The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but ...the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine.
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•Development of subject-personalized ex vivo batch cultures of the gut microbiome•Discovery of diverse drug-microbiome interactions using MDM-Screen•MDM-Screen quantifies drug metabolism by personalized gut microbial communities•Functional genomic and metagenomic screens identify drug-metabolizing enzymes
Each human has a diverse gut microbiome, which can metabolize drugs differently. In this resource, Javdan et al. present a way to capture and grow much of the unique diversity of human microbiomes in culture and also a way to detect many of our microbiome-derived metabolites. Together, they use these unique gut communities and the metabolomics pipeline to see how personalized microbiomes metabolize drugs in different ways.
Abstract
A recent hypothesis holds that changes to the East Asian summer rainfall are characterized by changes in the timing and duration of its intraseasonal stages, controlled by the meridional ...position of the westerlies relative to the Tibetan Plateau. This hypothesis is examined in the context of the leading mode of East Asian summer (July–August) rainfall. One phase of this “tripole” mode—characterized by less rainfall over central eastern China and increased rainfall over northeastern and southeastern China—is tied to an earlier termination of Meiyu that results in a significantly shorter Meiyu and longer Midsummer stage. This phase also exhibits an earlier northward transition of the westerlies to the north of the Plateau, essentially mirroring the changes to precipitation seasonality. The reverse does not hold true for the opposite phase. Our results show direct observational evidence for the meridional position of the westerlies to control East Asian summer monsoon seasonality.
Key Points
Leading mode of July‐August East Asian rainfall variability caused by changes in timing of Meiyu termination and duration of Meiyu/Midsummer
Changes to timing and duration associated with variation in the meridional migration of westerlies relative to the Tibetan Plateau
Results show direct observational evidence for meridional position of westerlies to control East Asian summer monsoon seasonality
The human gut microbiome contains thousands of small, novel peptides that could play a role in microbe–microbe and host–microbe interactions, contributing to human health and disease. Although these ...peptides have not yet been systematically characterized, computational tools can be used to elucidate the bioactivities they may have. This article proposes probing the functional space of gut microbiome‐derived peptides (MDPs) using in silico approaches for three bioactivities: antimicrobial, anticancer, and nucleomodulins. Machine learning programs that support peptide and protein queries are provided for each bioactivity. Considering the biases of an activity‐centric approach, activity‐agnostic tools using structural and chemical similarity and target prediction are also described. Gut MDPs represent a vast functional space that can not only contribute to our understanding of microbiome interactions but potentially even serve as a source of life‐changing therapeutics.
The human gut microbiome comprises thousands of small, novel peptides that could potentially contribute to microbe‐microbe and host–microbe interactions, thereby affecting human health and disease. This article proposes exploring the functional space of gut microbiome‐derived peptides using in silico approaches that include machine learning tools, as well as activity‐agnostic approaches.
Noroviruses (NoVs) are a leading cause of gastroenteritis globally, yet the host factors required for NoV infection are poorly understood. We identified host molecules that are essential for murine ...NoV (MNoV)-induced cell death, including CD300lf as a proteinaceous receptor. We found that CD300lf is essential for MNoV binding and replication in cell lines and primary cells. Additionally, Cd300lf-/- mice are resistant to MNoV infection. Expression of CD300lf in human cells breaks the species barrier that would otherwise restrict MNoV replication. The crystal structure of the CD300lf ectodomain reveals a potential ligand-binding cleft composed of residues that are critical for MNoV infection. Therefore, the presence of a proteinaceous receptor is the primary determinant of MNoV species tropism, whereas other components of cellular machinery required for NoV replication are conserved between humans and mice.
The East Asian summer monsoon is unique among summer monsoon systems in its complex seasonality, exhibiting distinct intraseasonal stages. Previous studies have alluded to the downstream influence of ...the westerlies flowing around the Tibetan Plateau as key to its existence. We explore this hypothesis using an atmospheric general circulation model that simulates the intraseasonal stages with fidelity. Without a Tibetan Plateau, East Asia exhibits only one primary convective stage typical of other monsoons. As the plateau is introduced, the distinct rainfall stages—spring, pre-mei-yu, mei-yu, and midsummer—emerge, and rainfall becomes more intense overall. This emergence coincides with a pronounced modulation of the westerlies around the plateau and extratropical northerlies penetrating northeastern China. The northerlies meridionally constrain the moist southerly flow originating from the tropics, leading to a band of lower-tropospheric convergence and humidity front that produces the rainband. The northward migration of the westerlies away from the northern edge of the plateau leads to a weakening of the extratropical northerlies, which, coupled with stronger monsoonal southerlies, leads to the northward migration of the rainband. When the peak westerlies migrate north of the plateau during the midsummer stage, the extratropical northerlies disappear, leaving only the monsoon low-level circulation that penetrates northeastern China; the rainband disappears, leaving isolated convective rainfall over northeastern China. In short, East Asian rainfall seasonality results from the interaction of two seasonally evolving circulations—the monsoonal southerlies that strengthen and extend northward, and the midlatitude northerlies that weaken and eventually disappear—as summer progresses.
Significance Current cancer treatments ultimately fail owing to metastasis and relapse. The discovery of therapeutic approaches that counteract relapse and metastasis is, therefore, extremely ...important for advancing cancer medicine. Hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, have been isolated from patients with a variety of tumor types and found to be highly malignant, tumorigenic, and resistant to chemotherapies. Our data that BBI608, a cancer stemness inhibitor in clinical development, effectively blocks cancer relapse and metastasis in xenografted human cancers, suggest targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.
Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine. Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug sensitivity, and their potential to metastasize and cause relapse. Indeed, hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types. Moreover, such stemness-high cancer cells are resistant to conventional chemotherapy and radiation. Here we show that BBI608, a small molecule identified by its ability to inhibit gene transcription driven by Stat3 and cancer stemness properties, can inhibit stemness gene expression and block spherogenesis of or kill stemness-high cancer cells isolated from a variety of cancer types. Moreover, cancer relapse and metastasis were effectively blocked by BBI608 in mice. These data demonstrate targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.
Great progress has been made in understanding gut microbiome’s products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here ...we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber, and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate and urea (but not glucose or amino acids) feed the gut microbiome. To determine nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We find systematic differences in nutrient use: Most genera in the phylum Firmicutes prefer dietary protein,
Bacteroides
dietary fiber, and
Akkermansia
circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
Isotope tracing into bacterial-specific protein sequences allows for a determination of nutrient preferences across gut microbes
in vivo
, and reveals how diet alters microbiome composition.
The tropical Atlantic interhemispheric gradient in sea surface temperature significantly influences the rainfall climate of the tropical Atlantic sector, including droughts over West Africa and ...Northeast Brazil. This gradient exhibits a secular trend from the beginning of the twentieth century until the 1980s, with stronger warming in the south relative to the north. This trend behavior is on top of a multidecadal variation associated with the Atlantic multidecadal oscillation. A similar long-term forced trend is found in a multimodel ensemble of forced twentieth-century climate simulations. Through examining the distribution of the trend slopes in the multimodel twentieth-century and preindustrial models, the authors conclude that the observed trend in the gradient is unlikely to arise purely from natural variations; this study suggests that at least half the observed trend is a forced response to twentieth-century climate forcings. Further analysis using twentieth-century single-forcing runs indicates that sulfate aerosol forcing is the predominant cause of the multimodel trend. The authors conclude that anthropogenic sulfate aerosol emissions, originating predominantly from the Northern Hemisphere, may have significantly altered the tropical Atlantic rainfall climate over the twentieth century.
•The aggregated effect size of early adversity on CRP is very small, z = .07.•The aggregated effect size of early adversity on IL-6 is very small, z = .17.•More studies looking at TNF-α are ...needed.•More studies using in vitro assays of immune cells are needed.
This study provides a comprehensive review of the published research on the association between early life adversity and markers of inflammation in children and adolescents. We conducted a systematic review of the published literature on the association between early life adversity and markers of inflammation in pediatric populations. To date, 27 studies have been published in this area representing a wide range of global populations and diverse methods of which nearly half were prospective, longitudinal studies. Of these 27, only 12 studies shared an inflammatory outcome with 4 or more other studies; 9 for CRP, and 6 for IL-6. The association between early life adversity and both CRP, z = .07 .04, .10, and IL-6, z = .17 −.07, .42, were small and only significant for CRP although comparable in magnitude to the effects observed in adult samples. Descriptively, the association between early life adversity and CRP appeared to be stronger in studies conducted in infants and adolescents compared with middle childhood. There was minimal evidence of publication bias for studies measuring CRP, but evidence of publication bias for studies using IL-6. Eight studies have looked at the association between early life adversity and stimulated inflammatory cytokines in vitro, and both the methods and results of these studies were mixed; the majority observed exaggerated production of inflammatory cytokines despite mixed methodological approaches that make comparisons across studies difficult. In summary, the evidence supporting an association between early life adversity and inflammation in pediatric samples is limited so far by the number of studies and their heterogeneous methodological approaches. More research that is grounded in a developmental framework and informed by the complexity of the innate immune system is needed in this area.
Phytochemicals have been used as potential chemopreventive or chemotherapeutic agents. However, there are data suggesting a mutagenic effect of some phytochemicals. We hypothesized that safrole would ...have anticancer effects on human oral squamous cell carcinoma HSC-3 cells. Safrole decreased the percentage of viable HSC-3 cells via induction of apoptosis by an increased level of cytosolic Ca2+ and a reduction in the mitochondrial membrane potential (ΔΨ
m
). Changes in the membrane potential were associated with changes in the Bax, release of cytochrome c from mitochondria, and activation of downstream caspases-9 and -3, resulting in apoptotic cell death. In vivo studies also showed that safrole reduced the size and volume of an HSC-3 solid tumor on a xenograft athymic nu/nu mouse model. Western blotting and flow cytometric analysis studies confirmed that safrole-mediated apoptotic cell death of HSC-3 cells is regulated by cytosolic Ca2+ and by mitochondria- and Fas-dependent pathways.
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