Untargeted Fecal Metabolomic Analyses across an Industrialization Gradient Reveal Shared Metabolites and Impact of Industrialization on Fecal Microbiome-Metabolome Interactions.

The metabolome is a central determinant of human phenotypes and includes the plethora of small molecules produced by host and microbiome or taken up from exogenous sources. However, studies of the metabolome have so far focused predominantly on urban, industrialized populations. Through an untargeted metabolomic analysis of 90 fecal samples from human individuals from Africa and the Americas-the birthplace and the last continental expansion of our species, respectively-we characterized a shared human fecal metabolome. The majority of detected metabolite features were ubiquitous across populations, despite any geographic, dietary, or behavioral differences. Such shared metabolite features included hyocholic acid and cholesterol. However, any characterization of the shared human fecal metabolome is insufficient without exploring the influence of industrialization. Here, we show chemical differences along an industrialization gradient, where the degree of industrialization correlates with metabolomic changes. We identified differential metabolite features such as amino acid-conjugated bile acids and urobilin as major metabolic correlates of these behavioral shifts. Additionally, coanalyses with over 5,000 publicly available human fecal samples and cooccurrence probability analyses with the gut microbiome highlight connections between the human fecal metabolome and gut microbiome. Our results indicate that industrialization significantly influences the human fecal metabolome, but diverse human lifestyles and behavior still maintain a shared human fecal metabolome. This study represents the first characterization of the shared human fecal metabolome through untargeted analyses of populations along an industrialization gradient. IMPORTANCE As the world becomes increasingly industrialized, understanding the biological consequences of these lifestyle shifts and what it means for past, present, and future human health is critical. Indeed, industrialization is associated with rises in allergic and autoimmune health conditions and reduced microbial diversity. Exploring these health effects on a chemical level requires consideration of human lifestyle diversity, but understanding the significance of any differences also requires knowledge of what molecular components are shared between human groups. Our study reveals the key chemistry of the human gut as defined by varied industrialization-based differences and ubiquitous shared features. Ultimately, these novel findings extend our knowledge of human molecular biology, especially as it is influenced by lifestyle and behavior, and provide steps toward understanding how human biology has changed over our species' history.

Timing is everything: impact of development, ageing and circadian rhythm on macrophage functions in urinary tract infections.

The bladder supports a diversity of macrophage populations with functional roles related to homeostasis and host defense, including clearance of cell debris from tissue, immune surveillance, and inflammatory responses. This review examines these roles with particular attention given to macrophage origins, differentiation, recruitment, and engagement in host defense against urinary tract infections (UTIs), where these cells recognize uropathogens through a combination of receptor-mediated responses. Time is an important variable that is often overlooked in many clinical and biological studies, including in relation to macrophages and UTIs. Given that ageing is a significant factor in urinary tract infection pathogenesis and macrophages have been shown to harbor their own circadian system, this review also explores the influence of age on macrophage functions and the role of diurnal variations in macrophage functions in host defense and inflammation during UTIs. We provide a conceptual framework for future studies that address these key knowledge gaps.

Spatial Metabolomics Reveals Localized Impact of Influenza Virus Infection on the Lung Tissue Metabolome.

The influenza virus (IAV) is a major cause of respiratory disease, with significant infection increases in pandemic years. Vaccines are a mainstay of IAV prevention but are complicated by IAV's vast strain diversity and manufacturing and vaccine uptake limitations. While antivirals may be used for treatment of IAV, they are most effective in early stages of the infection, and several virus strains have become drug resistant. Therefore, there is a need for advances in IAV treatment, especially host-directed therapeutics. Given the spatial dynamics of IAV infection and the relationship between viral spatial distribution and disease severity, a spatial approach is necessary to expand our understanding of IAV pathogenesis. We used spatial metabolomics to address this issue. Spatial metabolomics combines liquid chromatography-tandem mass spectrometry of metabolites extracted from systematic organ sections, 3D models, and computational techniques to develop spatial models of metabolite location and their role in organ function and disease pathogenesis. In this project, we analyzed serum and systematically sectioned lung tissue samples from uninfected or infected mice. Spatial mapping of sites of metabolic perturbations revealed significantly lower metabolic perturbation in the trachea compared to other lung tissue sites. Using random forest machine learning, we identified metabolites that responded differently in each lung position based on infection, including specific amino acids, lipids and lipid-like molecules, and nucleosides. These results support the implementation of spatial metabolomics to understand metabolic changes upon respiratory virus infection. IMPORTANCE The influenza virus is a major health concern. Over 1 billion people become infected annually despite the wide distribution of vaccines, and antiviral agents are insufficient to address current clinical needs. In this study, we used spatial metabolomics to understand changes in the lung and serum metabolome of mice infected with influenza A virus compared to uninfected controls. We determined metabolites altered by infection in specific lung tissue sites and distinguished metabolites perturbed by infection between lung tissue and serum samples. Our findings highlight the utility of a spatial approach to understanding the intersection between the lung metabolome, viral infection, and disease severity. Ultimately, this approach will expand our understanding of respiratory disease pathogenesis.

Enabling Quantitative Analysis of Surface Small Molecules for Exposomics and Behavioral Studies.

Workplace chemical exposures are a major source of occupational injury. Although over half of these are skin exposures, exposomics research often focuses on chemical levels in the air or in worker biofluids such as blood and urine. Until now, one limitation has been the lack of methods to quantitatively measure surface chemical transfer. Outside the realm of harmful chemicals, the small molecules we leave behind on surfaces can also reveal important aspects of human behavior. In this study, we developed a swab-based quantitative approach to determine small molecule concentrations across common surfaces. We demonstrate its utility using one drug, cyclobenzaprine, on metal surfaces, and two human-derived metabolites, carnitine and phenylacetylglutamine, on four common surfaces: linoleum flooring, plastified laboratory workbench, metal, and Plexiglas. We observed peak areas proportional to surface analyte concentrations at 45 min and 1 week after deposition, enabling quantification of molecule abundance on workplace built environment surfaces. In contrast, this method was unsuitable for analysis of oleanolic acid, for which we did not observe a strong linear proportional relationship following swab-based recovery from surfaces. Overall, this method paves the way for future quantitative exposomics studies in analyte-specific and surface-specific frameworks.

Dysregulation of Glycerophosphocholines in the Cutaneous Lesion Caused by Leishmania major in Experimental Murine Models.

Cutaneous leishmaniasis (CL) is the most common disease form caused by a Leishmania parasite infection and considered a neglected tropical disease (NTD), affecting 700,000 to 1.2 million new cases per year in the world. Leishmania major is one of several different species of the Leishmania genus that can cause CL. Current CL treatments are limited by adverse effects and rising resistance. Studying disease metabolism at the site of infection can provide knowledge of new targets for host-targeted drug development. In this study, tissue samples were collected from mice infected in the ear or footpad with L. major and analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in overall metabolite profiles were noted in the ear at the site of the lesion. Interestingly, lesion-adjacent, macroscopically healthy sites also showed alterations in specific metabolites, including selected glycerophosphocholines (PCs). Host-derived PCs in the lower m/z range (m/z 200-799) showed an increase with infection in the ear at the lesion site, while those in the higher m/z range (m/z 800-899) were decreased with infection at the lesion site. Overall, our results expanded our understanding of the mechanisms of CL pathogenesis through host metabolism and may lead to new curative measures against infection with Leishmania.

Tryp-ing Up Metabolism: Role of Metabolic Adaptations in Kinetoplastid Disease Pathogenesis.

Today, more than a billion people-one-sixth of the world's population-are suffering from neglected tropical diseases. Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected tropical diseases caused by protozoan parasites belonging to the genera Trypanosoma and Leishmania About half a million people living in tropical and subtropical regions of the world are at risk of contracting one of these three infections. Kinetoplastids have complex life cycles with different morphologies and unique physiological requirements at each life cycle stage. This review covers the latest findings on metabolic pathways impacting disease pathogenesis of kinetoplastids within the mammalian host. Nutrient availability is a key factor shaping in vivo parasite metabolism; thus, kinetoplastids display significant metabolic flexibility. Proteomic and transcriptomic profiles show that intracellular trypanosomatids are able to switch to an energy-efficient metabolism within the mammalian host system. Host metabolic changes can also favor parasite persistence, and contribute to symptom development, in a location-specific fashion. Ultimately, targeted and untargeted metabolomics studies have been a valuable approach to elucidate the specific biochemical pathways affected by infection within the host, leading to translational drug development and diagnostic insights.

Local Phenomena Shape Backyard Soil Metabolite Composition.

Soil covers most of Earth's continental surface and is fundamental to life-sustaining processes such as agriculture. Given its rich biodiversity, soil is also a major source for natural product drug discovery from soil microorganisms. However, the study of the soil small molecule profile has been challenging due to the complexity and heterogeneity of this matrix. In this study, we implemented high-resolution liquid chromatography-tandem mass spectrometry and large-scale data analysis tools such as molecular networking to characterize the relative contributions of city, state and regional processes on backyard soil metabolite composition, in 188 soil samples collected from 14 USA States, representing five USA climate regions. We observed that region, state and city of collection all influence the overall soil metabolite profile. However, many metabolites were only detected in unique sites, indicating that uniquely local phenomena also influence the backyard soil environment, with both human-derived and naturally-produced (plant-derived, microbially-derived) metabolites identified. Overall, these findings are helping to define the processes that shape the backyard soil metabolite composition, while also highlighting the need for expanded metabolomic studies of this complex environment.