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IgA + B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8 + T cells. The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA + ) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8 + T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8 + T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA + cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8 + T-lymphocyte activation as a tumour-promoting mechanism. Increased cancer risk in fatty livers Cancer progression beyond the early stages is thought to be caused in some cases by adaptive immunity, but its role remains controversial. In this study, Michael Karin and colleagues show that PD-L1-expressing IgA + B cells accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease. The inflammation-induced IgA + cells promote the progression to hepatocellular carcinoma by suppressing liver cytotoxic CD8 + T cells that prevent the emergence of this aggressive tumour.

Integrating multiomics datasets is critical for microbiome research; however, inferring interactions across omics datasets has multiple statistical challenges. We solve this problem by using neural networks (https://github.com/biocore/mmvec) to estimate the conditional probability that each molecule is present given the presence of a specific microorganism. We show with known environmental (desert soil biocrust wetting) and clinical (cystic fibrosis lung) examples, our ability to recover microbe–metabolite relationships, and demonstrate how the method can discover relationships between microbially produced metabolites and inflammatory bowel disease.

Huanglongbing (HLB), associated with the psyllid-vectored phloem-limited bacterium, Candidatus Liberibacter asiaticus (C Las), is a disease threat to all citrus production worldwide. Currently, there are no sustainable curative or prophylactic treatments available. In this study, we utilized mass spectrometry (MS)-based metabolomics in combination with 3D molecular mapping to visualize complex chemistries within plant tissues to explore how these chemistries change in vivo in HLB-infected trees. We demonstrate how spatial information from molecular maps of branches and single leaves yields insight into the biology not accessible otherwise. In particular, we found evidence that flavonoid biosynthesis is disrupted in HLB-infected trees, and an increase in the polyamine, feruloylputrescine, is highly correlated with an increase in disease severity. Based on mechanistic details revealed by these molecular maps, followed by metabolic modeling, we formulated and tested the hypothesis that C Las infection either directly or indirectly converts the precursor compound, ferulic acid, to feruloylputrescine to suppress the antimicrobial effects of ferulic acid and biosynthetically downstream flavonoids. Using in vitro bioassays, we demonstrated that ferulic acid and bioflavonoids are indeed highly bactericidal to C Las, with the activity on par with a reference antibiotic, oxytetracycline, recently approved for HLB management. We propose these compounds should be evaluated as therapeutics alternatives to the antibiotics for HLB treatment. Overall, the utilized 3D metabolic mapping approach provides a promising methodological framework to identify pathogen-specific inhibitory compounds in planta for potential prophylactic or therapeutic applications.

Our skin, our belongings, the world surrounding us, and the environment we live in are covered with molecular traces. Detecting and characterizing these molecular traces is necessary to understand the environmental impact on human health and disease, and to decipher complex molecular interactions between humans and other species, particularly microbiota. We recently introduced 3D molecular cartography for mapping small organic molecules (including metabolites, lipids, and environmental molecules) found on various surfaces, including the human body. Here, we provide a protocol and open-source software for 3D molecular cartography. The protocol includes step-by-step procedures for sample collection and processing, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, quality control (QC), molecular identification using MS/MS, data processing, and visualization with 3D models of the sampled environment. The LC-MS method was optimized for a broad range of small organic molecules. We enable scientists to reproduce our previously obtained results, and illustrate the broad utility of our approach with molecular maps of a rosemary plant and an ATM keypad after a PIN code was entered. To promote reproducibility, we introduce cartographical snapshots: files that describe a particular map and visualization settings, and that can be shared and loaded to reproduce the visualization. The protocol enables molecular cartography to be performed in any mass spectrometry laboratory and, in principle, for any spatially mapped data. We anticipate applications, in particular, in medicine, ecology, agriculture, biotechnology, and forensics. The protocol takes 78 h for a molecular map of 100 spots, excluding the reagent setup.

Elective transjugular intrahepatic portosystemic shunt (TIPS) placement can worsen cognitive dysfunction in hepatic encephalopathy (HE) patients due to toxins, including possible microbial metabolites, entering the systemic circulation. We conducted untargeted metabolomics on a prospective cohort of 22 patients with cirrhosis undergoing elective TIPS placement and followed them up to one year post TIPS for HE development. Here we suggest that pre-existing intrahepatic shunting predicts HE severity post-TIPS. Bile acid levels decrease in the peripheral vein post-TIPS, and the abundances of three specific conjugated di- and tri-hydroxylated bile acids are inversely correlated with HE grade. Bilirubins and glycerophosphocholines undergo chemical modifications pre- to post-TIPS and based on HE grade. Our results suggest that TIPS-induced metabolome changes can impact HE development, and that pre-existing intrahepatic shunting could be used to predict HE severity post-TIPS. Patients with liver disease undergoing transjugular intrahepatic portosystemic shunt (TIPS) are at a higher risk of hepatic encephalopathy (HE). Here, the authors show intrahepatic shunting and specific metabolites, especially bile acids, as potential biomarkers and treatment targets for HE.

Background Studies of the cystic fibrosis (CF) lung microbiome have consistently shown that lung function decline is associated with decreased microbial diversity due to the dominance of opportunistic pathogens. However, how this phenomenon is reflected in the metabolites and chemical environment of lung secretions remains poorly understood. Methods Here we investigated the microbial and molecular composition of CF sputum samples using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry to determine their interrelationships and associations with clinical measures of disease severity. Results The CF metabolome was found to exist in two states: one from patients with more severe disease that had higher molecular diversity and more Pseudomonas aeruginosa and the other from patients with better lung function having lower metabolite diversity and fewer pathogenic bacteria. The two molecular states were differentiated by the abundance and diversity of peptides and amino acids. Patients with severe disease and more pathogenic bacteria had higher levels of peptides. Analysis of the carboxyl terminal residues of these peptides indicated that neutrophil elastase and cathepsin G were responsible for their generation, and accordingly, these patients had higher levels of proteolytic activity from these enzymes in their sputum. The CF pathogen Pseudomonas aeruginosa was correlated with the abundance of amino acids and is known to primarily feed on them in the lung. Conclusions In cases of severe CF lung disease, proteolysis by host enzymes creates an amino acid-rich environment that P. aeruginosa comes to dominate, which may contribute to the pathogen’s persistence by providing its preferred carbon source.

An important challenge to pulmonary arterial hypertension (PAH) diagnosis and treatment is early detection of occult pulmonary vascular pathology. Symptoms are frequently confused with other disease entities that lead to inappropriate interventions and allow for progression to advanced states of disease. There is a significant need to develop new markers for early disease detection and management of PAH. Exhaled breath condensate (EBC) samples were compared from 30 age-matched normal healthy individuals and 27 New York Heart Association functional class III and IV idiopathic pulmonary arterial hypertenion (IPAH) patients, a subgroup of PAH. Volatile organic compounds (VOC) in EBC samples were analyzed using gas chromatography/mass spectrometry (GC/MS). Individual peaks in GC profiles were identified in both groups and correlated with pulmonary hemodynamic and clinical endpoints in the IPAH group. Additionally, GC/MS data were analyzed using autoregression followed by partial least squares regression (AR/PLSR) analysis to discriminate between the IPAH and control groups. After correcting for medicaitons, there were 62 unique compounds in the control group, 32 unique compounds in the IPAH group, and 14 in-common compounds between groups. Peak-by-peak analysis of GC profiles of IPAH group EBC samples identified 6 compounds significantly correlated with pulmonary hemodynamic variables important in IPAH diagnosis. AR/PLSR analysis of GC/MS data resulted in a distinct and identifiable metabolic signature for IPAH patients. These findings indicate the utility of EBC VOC analysis to discriminate between severe IPAH and a healthy population; additionally, we identified potential novel biomarkers that correlated with IPAH pulmonary hemodynamic variables that may be important in screening for less severe forms IPAH.

Mass spectrometry is a predominant experimental technique in metabolomics and related fields, but metabolite structural elucidation remains highly challenging. We report SIRIUS 4 (https://bio.informatik.uni-jena.de/sirius/), which provides a fast computational approach for molecular structure identification. SIRIUS 4 integrates CSI:FingerID for searching in molecular structure databases. Using SIRIUS 4, we achieved identification rates of more than 70% on challenging metabolomics datasets.SIRIUS 4 is a fast and highly accurate tool for molecular structure interpretation from mass-spectrometry-based metabolomics data.

The impact of silver-threaded material on human skin chemistry and microbiome is largely unknown. Although the most abundant taxa remained unaffected, silver caused an increase in diversity and richness of low-abundant bacteria and a decrease in chemical diversity. With growing awareness that what we put in and on our bodies affects our health and wellbeing, little is still known about the impact of textiles on the human skin. Athletic wear often uses silver threading to improve hygiene, but little is known about its effect on the body’s largest organ. In this study, we investigated the impact of such clothing on the skin’s chemistry and microbiome. Samples were collected from different body sites of a dozen volunteers over the course of 12 weeks. The changes induced by the antibacterial clothing were specific for individuals, but more so defined by gender and body site. Unexpectedly, the microbial biomass on skin increased in the majority of the volunteers when wearing silver-threaded T-shirts. Although the most abundant taxa remained unaffected, silver caused an increase in diversity and richness of low-abundant bacteria and a decrease in chemical diversity. Both effects were mainly observed for women. The hallmark of the induced changes was an increase in the abundance of various monounsaturated fatty acids (MUFAs), especially in the upper back. Several microbe-metabolite associations were uncovered, including Cutibacterium , detected in the upper back area, which was correlated with the distribution of MUFAs, and Anaerococcus spp. found in the underarms, which were associated with a series of different bile acids. Overall, these findings point to a notable impact of the silver-threaded material on the skin microbiome and chemistry. We observed that relatively subtle changes in the microbiome result in pronounced shifts in molecular composition. IMPORTANCE The impact of silver-threaded material on human skin chemistry and microbiome is largely unknown. Although the most abundant taxa remained unaffected, silver caused an increase in diversity and richness of low-abundant bacteria and a decrease in chemical diversity. The major change was an increase in the abundance of various monounsaturated fatty acids that were also correlated with Cutibacterium . Additionally, Anaerococcus spp., found in the underarms, were associated with different bile acids in the armpit samples. Overall, the impact of the silver-threaded clothing was gender and body site specific.