-quality genomes that were prevalent (≥75% samples) in that donor, and six showed evidence of engraftment in patients. Taxonomic differences between donors translated to substantial microbial functional differences that were validated using metabolomics. CONCLUSION: Donor microbiota stability and species evenness were identified as novel metrics that were associated with therapeutic efficacy in UC, beyond individual microbial species or metabolites. These metrics may represent community resilience that translates to better engraftment in the host. TRIAL REGISTRATION NUMBER: ACTRN12619000611123.
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The gut microbiome has been implicated in polycystic ovary syndrome (PCOS) pathophysiology. PCOS is a disorder with reproductive, endocrine and metabolic irregularities, and several studies report that PCOS is associated with a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, as alterations in macronutrient composition impact the balance of gut microbial communities. This study investigated the interplay between macronutrient balance and PCOS on the gut microbiome of control and dihydrotestosterone (DHT)-induced PCOS-like mice exposed to diets that varied in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha (α) and beta (ß) diversity of the gut microbiota of control and PCOS-like mice. However, α-diversity between control and PCOS-like mice on the same diet did not differ significantly. In contrast, ß-diversity was significantly altered by PCOS pathology. Further analysis identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) with 99.2% similarity to Bacteroides acidifaciens, which is inversely associated with obesity, to be significantly decreased in PCOS-like mice. Additionally, this study investigated the role of the gut microbiome in the development of PCOS traits, whereby PCOS-like mice were transplanted with healthy fecal microbiota from control mice. Although the PCOS gut microbiome shifted toward that of control mice, PCOS traits were not ameliorated. Overall, these findings demonstrate that while diet exerts a stronger influence over gut microbiota diversity than PCOS pathology, overall gut microbiota composition is affected by PCOS pathology.
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Microbioma Gastrointestinal , Síndrome del Ovario Poliquístico , Animales , Dieta , Modelos Animales de Enfermedad , Heces , Femenino , Microbioma Gastrointestinal/fisiología , Humanos , RatonesRESUMEN
Clostridium species are a group of Gram-positive bacteria that cause diseases in humans, such as food poisoning, botulism, and tetanus. Here, we analyzed 10 different Clostridium species and identified that Clostridium septicum, a pathogen that causes sepsis and gas gangrene, activates the mammalian cytosolic inflammasome complex in mice and humans. Mechanistically, we demonstrate that α-toxin secreted by C. septicum binds to glycosylphosphatidylinositol (GPI)-anchored proteins on the host plasma membrane, oligomerizing and forming a membrane pore that is permissive to efflux of magnesium and potassium ions. Efflux of these cytosolic ions triggers the activation of the innate immune sensor NLRP3, inducing activation of caspase-1 and gasdermin D, secretion of the proinflammatory cytokines interleukin-1ß and interleukin-18, pyroptosis, and plasma membrane rupture via ninjurin-1. Furthermore, α-toxin of C. septicum induces rapid inflammasome-mediated lethality in mice and pharmacological inhibition of the NLRP3 inflammasome using MCC950 prevents C. septicum-induced lethality. Overall, our results reveal that cytosolic innate sensing of α-toxin is central to the recognition of C. septicum infection and that therapeutic blockade of the inflammasome pathway may prevent sepsis and death caused by toxin-producing pathogens.
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Toxinas Bacterianas , Proteínas Ligadas a GPI , Inflamasomas , Animales , Toxinas Bacterianas/metabolismo , Clostridium septicum/química , Proteínas Ligadas a GPI/metabolismo , Glicosilfosfatidilinositoles/metabolismo , Inflamasomas/metabolismo , Mamíferos/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR , SepsisRESUMEN
Obesity is a risk factor for endometrial cancer. The aim of this study was to determine whether actively replicating microbiota in the endometrium differ between obese vs. lean and cancer vs. benign states. We performed 16S rRNA amplicon sequencing on endometrial tissues from lean and obese women with and without endometrial cancer, and lean and obese mice. Results displayed human endometrial microbiota clustered into three community types (R = 0.363, p = 0.001). Lactobacillus was dominant in community type 1 (C1) while community type 2 (C2) had high levels of Proteobacteria and more cancer samples when compared to C1 (p = 0.007) and C3 (p = 0.0002). A significant increase in the prevalence of the C2 community type was observed across body mass index and cancer (χ2 = 14.24, p = 0.0002). The relative abundance of Lactobacillus was lower in cancer samples (p = 0.0043), and an OTU with 100% similarity to Lactobacillus iners was enriched in control samples (p = 0.0029). Mouse endometrial microbiota also clustered into three community types (R = 0.419, p = 0.001) which were not influenced by obesity. In conclusion, obesity and cancer are associated with community type prevalence in the human endometrium, and Lactobacillus abundance is associated with normal uterine histologies in humans and mice.