Resident Gut Microbiome Research Articles

Ethanolamine metabolism through two genetically distinct loci enables Klebsiella pneumoniae to bypass nutritional competition in the gut.

Successful microbial colonization of the gastrointestinal (GI) tract hinges on an organism's ability to overcome the intense competition for nutrients in the gut between the host and the resident gut microbiome. Enteric pathogens can exploit ethanolamine (EA) in the gut to bypass nutrient competition. However, Klebsiella pneumoniae (K. pneumoniae) is an asymptomatic gut colonizer and, unlike well-studied enteric pathogens, harbors two genetically distinct ethanolamine utilization (eut) loci. Our investigation uncovered unique roles for each eut locus depending on EA utilization as a carbon or nitrogen source. Murine gut colonization studies demonstrated the necessity of both eut loci in the presence of intact gut microbiota for robust GI colonization by K. pneumoniae. Additionally, while some Escherichia coli gut isolates could metabolize EA, other commensals were incapable, suggesting that EA metabolism likely provides K. pneumoniae a selective advantage in gut colonization. Molecular and bioinformatic analyses unveiled the conservation of two eut loci among K. pneumoniae and a subset of the related taxa in the K. pneumoniae species complex, with the NtrC-RpoN regulatory cascade playing a pivotal role in regulation. These findings identify EA metabolism as a critical driver of K. pneumoniae niche establishment in the gut and propose microbial metabolism as a potential therapeutic avenue to combat K. pneumoniae infections.

Neuroprotection by agmatine: Possible involvement of the gut microbiome?

Agmatine, an endogenous polyamine derived from L-arginine, elicits tremendous multimodal neuromodulant properties. Alterations in agmatinergic signalling are closely linked to the pathogeneses of several brain disorders. Importantly, exogenous agmatine has been shown to act as a potent neuroprotectant in varied pathologies, including brain ageing and associated comorbidities. The antioxidant, anxiolytic, analgesic, antidepressant and memory-enhancing activities of agmatine may derive from its ability to regulate several cellular pathways; including cell metabolism, survival and differentiation, nitric oxide signalling, protein translation, oxidative homeostasis and neurotransmitter signalling. This review briefly discusses mammalian metabolism of agmatine and then proceeds to summarize our current understanding of neuromodulation and neuroprotection mediated by agmatine. Further, the emerging exciting bidirectional links between agmatine and the resident gut microbiome and their implications for brain pathophysiology and ageing are also discussed.

Bacterial clade-specific analysis identifies distinct epithelial responses in inflammatory bowel disease

Abnormal immune responses to the resident gut microbiome can drive inflammatory bowel disease (IBD). Here, we combine high-resolution, culture-based shotgun metagenomic sequencing and analysis with matched host transcriptomics across three intestinal sites (terminal ileum, cecum, rectum) from pediatric IBD (PIBD) patients (n= 58) and matched controls (n= 42) to investigate this relationship. Combining our site-specific approach with bacterial culturing, we establish a cohort-specific bacterial culture collection, comprising 6,620 isolates (170 distinct species, 32 putative novel), cultured from 286 mucosal biopsies. Phylogeny-based, clade-specific metagenomic analysis identifies key, functionally distinct Enterococcus clades associated with either IBD or health. Strain-specific invitro validation demonstrates differences in cell cytotoxicity and inflammatory signaling in intestinal epithelial cells, consistent with the colonic mucosa-specific response measured in patients with IBD. This demonstrates the importance of strain-specific phenotypes and consideration of anatomical sites in exploring the dysregulated host-bacterial interactions in IBD.

The Role of Phytochemicals and Gut Microbiome in Atherosclerosis in Preclinical Mouse Models.

Gut microbiome alterations have recently been linked to many chronic conditions including cardiovascular disease (CVD). There is an interplay between diet and the resident gut microbiome, where the food eaten affects populations of certain microbes. This is important, as different microbes are associated with various pathologies, as they can produce compounds that are disease-promoting or disease-protecting. The Western diet negatively affects the host gut microbiome, ultimately resulting in heightened arterial inflammation and cell phenotype changes as well as plaque accumulation in the arteries. Nutritional interventions including whole foods rich in fiber and phytochemicals as well as isolated compounds including polyphenols and traditional medicinal plants show promise in positively influencing the host gut microbiome to alleviate atherosclerosis. This review investigates the efficacy of a vast array of foods and phytochemicals on host gut microbes and atherosclerotic burden in mice. Reduction in plaque by interventions was associated with increases in bacterial diversity, reduction in the Firmicutes/Bacteroidetes (F/B) ratio, and upregulation of Akkermansia. Upregulation in CYP7 isoform in the liver, ABC transporters, bile acid excretion, and the level of acetic acid, propionic acid, and butyric acid were also noted in several studies reducing plaque. These changes were also associated with attenuated inflammation and oxidative stress. In conclusion, an increase in the abundance of Akkermansia with diets rich in polyphenols, fiber, and grains is likely to reduce plaque burden in patients suffering from CVD.

Harnessing the small intestinal axis to resolve systemic inflammation

This Perspective presents the potential of the Small Intestinal Axis, a sub-division of the Gut-immune Axis, to modulate systemic inflammation based on sensing contents of the gut lumen. Gut mucosal immunity regulates tolerance to food and gut contents and is a significant factor in maintaining systemic homeostasis without compromising immunity to pathogens. This is achieved through anatomical structures and signaling pathways that link the tolerogenic potential of the proximal small intestine to systemic immunity. Non-live preparations of microbes isolated from human small intestinal mucosa, and the extracellular vesicles (EVs) which they shed, can resolve systemic inflammation without systemic exposure after oral delivery. The mechanism involves primary interactions with pattern recognition receptors followed by trafficking of immune cells through mesenteric lymph nodes. This generates in the periphery a population of circulating CD4+ T cells which have regulatory function but an atypical FoxP3- phenotype. There is no modification of the resident gut microbiome. Discoveries using this novel approach of targeting mucosal microbial elements to the tolerogenic proximal regions of the small intestine are revealing some of the mysteries of the relationship between the gut and immune system.

The microbiome of the pelagic tunicate Dolioletta gegenbauri: Apotential link between the grazing and microbial food web.

Bloom-forming gelatinous zooplankton occur circumglobally and significantly influence the structure of pelagic marine food webs and biogeochemical cycling through interactions with microbial communities. During bloom conditions especially, gelatinous zooplankton are keystone taxa that help determine the fate of primary production, nutrient remineralization, and carbon export. Using the pelagic tunicate Dolioletta gegenbauri as a model system for gelatinous zooplankton, we carried out a laboratory-based feeding experiment to investigate the potential ecosystem impacts of doliolid gut microbiomes and microbial communities associated with doliolid faecal pellets and the surrounding seawater. Metabarcoding targeting Bacteria and Archaea 16S rRNA genes/Archaea) and qPCR approaches were used to characterize microbiome assemblages. Comparison between sample types revealed distinct patterns in microbial diversity and biomass that were replicable across experiments. These observations support the hypothesis that through their presence and trophic activity, doliolids influence the structure of pelagic food webs and biogeochemical cycling in subtropical continental shelf systems where tunicate blooms are common. Bacteria associated with starved doliolids (representative of the resident gut microbiome) possessed distinct low-biomass and low-diversity microbial assemblages, suggesting that the doliolid microbiome is optimized to support a detrital trophic mode. Bacterial genera Pseudoalteromomas and Shimia were the most abundant potential core microbiome taxa, similar to patterns observed in other marine invertebrates. Exploratory bioinformatic analyses of predicted functional genes suggest that doliolids, via their interactions with bacterial communities, may affect important biogeochemical processes including nitrogen, sulphur, and organic matter cycling.

Grazing by an endemic atyid shrimp controls microbial communities in the Hawaiian anchialine ecosystem

AbstractAnimals often shape environmental microbial communities, which can in turn influence animal gut microbiomes. Invasive species in critical habitats may reduce grazing pressure from native species and shift microbial communities. The landlocked coastal ponds, pools, and caves that make up the Hawaiian anchialine ecosystem support an endemic shrimp (Halocaridina rubra) that grazes on diverse benthic microbial communities, including orange cyanobacterial‐bacterial crusts and green algal mats. Here, we asked how shrimp: (1) shape the abundance and composition of microbial communities, (2) respond to invasive fishes, and (3) whether their gut microbiomes are affected by environmental microbial communities. We demonstrate that ecologically relevant levels of shrimp grazing significantly reduce epilithon biomass. Shrimp grazed readily and grew well on both orange crusts and green mat communities. However, individuals from orange crusts were larger, despite crusts having reduced concentrations of key fatty acids. DNA profiling revealed shrimp harbor a resident gut microbiome distinct from the environment, which is relatively simple and stable across space (including habitats with different microbial communities) and time (between wild‐caught individuals and those maintained in the laboratory for >2 yr). DNA profiling also suggests shrimp grazing alters environmental microbial community composition, possibly through selective consumption and/or physical interactions. While this work suggests grazing by endemic shrimp plays a key role in shaping microbial communities in the Hawaiian anchialine ecosystem, the hypothesized drastic ecological shifts resulting from invasive fishes may be an oversimplification as shrimp may largely avoid predation. Moreover, environmental microbial communities may have little influence on shrimp gut microbiomes.

A dysbiotic gut microbiome suppresses antibody-mediated protection against Vibrio cholerae

Abstract Vibrio cholerae is the etiologic agent of cholera, a severe diarrheal disease that represents a significant burden on global health and productivity. Given the need for more effective prophylactics, more research is needed to ascertain the interplay of protective immune responses and the resident gut microbiome, which in cholera-endemic areas is strongly and repeatedly modulated by malnutrition, cholera, and non-cholera infectious diarrhea. Initially, we conducted fecal transplants from healthy human donors into germ-free mice in order to characterize differential immune response activity. As we observed distinctive responses in our initial sampling, we moved to a more tractable antibiotic-treated mouse model where we assemble representative model communities of either human gut microbes resembling those of healthy individuals or those of individuals recovering from diarrhea or malnutrition. We establish these communities in a murine infection model, and show that the dysbiotic gut microbiome, commonly present in areas where malnutrition and diarrhea are common, suppresses the immune response against Vibrio cholerae through the action of CD4+ cells. Our findings suggest that the composition of the gut microbiome at time of infection may be pivotal for providing robust mucosal immunity, suggesting a target for the improvement of responses to oral cholera vaccines.

Differential Impact of Urban vs. Rural Diets on Gut Microbiome Composition and Circulating Endotoxin in Mourning Doves

Human and rodent studies suggest a Western diet (high in refined carbohydrates, saturated fats, and salt) promotes gut dysbiosis that arises from changes in the resident gut microbiome (GM). This dietary pattern has also been associated with increased circulating concentrations of the endotoxin and immunostimulant, lipopolysaccharide (LPS), which is mediated, in part, through alterations in the GM. In relation, urbanization influences food quality and availability for many wild species which may promote a shift in the GM that could ultimately impact host physiology. As a heavily affected class it is currently unknown how the avian GM is affected following consumption of this dietary model. Therefore, we investigated the potential differential effects of an urban vs. rural dietary intervention on the GM and circulating LPS in Mourning doves (Zenaida macroura). Specifically, adult animals were brought into captivity from a wild population on the Arizona State University campus (Tempe, Arizona; 33° 25′ 11.5” N - 111° 55′ 55.6” W; altitude: 365 m.a.s.l.) and fed either a seed-based diet (rural; n = 6) or urbanized diet (urban; n = 7) over 4-weeks. The urban diet consisted of a mixture of seed and French fries (a food source readily available to birds in urban environments). We hypothesized that the urban diet would differently impact the GM community and increase plasma LPS compared to animals fed a rural diet. After the 4-week intervention, there were no differences in alpha diversity (Shannon index, Pielou's e, Faith's PD; P's ≥ 0.33) or beta diversity (Bray-Curtis, weighted and unweighted UniFrac; P's ≥ 0.35) between groups. However, linear discriminant analysis (LDA) of effect sizes revealed significant differences between the two diets, with rural-fed birds showing increased Chloroflexi (Chloroflexi and Anaerolineae) and Cyanobacteria (Phormidiaceae, Oscillatoriales, Oscillatoriophycideae, Phormidium) (LDA scores ~ 6.0). Moreover, and contrary to our hypothesis, plasma LPS concentrations were significantly higher in the rural group (51.01 ± 1.18 ng/L vs. 45.11 ± 1.02 ng/L, P = 0.003). Notably, birds are transporters of Cyanobacteria which often reside in bodies of water. The LPS molecules in Cyanobacteria also seem to provide protection from antimicrobial compounds which could be beneficial for these animals by promoting the proliferation of commensal microbes. Interesting to note that the lipid A portion of Cyanobacterial LPS is structurally similar to a well-known toll-like receptor 4 (TLR4) antagonist called lipid IVa and is less toxic than other gram-negative-derived LPS. It may be that higher LPS in the seed diet animals could be similarly protective against the TLR4 pathway as they had significantly higher abundance of Cyanobacteria. Future work should look at inflammatory markers downstream of LPS activation to confirm if these diets differ in relation to host health. In conclusion, the urban diet did not support the proliferation of several beneficial microbes that release protective endotoxins, which may have important physiological relevance for birds living in urban environments.

Effect of chlorpyrifos on the earthworm Eudrilus euginae and their gut microbiomeby toxicological and metagenomic analysis.

The earthworms are important soil invertebrates and play a crucial role in pedogenesis. The application of pesticides and prolonged exposure to pesticides causes mortality of earthworms apart from profoundly affecting the resident gut microbiome. The microbiome plays a significant effect on the metabolic processes associated with earthworms. The pesticide Chlorpyrifos (CPF) was studied for its toxicity on Eudrilus euginae by toxicity studies. The LC50 value of filter paper contact test and acute toxicity test was 3.8mg/mL and 180mg/kg. The prolonged exposure of earthworms to pesticide on reproductive toxicity resulted in the mortality of earthworms and absence of cocoon formation. Further, the effects of CPF on the whole gut microbiome of E. euginae was analyzed using a long amplicon Nanopore sequencing. Results indicated no fluctuations with Firmicutes and Bacteroidetes, that were found to be dominant at bacterial phyla level while at the genus level, remarkable differences were noticed. Clostridium dominated the earthworm gut prior to CPF exposure while Bacillus dominated after exposure. Similarly, the fungal members such as Ascomycota and Basidiomycota were observed to dominate the gut of earthworm at the phyla level before and after exposure to CPF. In contrast, Clavispora (65%) was the dominant genus before CPF exposure and Taloromyces (42%) dominated after the CPF exposure. Our study demonstrates the effect of CPF on the mortality of E. euginae while the amplicon sequencing established the unique microbiome of the gut in response to the CPF exposure.

Fiber and Prebiotic Interventions in Pediatric Inflammatory Bowel Disease: What Role Does the Gut Microbiome Play?

The etiology of inflammatory bowel disease (IBD) is complex but is thought to be linked to an intricate interaction between the host’s immune system, resident gut microbiome and environment, i.e., diet. One dietary component that has a major impact on IBD risk and disease management is fiber. Fiber intakes in pediatric IBD patients are suboptimal and often lower than in children without IBD. Fiber also has a significant impact on beneficially shaping gut microbiota composition and functional capacity. The impact is likely to be particularly important in IBD patients, where various studies have demonstrated that an imbalance in the gut microbiome, referred to as dysbiosis, occurs. Microbiome-targeted therapeutics, such as fiber and prebiotics, have the potential to restore the balance in the gut microbiome and enhance host gut health and clinical outcomes. Indeed, studies in adult IBD patients demonstrate that fiber and prebiotics positively alter the microbiome and improve disease course. To date, no studies have been conducted to evaluate the therapeutic potential of fiber and prebiotics in pediatric IBD patients. Consequently, pediatric IBD specific studies that focus on the benefits of fiber and prebiotics on gut microbiome composition and functional capacity and disease outcomes are required.

Friend or foe? Effects of host immune activation on the gut microbiome in the caterpillar Manduca sexta.

For many animals, the gut microbiome plays an essential role in immunity and digestion. However, certain animals, such as the caterpillar Manduca sexta, do not have a resident gut microbiome. Although these animals do have bacteria that pass through their gut from their natural environment, the absence of such bacteria does not reduce growth or survival. We hypothesized that M. sexta would sterilize their gut as a protective measure against secondary infection when faced with a gut infection or exposure to heat-killed bacteria in the blood (haemolymph). However, we found that gut sterilization did not occur during either type of immune challenge, i.e. bacterial numbers did not decrease. By examining the pattern of immune-related gene expression, gut pH, live bacterial counts and mass change (as a measure of sickness behaviour), we found evidence for physiological trade-offs between regulating the microbiome and defending against systemic infections. Caterpillars exposed to both gut pathogens and a systemic immune challenge had higher numbers of bacteria in their gut than caterpillars exposed to a single challenge. Following a multivariate analysis of variance, we found that the response patterns following an oral challenge, systemic challenge or dual challenge were unique. Our results suggest that the immune response for each challenge resulted in a different configuration of the immunophysiological network. We hypothesize that these different configurations represent different resolutions of physiological trade-offs based on the immune responses needed to best protect the animal against the present immune challenges.

The earthworm microbiome is resilient to exposure to biocidal metal nanoparticles

Environmental pollution can disrupt the interactions between animals and their symbiotic bacteria, which can lead to adverse effects on the host even in the absence of direct chemical toxicity. It is therefore crucial to understand how environmental pollutants affect animal microbiomes, especially for those chemicals that are designed to target microbes. Here, we study the effects of two biocidal nanoparticles (NPs) (Ag and CuO) on the soil bacterial community and the resident gut microbiome of the earthworm Eisenia fetida over a 28-day period using metabarcoding techniques. Exposures to NPs were conducted following OECD test guidelines and effects on earthworm reproduction and juvenile biomass were additionally recorded in order to compare effects on the host to effects on microbiomes. By employing a full concentration series, we were able to link pollutants to microbiome effects in high resolution. Multivariate analysis, differential abundance analysis and species sensitivity distribution analysis showed that Ag-NPs are more toxic to soil bacteria than CuO-NPs. In contrast to the strong effects of CuO-NPs and Ag-NPs on the soil bacterial community, the earthworm gut microbiome is largely resilient to exposure to biocidal NPs. Despite this buffering effect, CuO-NPs did negatively affect the relative abundance of some earthworm symbionts, including ‘Candidatus Lumbricincola’. Changes in the soil bacterial community and the earthworm microbiome occur at total copper concentrations often found or modelled to occur in agricultural fields, demonstrating that soil bacterial communities and individual taxa in the earthworm microbiome may be at risk from environmental copper exposure including in nanomaterial form.

Schizasterid Heart Urchins Host Microorganisms in a Digestive Symbiosis of Mesozoic Origin.

Because of their lifestyles, abundance, and feeding habits, infaunal marine deposit feeders have a significant impact on the ocean floor. As these animals also ingest microorganisms associated with their sediment and seawater diet, their digestive tract usually contains a diverse array of bacteria. However, while most of these microorganisms are transients, some may become part of a resident gut microbiome, in particular when sheltered from the main flow of digesta in specialized gut compartments. Here, we provide an in-depth analysis of the structure and contents of the intestinal caecum (IC), a hindgut diverticulum found exclusively in schizasterid heart urchins (Echinoidea: Spatangoida: Schizasteridae). Based on specimens of Brisaster townsendi, in addition to various other schizasterid taxa, our structural characterization of the IC shows that the organ is a highly specialized gut compartment with unique structural properties. Next generation sequencing shows that the IC contains a microbial population composed predominantly of Bacteroidales, Desulfobacterales, and Spirochaetales. The microbiome of this gut compartment is significantly different in composition and lower in diversity than the microbial population in the sediment-filled main digestive tract. Inferences on the function and evolution of the IC and its microbiome suggest that this symbiosis plays a distinct role in host nutrition and that it evolved at least 66 million years ago during the final phase of the Mesozoic.

Gut Dysbiosis in Animals Due to Environmental Chemical Exposures.

The gut microbiome consists of over 103–104 microorganism inhabitants that together possess 150 times more genes that the human genome and thus should be considered an “organ” in of itself. Such communities of bacteria are in dynamic flux and susceptible to changes in host environment and body condition. In turn, gut microbiome disturbances can affect health status of the host. Gut dysbiosis might result in obesity, diabetes, gastrointestinal, immunological, and neurobehavioral disorders. Such host diseases can originate due to shifts in microbiota favoring more pathogenic species that produce various virulence factors, such as lipopolysaccharide. Bacterial virulence factors and metabolites may be transmitted to distal target sites, including the brain. Other potential mechanisms by which gut dysbiosis can affect the host include bacterial-produced metabolites, production of hormones and factors that mimic those produced by the host, and epimutations. All animals, including humans, are exposed daily to various environmental chemicals that can influence the gut microbiome. Exposure to such chemicals might lead to downstream systemic effects that occur secondary to gut microbiome disturbances. Increasing reports have shown that environmental chemical exposures can target both host and the resident gut microbiome. In this review, we will first consider the current knowledge of how endocrine disrupting chemicals (EDCs), heavy metals, air pollution, and nanoparticles can influence the gut microbiome. The second part of the review will consider how potential environmental chemical-induced gut microbiome changes might subsequently induce pathophysiological responses in the host, although definitive evidence for such effects is still lacking. By understanding how these chemicals result in gut dysbiosis, it may open up new remediation strategies in animals, including humans, exposed to such chemicals.

Interactions between Campylobacter jejuni and AB5 toxins in the gut

Campylobacter jejuni is a ubiquitous commensal in chickens, but a major cause of human diarrheal disease worldwide. To avoid immune detection by its host, most C. jejuni isolates express human ganglioside‐mimicking lipooligosaccharide (LOS) structures and it has been shown that host recognition of these antigens as non‐self results in the development of Guillain‐Barré syndrome. In addition to immune evasion, expression of ganglioside mimics in C. jejuni has been associated with improved host cell invasion and resistance to human serum. Although only positive benefits for ganglioside mimic expression have been described for C. jejuni, the organism has the ability to quickly switch off the mimicry through a phase‐variable galactosyltransferase, CgtB, involved in LOS biosynthesis. Vibrio cholerae secretes the bacteriophage‐encoded cholera toxin (CT) which binds to GM1 ganglioside structures on human cells as well as to C. jejuni GM1 ganglioside‐mimics. Enterotoxigenic Escherichia coli secretes heat‐labile enterotoxin I (LT), which also binds to these structures. Since C. jejuni, V. cholerae and E. coli can co‐infect the same niche, we examined the effects of these AB5 toxins on C. jejuni biology in order to determine if this relationship could represent a new mechanism for interpathogen competition in the intestine. We demonstrate that CT and LT specifically bind only to C. jejuni strains expressing GM1 mimics. Interestingly, our experiments show that addition of CT or LT to C. jejuni strains expressing GM1‐mimicking LOS partially clears cell growth on agar. LOS from bacteria remaining inside these zones of clearance was isolated and compared to LOS from untreated bacteria. SDS‐PAGE and silver staining of the LOS showed the loss of a band from the exposed cells compared to untreated cells, and Western blot analysis revealed reduced binding of LOS to CT. Sequencing cgtB in these two groups demonstrated that this enzyme is “on” or “off” in the unexposed group, while cgtB in the CT‐ and LT‐treated cells showed a frameshift mutation, causing premature truncation of the galactosyltransferase. Examination of an engineered E. coli strain expressing GM1 mimics shows that CT is capable of binding to the mimicking cells without inducing growth clearance, pointing toward a Campylobacter‐specific mechanism of action. These results suggest that CT and LT have a negative influence on C. jejuni and could contribute to competition between these pathogens. Further studies describing the interactions between these zoonotic pathogens, the resident gut microbiome and poultry will be described.Support or Funding InformationCMS is an Alberta Innovates Technology Futures iCORE Strategic Chair in Bacterial Glycomics.

Selective biologics for ulcerative colitis and Crohn's disease - clinical utility of vedolizumab.

Inflammatory bowel disease (IBD) encompasses a cluster of different disease phenotypes which are broadly classified into ulcerative colitis and Crohn’s disease. Disease pathogenesis is driven by abnormal host immune responses to their resident gut microbiome in genetically susceptible individuals. Clinical disease features and outcomes are heterogenous and not unexpected as over 163 genetic loci are associated with disease susceptibility, and there are great variability in environmental exposures. Despite this variability, there has been relatively few efficacious therapies for particularly moderate-to-severe IBD. Treatment has been dominated by antitumor necrosis alpha agents with significant success but equally potentially serious adverse events. Therapeutic targeting of leucocyte trafficking has emerged as a viable alternative therapy, with vedolizumab being the lead compound. This review focuses primarily on its biological function as a selective gut immunotherapy, its safety and efficacy, and its emerging role as a mainstream therapy in managing IBD.

Nutrimetabonomics:Applications for Nutritional Sciences, with Specific Reference to Gut Microbial Interactions

Understanding the role of the diet in determining human health and disease is one major objective of modern nutrition. Mammalian biocomplexity necessitates the incorporation of systems biology technologies into contemporary nutritional research. Metabonomics is a powerful approach that simultaneously measures the low-molecular-weight compounds in a biological sample, enabling the metabolic status of a biological system to be characterized. Such biochemical profiles contain latent information relating to inherent parameters, such as the genotype, and environmental factors, including the diet and gut microbiota. Nutritional metabonomics, or nutrimetabonomics, is being increasingly applied to study molecular interactions between the diet and the global metabolic system. This review discusses three primary areas in which nutrimetabonomics has enjoyed successful application in nutritional research: the illumination of molecular relationships between nutrition and biochemical processes; elucidation of biomarker signatures of food components for use in dietary surveillance; and the study of complex trans-genomic interactions between the mammalian host and its resident gut microbiome. Finally, this review illustrates the potential for nutrimetabonomics in nutritional science as an indispensable tool to achieve personalized nutrition.