Host Physiology Research Articles

Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice

BackgroundRecent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored. ObjectiveThis study investigates the impact of Bifidobacterium breve UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy. MethodsGerm-free pregnant mice were colonized with or without B. breve UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways. ResultsMaternal colonization with B. breve resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-β-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function. ConclusionsThe presence of maternal B. breve during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that Bifidobacterium could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions.

The Influence of Environmental Conditions and Coinfection by Blood-Feeding Parasites on Red Blood Cell Physiology of an Ectothermic Host.

AbstractVector-borne blood parasites cause myriad sublethal effects and can even be deadly to endotherms, but far less is known about their impacts on ectothermic hosts. Moreover, the pathologies documented in endotherms are generally linked to infection by blood parasites rather than by their vectors. Here, we measured hematocrit, hemoglobin, and relative proportions of immature red blood cells to evaluate the physiological effects of two blood-feeding parasites and coinfection on ectothermic hosts, differentiating among pathological responses, extrinsic factors, and natural variations. We investigated a population of wild eastern hellbender salamanders (Cryptobranchus alleganiensis), which harbor leeches (Placobdella appalachiensis) that transmit blood parasites (Trypanosoma spp.) to their hosts, often resulting in coinfection. We observed seasonal changes in host hematology corresponding to water temperature and demonstrated their ability to modulate hematological parameters in response to acute stress. We reveal seasonal relationships between parasite dynamics and host physiology, in which peak parasitemia occurred when hosts had seasonally high hematocrit and hemoglobin concentrations. We found that coinfected individuals expressed symptoms of anemia, including a regenerative response to depletion of their red blood cells. We also documented a more pronounced pathological response to leech vectors than to the trypanosomes they transmit. Our research underscores the complex interactions between host physiology, multiple parasites, and environmental factors and highlights the pathologies associated with the vector in coinfections. Given the contributions of climate change and disease in the rapid global decline of ectotherms such as amphibians, our study provides timely foundational insights into multiple factors that influence their red blood cell physiology.

A systematic review and meta-analysis of cortisol levels in Plasmodium infections

Malaria has complex interactions with host physiology, including alterations in cortisol levels. Cortisol, a key hormone in the stress response, is known to be dysregulated in various infectious diseases. This systematic review and meta-analysis aimed to elucidate the relationship between Plasmodium infection and cortisol levels, shedding light on the intricate interplay between the parasite and the host’s endocrine system. The methodological protocol for assessing cortisol levels in malaria patients was registered in PROSPERO (CRD42024496578), a widely recognized international prospective register of systematic reviews. This registration ensures transparency and minimizes the risk of bias in our research. A comprehensive search strategy was employed across major databases, including Embase, PubMed, Scopus, and Medline, to include studies that reported cortisol levels in infected patients. The qualitative synthesis was undertaken to synthesize the difference in cortisol levels between malaria-infected and uninfected individuals. The meta-analysis employed the random effects model in the quantitative synthesis to calculate the effect estimate. The review included a total of 20 studies, with a substantial number conducted in Africa, followed by Asia and South America. Most included studies (13/20, 65%) reported higher cortisol levels in infected patients than in uninfected patients. The meta-analysis confirmed significantly higher cortisol levels in infected patients compared to uninfected individuals (P < 0.0001, standardized mean difference (SMD): 1.354, 95% confidence interval: 0.913 to 1.795, I2: 88.3%, across 15 studies). Notably, the method for cortisol measurement and the type of blood sample used (serum or plasma) were significant moderators in the analysis, indicating that these factors may influence the observed relationship between Plasmodium infection and cortisol levels. The systematic review and meta-analysis confirmed that Plasmodium infection is associated with increased cortisol levels, highlighting the intricate relationship between the disease and the host stress response. These findings underscore the potential of cortisol as a supplementary biomarker for understanding the pathophysiological impact of malaria. By providing insights into the stress-related mechanisms of malaria, this comprehensive understanding can inform future research and potentially enhance disease management and treatment strategies, particularly in regions heavily burdened by malaria.

Neuromicrobiology Comes of Age: The Multifaceted Interactions between the Microbiome and the Nervous System.

The past decade has seen an explosion in our knowledge about the interactions between gut microbiota, the central nervous system, and the immune system. The gut-brain axis has recently gained much attention due to its role in regulating host physiology. This review explores recent findings concerning potential pathways linking the gut-brain axis to the initiation, pathophysiology, and development of neurological disorders. Our objective of this work is to uncover causative factors and pinpoint particular pathways and therapeutic targets that may facilitate the translation of experimental animal research into practical applications for human patients. We highlight three distinct yet interrelated mechanisms: (1) disruptions of both the intestinal and blood-brain barriers, (2) persistent neuroinflammation, and (3) the role of the vagus nerve.

Exploring the influence of fertilization on bacterial community fluctuations in Ulva cultivation

Ulva are green algae known for their biomass accumulation on the coast due to eutrophication. As these algae are able to bioremediate nitrate loadings, they are used as biofilters of enriched waters in aquaculture. Ulva form a holobiont by naturally hosting various microbes, also involved in nitrate metabolism. However, little is known about fluctuations of the Ulva holobiont in fertilized waters over time. We surveyed fluctuations of the bacterial community associated with Ulva lacinulata cultivation, with (enriched, ENR) and without (seawater only, SW) nitrate-based fertilization. Ulva biofilm and cultivation water were regularly collected and contextual parameters (nutrients, temperature, pH) were regularly measured over twelve weeks. Metabarcoding of the 16S rDNA in the biofilm and water compartments revealed that fertilization led to higher alpha-diversity. Diversity patterns indicated that samples clustered together for each compartment in SW or ENR. Fertilization led to a different genus composition in the water after 5 days, and it led to a more even community in the biofilm, from few very dominant genera at the beginning of the experiment to more less dominant genera at the end. The core microbiota in the biofilm common to SW and ENR was mainly composed of genera involved in the host fitness and physiology. Core genera common to SW and ENR in the water were likely beneficiating from the culture conditions. Microbiota's predicted metabolic pathways revealed a heightened capacity for nitrate reduction in ENR. These results may serve as a foundation to understand nitrate loadings impact on Ulva's microbiota in eutrophication conditions.

Dietary fibre optimisation in support of global health.

The human gut microbiota influences its host via multiple molecular pathways, including immune system interactions, the provision of nutrients and regulation of host physiology. Dietary fibre plays a crucial role in maintaining a healthy microbiota as its primary nutrient and energy source. Industrialisation has led to a massive decrease of habitual fibre intake in recent times, and fibre intakes across the world are below the national recommendations. This goes hand in hand with other factors in industrialised societies that may negatively affect the gut microbiota, such as medication and increased hygiene. Non-communicable diseases are on the rise in urbanised societies and the optimisation of dietary fibre intake can help to improve global health and prevent disease. Early life interventions shape the developing microbiota to counteract malnutrition, both in the context of industrialised nations with an overabundance of cheap, highly processed foods, as well as in Low- and Middle-Income Countries (LMICs). Adequate fibre intake should, however, be maintained across the life course to promote health. Here we will discuss the current state of dietary fibre research in the global context and consider different intervention approaches.

The gut microbiota-brain axis in neurological disorders.

Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota-gut-brain axis (MGBA). The MGBA influences the host's nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer's and Parkinson's disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe-based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.

Towards targeting the breast cancer immune microenvironment.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, itis also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.

Gut colonization with antibiotic-resistant Escherichia coli pathobionts leads to disease severity in ulcerative colitis

Escherichia coli is a Gram-negative commensal of human gut. Surprisingly, the role of E. coli in the pathogenesis of ulcerative colitis (UC) has not been explored until now. Human gut microbiota composition and meta-gut resistome were evaluated using metagenomics. Antibiotic susceptibility of E. coli isolates against different class of antibiotics was investigated. Further, the genome sequence analysis of E. coli isolates was performed to gain insight into the antimicrobial resistance (AMR) mechanism and virulence factors. Gut proteome of UC and non-UC was examined to understand the effect of resistant bacteria on host physiology. In UC patients, meta-gut resistome was found to be dominated by AMR genes (829) compared to healthy controls (HC) [518]. The metagenome study revealed a higher prevalence of AMR genes in the rural population (378 in HC; 607 in UC) compared to the urban (340 in HC; 578 in UC). Approximately, 40% of all E. coli isolates were multi-drug resistant (MDR), with higher prevalence in UC (43.75%) compared to HC (33.33%). Up-regulated expression of antimicrobial human proteins (lactotransferrin, azurocidin, cathepsin G, neutrophil elastase, and neutrophil defensin 3) and inflammatory mediator (Protein S100-A9 and Protein S100-A8) suggest microbial infection in UC gut. In addition to the conventional culturomics method, a multi-omics strategy provides deeper insights into the disease etiology, emergence of MDR pathobionts, and their roles in the disruption of the healthy gut environment in UC patients.

Enteropathway: the metabolic pathway database for the human gut microbiota.

The human gut microbiota produces diverse, extensive metabolites that have the potential to affect host physiology. Despite significant efforts to identify metabolic pathways for producing these microbial metabolites, a comprehensive metabolic pathway database for the human gut microbiota is still lacking. Here, we present Enteropathway, a metabolic pathway database that integrates 3269 compounds, 3677 reactions, and 876 modules that were obtained from 1012 manually curated scientific literature. Notably, 698 modules of these modules are new entries and cannot be found in any other databases. The database is accessible from a web application (https://enteropathway.org) that offers a metabolic diagram for graphical visualization of metabolic pathways, a customization interface, and an enrichment analysis feature for highlighting enriched modules on the metabolic diagram. Overall, Enteropathway is a comprehensive reference database that can complement widely used databases, and a tool for visual and statistical analysis in human gut microbiota studies and was designed to help researchers pinpoint new insights into the complex interplay between microbiota and host metabolism.

Exploring the Gut Microbiota: Key Insights Into Its Role in Obesity, Metabolic Syndrome, and Type 2 Diabetes.

The gut microbiota (GM), comprising trillions of microorganisms in the gastrointestinal tract, is a key player in the development of obesity and related metabolic disorders, such as type 2 diabetes (T2D), metabolic syndrome (MS), and cardiovascular diseases. This mini-review delves into the intricate roles and mechanisms of the GM in these conditions, offering insights into potential therapeutic strategies targeting the microbiota. The review elucidates the diversity and development of the human GM, highlighting its pivotal functions in host physiology, including nutrient absorption, immune regulation, and energy metabolism. Studies show that GM dysbiosis is linked to increased energy extraction, altered metabolic pathways, and inflammation, contributing to obesity, MS, and T2D. The interplay between dietary habits and GM composition is explored, underscoring the influence of diet on microbial diversity and metabolic functions. Additionally, the review addresses the impact of common medications and therapeutic interventions like fecal microbiota transplantation on GM composition. The evidence so far advocates for further research to delineate the therapeutic potential of GM modulation in mitigating obesity and metabolic diseases, emphasizing the necessity of clinical trials to establish effective and sustainable treatment protocols.

From vacant to vivid: The nutritional landscape drives infant gut microbiota establishment.

From the moment of birth, the newborn gastrointestinal tract is infiltrated by various bacteria originating from both maternal and environmental sources. These colonizing bacteria form a complex microbiota community that undergoes continuous changes until adulthood and plays an important role in infant health. The maturation of the infant gut microbiota is driven by many factors and follows a distinct patterned trajectory, with specific bacterial taxa establish in the intestine in accordance with developmental milestones as the infant grows. In this review, we highlight how elements such as diet and host physiology select for specific microbial functions and shape the composition of the bacterial community in the large intestine.

Enhancing gut microbiota and microbial function with inulin supplementation in children with obesity.

Gut dysbiosis that resulted from the alteration between host-microbe interaction might worsen obesity-induced systemic inflammation. Gut microbiota manipulation by supplementation of prebiotic inulin may reverse metabolic abnormalities and improve obesity. This study aimed to determine whether inulin supplementation improved intestinal microbiota and microbial functional pathways in children with obesity. Children with obesity whose BMI above median + 2SDs were recruited to a randomized, double-blinded placebo-controlled study. The participants aged 7-15 years were assigned to inulin supplement extracted from Thai Jerusalem artichoke (intervention), maltodextrin (placebo), and dietary fiber advice groups. All participants received similar monthly conventional advice and follow-up for 6 months. Fecal samples were collected for gut microbiome analysis using 16S rRNA sequencing. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was performed to infer microbial functional pathways. One hundred and forty-three children with available taxonomic and functional pathway abundance profiles were evaluated. A significant increase in alpha-diversity was observed in the inulin group. Inulin supplementation substantially enhanced Bifidobacterium, Blautia, Megasphaera, and several butyrate-producing bacteria, including Agathobacter, Eubacterium coprostanoligenes, and Subdoligranulum, compared to the other groups. The inulin group showed a significant difference in functional pathways of proteasome and riboflavin metabolism. These changes correlated with clinical and metabolic outcomes exclusively in the inulin group. Inulin supplementation significantly promoted gut bacterial diversity and improved gut microbiota dysbiosis in children with obesity. The modulation of functional pathways by inulin suggests its potential to establish beneficial interactions between the gut microbiota and host physiology. Inulin supplementation could be a strategic treatment to restore the balance of intestinal microbiota and regulate their functions in childhood obesity.

Neonatal Gut Mycobiome: Immunity, Diversity of Fungal Strains, and Individual and Non-Individual Factors.

The human gastrointestinal ecosystem, or microbiome (comprising the total bacterial genome in an environment), plays a crucial role in influencing host physiology, immune function, metabolism, and the gut-brain axis. While bacteria, fungi, viruses, and archaea are all present in the gastrointestinal ecosystem, research on the human microbiome has predominantly focused on the bacterial component. The colonization of the human intestine by microbes during the first two years of life significantly impacts subsequent composition and diversity, influencing immune system development and long-term health. Early-life exposure to pathogens is crucial for establishing immunological memory and acquired immunity. Factors such as maternal health habits, delivery mode, and breastfeeding duration contribute to gut dysbiosis. Despite fungi's critical role in health, particularly for vulnerable newborns, research on the gut mycobiome in infants and children remains limited. Understanding early-life factors shaping the gut mycobiome and its interactions with other microbial communities is a significant research challenge. This review explores potential factors influencing the gut mycobiome, microbial kingdom interactions, and their connections to health outcomes from childhood to adulthood. We identify gaps in current knowledge and propose future research directions in this complex field.

When the Host Encounters the Cell Wall and Vice Versa.

Peptidoglycan (PGN) and associated surface structures such as secondary polymers and capsules have a central role in the physiology of bacteria. The exoskeletal PGN heteropolymer is the major determinant of cell shape and allows bacteria to withstand cytoplasmic turgor pressure. Thus, its assembly, expansion, and remodeling during cell growth and division need to be highly regulated to avoid compromising cell survival. Similarly, regulation of the assembly impacts bacterial cell shape; distinct shapes enhance fitness in different ecological niches, such as the host. Because bacterial cell wall components, in particular PGN, are exposed to the environment and unique to bacteria, these have been coopted during evolution by eukaryotes to detect bacteria. Furthermore, the essential role of the cell wall in bacterial survival has made PGN an important signaling molecule in the dialog between host and microbes and a target of many host responses. Millions of years of coevolution have resulted in a pivotal role for PGN fragments in shaping host physiology and in establishing a long-lasting symbiosis between microbes and the host. Thus, perturbations of this dialog can lead to pathologies such as chronic inflammatory diseases. Similarly, pathogens have devised sophisticated strategies to manipulate the system to enhance their survival and growth.

Adaptation of turnip mosaic virus to Arabidopsis thaliana involves rewiring of VPg-host proteome interactions.

The outcome of a viral infection depends on a complex interplay between the host physiology and the virus, mediated through numerous protein-protein interactions. In a previous study, we used high-throughput yeast two-hybrid (HT-Y2H) to identify proteins in Arabidopsis thaliana that bind to the proteins encoded by the turnip mosaic virus (TuMV) genome. Furthermore, after experimental evolution of TuMV lineages in plants with mutations in defense-related or proviral genes, most mutations observed in the evolved viruses affected the VPg cistron. Among these mutations, D113G was a convergent mutation selected in many lineages across different plant genotypes, including cpr5-2 with constitutive expression of systemic acquired resistance. In contrast, mutation R118H specifically emerged in the jin1 mutant with affected jasmonate signaling. Using the HT-Y2H system, we analyzed the impact of these two mutations on VPg's interaction with plant proteins. Interestingly, both mutations severely compromised the interaction of VPg with the translation initiation factor eIF(iso)4E, a crucial interactor for potyvirus infection. Moreover, mutation D113G, but not R118H, adversely affected the interaction with RHD1, a zinc-finger homeodomain transcription factor involved in regulating DNA demethylation. Our results suggest that RHD1 enhances plant tolerance to TuMV infection. We also discuss our findings in a broad virus evolution context.

Acute physiological effects on macromolecule digestion following oral ingestion of the enzyme blend Elevase® in individuals that had undergone an ileostomy, but were otherwise healthy-a randomized, double blinded, placebo-controlled exploratory study.

Digestive enzymes can selectively degrade proteins, carbohydrates and lipids; and their supplementation alongside food may accelerate the breakdown of complex food matrices, facilitate greater nutrient absorption, decrease food sensitivities and aid in the management of certain disease states. Several intrinsic and extrinsic factors govern food digestion and for every individual this phenomenon is unique. This study was conducted as a randomized, crossover, placebo-controlled design where each participant served as their own control. This post-hoc analysis investigated the impact of a dietary enzyme supplementation blend known as Elevase® on dietary macromolecule digestion in samples from otherwise healthy participants that had previously undergone a small bowel resection, resulting in an ileostomy (NCT04489810). This is the first time this study-paradigm has been used for the assessment of in vivo dietary breakdown following enzyme supplementation. Arguably, this technique offers superior data when compared to that generated in artificial gut digestion models, preclinical animal models, or indeed conventional clinical studies using stool analyses, as it allows real-time access to samples in situ in the small intestine where the majority of nutritional absorption takes place. It was demonstrated that after 4 h, Elevase® significantly increased monosaccharide levels (predominantly glucose and fructose) in the ileostomy samples taken from the same individuals on the same diet on a different day. In addition, the bile salt taurohyodeoxycholic acid was also increased, suggesting a physiological host response to the macromolecule digestion induced by the enzymatic blend. Overall, these findings suggest Elevase® could accelerate food digestion and potentially increase nutrient availability from the diet.

Indole induces anxiety-like behaviour in mice mediated by brainstem locus coeruleus activation

The gut microbiota produces metabolites that enrich the host metabolome and play a part in host physiology, including brain functions. Yet the biological mediators of this gut-brain signal transduction remain largely unknown. In this study, the possible role of the gut microbiota metabolite indole, originating from tryptophan, was investigated. Oral administration of indole to simulate microbial overproduction of this compound in the gut consistently led to impaired locomotion and anxiety-like behaviour in both C3H/HeN and C57BL/6J mice. By employing c-Fos protein expression mapping in mice, we observed a noticeable increase in brain activation within the dorsal motor nucleus of the vagus nerve (DMX) and the locus coeruleus (LC) regions in a dose-dependent manner. Further immune co-labelling experiments elucidated that the primary cells activated within the LC were tyrosine hydroxylase positive. To delve deeper into the mechanistic aspects, we conducted chemogenetic activation experiments on LC norepinephrine neurons with two doses of clozapine N-oxide (CNO). Low dose of CNO at 0.5 mg/kg induced no change in locomotion but anxiety-like behaviour, while high dose of CNO at 2 mg/kg resulted in locomotion impairment and anxiety-like behaviour. These findings support the neuroactive roles of indole in mediating gut-brain communication. It also highlights the LC as a novel hub in the gut-brain axis, encouraging further investigations.

Aging Modulates the Effect of Dietary Glycemic Index on Gut Microbiota Composition in Mice

BackgroundGut microbiome composition profoundly impacts host physiology and is modulated by several environmental factors, most prominently diet. The composition of gut microbiota changes over the lifespan, particularly during the earliest and latest stages. However, we know less about diet-aging interactions on the gut microbiome. We previously showed that diets with different glycemic indices, based on the ratio of rapidly digested amylopectin to slowly digested amylose, led to altered composition of gut microbiota in male C57BL/6J mice. ObjectivesHere, we examined the role of aging in influencing dietary effects on gut microbiota composition and aimed to identify gut bacterial taxa that respond to diet and aging. MethodsWe studied 3 age groups of male C57BL/6J wild-type mice: young (4 mo), middle-aged (13.5 mo), and old (22 mo), all fed either high glycemic (HG) or low glycemic (LG) diets matched for caloric content and macronutrient composition. Fecal microbiome composition was determined by 16S rDNA metagenomic sequencing and was evaluated for changes in α- and β-diversity and bacterial taxa that change by age, diet, or both. ResultsYoung mice displayed lower α-diversity scores than middle-aged counterparts but exhibited more pronounced differences in β-diversity between diets. In contrast, old mice had slightly lower α-diversity scores than middle-aged mice, with significantly higher β-diversity distances. Within-group variance was lowest in young, LG-fed mice and highest in old, HG-fed mice. Differential abundance analysis revealed taxa associated with both aging and diet. Most differential taxa demonstrated significant interactions between diet and aging. Notably, several members of the Lachnospiraceae family increased with aging and HG diet, whereas taxa from the Bacteroides_H genus increased with the LG diet. Akkermansia muciniphila decreased with aging. ConclusionsThese findings illustrate the complex interplay between diet and aging in shaping the gut microbiota, potentially contributing to age-related disease.

Bacteria are a major determinant of Orsay virus transmission and infection in Caenorhabditis elegans.

The microbiota is a key determinant of the physiology and immunity of animal hosts. The factors governing the transmissibility of viruses between susceptible hosts are incompletely understood. Bacteria serve as food for Caenorhabditis elegans and represent an integral part of the natural environment of C. elegans. We determined the effects of bacteria isolated with C. elegans from its natural environment on the transmission of Orsay virus in C. elegans using quantitative virus transmission and host susceptibility assays. We observed that Ochrobactrum species promoted Orsay virus transmission, whereas Pseudomonas lurida MYb11 attenuated virus transmission relative to the standard laboratory bacterial food Escherichia coli OP50. We found that pathogenic Pseudomonas aeruginosa strains PA01 and PA14 further attenuated virus transmission. We determined that the amount of Orsay virus required to infect 50% of a C. elegans population on P. lurida MYb11 compared with Ochrobactrum vermis MYb71 was dramatically increased, over three orders of magnitude. Host susceptibility was attenuated even further in the presence of P. aeruginosa PA14. Genetic analysis of the determinants of P. aeruginosa required for attenuation of C. elegans susceptibility to Orsay virus infection revealed a role for regulators of quorum sensing. Our data suggest that distinct constituents of the C. elegans microbiota and potential pathogens can have widely divergent effects on Orsay virus transmission, such that associated bacteria can effectively determine host susceptibility versus resistance to viral infection. Our study provides quantitative evidence for a critical role for tripartite host-virus-bacteria interactions in determining the transmissibility of viruses among susceptible hosts.