Modeling metastatic progression from cross-sectional cancer genomics data.

MOTIVATION: Metastasis formation is a hallmark of cancer lethality. Yet, metastases are generally unobservable during their early stages of dissemination and spread to distant organs. Genomic datasets of matched primary tumors and metastases may offer insights into the underpinnings and the dynamics of metastasis formation. RESULTS: We present metMHN, a cancer progression model designed to deduce the joint progression of primary tumors and metastases using cross-sectional cancer genomics data. The model elucidates the statistical dependencies among genomic events, the formation of metastasis, and the clinical emergence of both primary tumors and their metastatic counterparts. metMHN enables the chronological reconstruction of mutational sequences and facilitates estimation of the timing of metastatic seeding. In a study of nearly 5000 lung adenocarcinomas, metMHN pinpointed TP53 and EGFR as mediators of metastasis formation. Furthermore, the study revealed that post-seeding adaptation is predominantly influenced by frequent copy number alterations. AVAILABILITY AND IMPLEMENTATION: All datasets and code are available on GitHub at https://github.com/cbg-ethz/metMHN.

Comparative Study of the Effects of Dietary-Free and -Bound Nε-Carboxymethyllysine on Gut Microbiota and Intestinal Barrier.

Nε-carboxymethyllysine (CML) is produced by a nonenzymatic reaction between reducing sugar and ε-amino group of lysine in food and exists as free and bound forms with varying digestibility and absorption properties in vivo, causing diverse interactions with gut microbiota. The effects of different forms of dietary CML on the gut microbiota and intestinal barrier of mice were explored. Mice were exposed to free and bound CML for 12 weeks, and colonic morphology, gut microbiota, fecal short-chain fatty acids (SCFAs), intestinal barrier, and receptor for AGE (RAGE) signaling cascades were measured. The results indicated that dietary-free CML increased the relative abundance of SCFA-producing genera including Blautia, Faecalibacterium, Agathobacter, and Roseburia. In contrast, dietary-bound CML mainly increased the relative abundance of Akkermansia. Moreover, dietary-free and -bound CML promoted the gene and protein expression of zonula occludens-1 and claudin-1. Additionally, the intake of free and bound CML caused an upregulation of RAGE expression but did not activate downstream inflammatory pathways due to the upregulation of oligosaccharyl transferase complex protein 48 (AGER1) expression, indicating a delicate balance between protective and proinflammatory effects in vivo. Dietary-free and -bound CML could modulate the gut microbiota community and increase tight-junction expression, and dietary-free CML might exert a higher potential benefit on gut microbiota and SCFAs than dietary-bound CML.

Highland barley ß-glucan supplementation attenuated hepatic lipid accumulation in Western diet-induced non-alcoholic fatty liver disease mice by modulating gut microbiota.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. NAFLD is caused by numerous factors, including the genetic susceptibility, oxidative stress, unhealthy diet, and gut microbiota dysbiosis. Among these, gut microbiota is a key factor and plays an important role in the development of NAFLD. Therefore, modulating the composition and structure of gut microbiota might provide a new intervention strategy for NAFLD. Highland barley ß-glucan (HBG) is a polysaccharide that can interact with gut microbiota after entering the lower gastrointestinal tract and subsequently improves NAFLD. Therefore, a Western diet was used to induce NAFLD in mouse models and the intervention effects and underlying molecular mechanisms of HBG on NAFLD mice based on gut microbiota were explored. The results indicated that HBG could regulate the composition of gut microbiota in NAFLD mice. In particular, HBG increased the abundance of short-chain fatty acids (SCFA)-producing bacteria (Prevotella-9, Bacteroides, and Roseburia) as well as SCFA contents. The increase in SCFA contents might activate the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby improving the liver lipid metabolism disorder and reducing liver lipid deposition.

Ion Sieve Interface Assisted Zinc Anode with High Zinc Utilization and Ultralong Cycle Life for 61 Wh/kg Mild Aqueous Pouch Battery.

The cycling stability of a thin zinc anode under high zinc utilization has a critical impact on the overall energy density and practical lifetime of zinc ion batteries. In this study, an ion sieve protection layer (ZnSnF@Zn) was constructed in situ on the surface of a zinc anode by chemical replacement. The ion sieve facilitated the transport and desolvation of zinc ions at the anode/electrolyte interface, reduced the zinc deposition overpotential, and inhibited side reactions. Under a 50% zinc utilization, the symmetrical battery with this protection layer maintained stable cycling for 250 h at 30 mA cm-2. Matched with high-load self-supported vanadium-based cathodes (18-20 mg cm-2), the coin battery with 50% zinc utilization possessed an energy density retention of 94.3% after 1000 cycles at 20 mA cm-2. Furthermore, the assembled pouch battery delivered a whole energy density of 61.3 Wh kg-1, surpassing the highest mass energy density among reported mild zinc batteries, and retained 76.7% of the energy density and 85.3% (0.53 Ah) of the capacity after 300 cycles.

High-temperature effects for transition state calculations in solids.

Transition state calculation is a critical technique to understand and predict versatile dynamical phenomena in solids. However, the transition state results obtained at 0 K are often utilized for the prediction or interpretation of dynamical processes at high temperatures, and the error bars of such an approximation are largely unknown. In this benchmark study, all the major temperature effects, including lattice expansion, lattice vibration, electron excitation, and band-edge shift, are evaluated with first-principles calculations for defect diffusion in solids. With the inclusion of these temperature effects, the notable discrepancies between theoretical predictions at 0 K and the experimental diffusivities at high temperatures are dramatically reduced. In particular, we find that lattice expansion and lattice vibration are the dominant factors lowering the defect formation energies and hopping barriers at high temperatures, but the electron excitation exhibits minor effects. In sharp contrast to typical assumptions, the attempt frequency with lattice expansion and vibration varies significantly with materials: several THz for aluminum bulk but surprisingly over 500 THz for 4H-SiC. For defects in semiconductors, the band-edge shift is also significant at high temperatures and plays a vital role in defect diffusion. We expect that this study would help accurately predict the dynamical processes at high temperatures.

Galactooligosaccharide or 2'-Fucosyllactose Modulates Gut Microbiota and Inhibits LPS/TLR4/NF-κB Signaling Pathway to Prevent DSS-Induced Colitis Aggravated by a High-Fructose Diet in Mice.

A high-fructose diet (HFrD) has been reported to exacerbate dextran sulfate sodium (DSS)-induced colitis. 2'-Fucosyllactose (FL) and galactooligosaccharide (GOS) have been shown, respectively, to have preventive and ameliorative effects on colitis, while limited research has explored whether GOS and FL may be equally protective or preventive in mice with HFrD. Here, we evaluated the protective effects of FL and GOS on colitis exacerbated by feeding HFrD and explored the underlying mechanisms. DSS-induced colitis was studied in four randomized C57BL/6J male mice (n = 8 mice/group). Among them, three groups were fed with HFrD, and two received either GOS or FL treatment, respectively. Gut microbial composition was analyzed by 16S rDNA gene sequencing. Intestinal barrier integrity and inflammatory pathway expression were measured using qPCR, immunofluorescence, and Western blot methods. Compared to the HFrD group, GOS or FL treatment increased the α-diversity of the gut microbiota, reduced the relative abundance of Akkermansia, and increased the content of short-chain fatty acids (SCFAs), respectively. Compared with the HFrD group, GOS or FL treatment improved the loss of goblet cells and the reduction of tight junction protein expression, thereby improving intestinal barrier integrity. Also, GOS or FL inhibited the LPS/TLR4/NF-κB signaling pathway and oxidative stress to suppress the inflammatory cascade compared with the HFrD group. These findings suggest that GOS or FL intake can alleviate HFrD-exacerbated colitis, with no significant difference observed between GOS and FL treatments.

Comparison of metabolic fate, target organs, and microbiota interactions of free and bound dietary advanced glycation end products.

Increased intake of Western diets and ultra-processed foods is accompanied by increased intake of advanced glycation end products (AGEs). AGEs can be generated exogenously in the thermal processing of food and endogenously in the human body, which associated with various chronic diseases. In food, AGEs can be divided into free and bound forms, which differ in their bioavailability, digestion, absorption, gut microbial interactions and untargeted metabolites. We summarized the measurements and contents of free and bound AGE in foods. Moreover, the ingestion, digestion, absorption, excretion, gut microbiota interactions, and metabolites and metabolic pathways between free and bound AGEs based on animal and human studies were compared. Bound AGEs were predominant in most of the selected foods, while beer and soy sauce were rich in free AGEs. Only 10%-30% of AGEs were absorbed into the systemic circulation when orally administered. The excretion of ingested free and bound AGEs was approximately 90% and 60%, respectively. Dietary free CML has a detrimental effect on gut microbiota composition, while bound AGEs have both detrimental and beneficial impacts. Free and bound dietary AGEs changed amino acid metabolism, energy metabolism and carbohydrate metabolism. And besides, bound dietary AGEs altered vitamin metabolism, and glycerolipid metabolism.

Galactooligosaccharides ameliorate dietary advanced glycation end product-induced intestinal barrier damage in C57BL/6 mice by modulation of the intestinal microbiome.

Advanced glycation end products (AGEs) are increasingly recognized as potentially pathogenic components of processed foods, and long-term consumption of dietary AGEs triggers disruption of the intestinal barrier integrity and increases the risk of chronic diseases. Galactooligosaccharides (GOS) as prebiotics can modulate the intestinal microbiota and improve the intestinal barrier integrity. In this study, we aimed to investigate whether GOS could ameliorate the intestinal barrier damage induced by AGEs. The results showed an increased number of goblet cells (AGEs vs. H-GOS, 133.4 vs. 174.7, p < 0.05) and neutral mucin area (PAS positive area, 7.29% vs. 10.05%, p < 0.05). Upregulated expressions of occludin and claudin-1 and improved intestinal barrier integrity were observed in the H-GOS group. Using 16S rRNA sequencing analysis, we found that GOS significantly reduced the high enrichment of Akkermansia (16.95% vs. 1.29%, p < 0.05) induced by dietary AGEs while increasing the content of short-chain fatty acids. Fecal microbiota transplantation (FMT) showed that AGE-induced damage to the intestinal mucus barrier was reversed in the H-GOS transplanted group. Collectively, GOS ameliorated dietary AGE-induced intestinal barrier damage by reversing the dysregulated state of the intestinal microbiota. Our study lays the foundation for further research on dietary guidelines for populations with high AGE diets.

Highland barley ß-glucan alleviated western diet-induced non-alcoholic fatty liver disease via increasing energy expenditure and regulating bile acid metabolism in mice.

Non-alcoholic fatty liver disease (NAFLD) has become a public health burden. Controlling bile acids (BAs) metabolism and energy expenditure are  potential therapies for NAFLD. Because one of the main health effects of cereal ß-glucan (BG) is its ability to lower cholesterol by interacting with BAs, BG may regulate imbalances of the metabolism of BAs during NAFLD. Therefore, by using metabolic tests coupled with the profiling of hepatic BAs, we have assessed the effect of BG from highland barley on western diet (WD) induced NAFLD mice. BG treatment prevented fat accumulation and increased adipose lipolysis. These moderating effects were associated with an increased energy expenditure. Moreover, BG-treated mice enhanced the production of hepatic BAs, which may be connected with the activation of farnesoid X receptor (FXR) signaling in the liver and inhibition of FXR signaling in the ileum. Our results suggest that BG prevents fat accumulation by increasing energy expenditure, a mechanism associated with major changes in the composition of hepatic BAs.

Comparison of tissue distribution of free and protein bound Nɛ-carboxymethyllysine after long-term oral administration to mice.

Nɛ-Carboxymethyl-lysine (CML) is a primary advanced glycation end product that exists in the body and food as free and bound forms with different bioavailability and physiological effects. To compare the uptake, tissue distribution, and fecal excretion of dietary free and bound CML, free or bound CML were administered to healthy mice at 10 mg CML kg-1 body weight per day for 12 weeks. The results demonstrated that free CML was significantly absorbed in serum and accumulated in the colon, ileum, lung, kidneys, heart, spleen, brain, and liver after intake of free and bound CML, whereas no statistical increase was found in the accumulation of bound CML in the serum, lung, spleen, kidneys, and liver. The colon was the main tissue for the accumulation of free and total CML. Moreover, the accumulation of free CML in tissues and organs was significantly correlated with free CML levels in serum. In conclusion, consumption of bound CML caused a higher uptake, accumulation, and fecal excretion of CML in the body than intake of free CML.

Hypoglycemic Effects of Lycium barbarum Polysaccharide in Type 2 Diabetes Mellitus Mice via Modulating Gut Microbiota.

This study aims to explore the molecular mechanisms of Lycium barbarum polysaccharide (LBP) in alleviating type 2 diabetes through intestinal flora modulation. A high-fat diet (HFD) combined with streptozotocin (STZ) was applied to create a diabetic model. The results indicated that LBP effectively alleviated the symptoms of hyperglycemia, hyperlipidemia, and insulin resistance in diabetic mice. A high dosage of LBP exerted better hypoglycemic effects than low and medium dosages. In diabetic mice, LBP significantly boosted the activities of CAT, SOD, and GSH-Px and reduced inflammation. The analysis of 16S rDNA disclosed that LBP notably improved the composition of intestinal flora, increasing the relative abundance of Bacteroides, Ruminococcaceae_UCG-014, Intestinimonas, Mucispirillum, Ruminococcaceae_UCG-009 and decreasing the relative abundance of Allobaculum, Dubosiella, Romboutsia. LBP significantly improved the production of short-chain fatty acids (SCFAs) in diabetic mice, which corresponded to the increase in the beneficial genus. According to Spearman's correlation analysis, Cetobacterium, Streptococcus, Ralstonia. Cetobacterium, Ruminiclostridium, and Bifidobacterium correlated positively with insulin, whereas Cetobacterium, Millionella, Clostridium_sensu_stricto_1, Streptococcus, and Ruminococcaceae_UCG_009 correlated negatively with HOMA-IR, HDL-C, ALT, AST, TC, and lipopolysaccharide (LPS). These findings suggested that the mentioned genus may be beneficial to diabetic mice's hypoglycemia and hypolipidemia. The up-regulation of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and insulin were remarkably reversed by LBP in diabetic mice. The real-time PCR (RT-PCR) analysis illustrated that LBP distinctly regulated the glucose metabolism of diabetic mice by activating the IRS/PI3K/Akt signal pathway. These results indicated that LBP effectively alleviated the hyperglycemia and hyperlipidemia of diabetic mice by modulating intestinal flora.

The Lon protease negatively regulates pyoluteorin biosynthesis through the Gac/Rsm-RsmE cascade and directly degrades the transcriptional activator PltR in Pseudomonas protegens H78.

Pyoluteorin (Plt) is a broad-spectrum antibiotic with antibacterial and antifungal activities. In Pseudomonas protegens H78, the Plt biosynthetic operon pltLABCDEFG is transcriptionally activated by the LysR-type regulator PltR and is positively regulated by the Gac/Rsm signal transduction cascade (GacS/A-RsmXYZ-RsmE-pltR/pltAB). Additionally, Plt biosynthesis has been shown to be significantly enhanced by mutation of the Lon protease-encoding gene. This study aims to understand the negative regulation pathway and molecular mechanism by which Lon functions in Plt biosynthesis. lon deletion was first found to improve the antimicrobial ability of strain H78 due to its increased Plt production, while partially inhibiting the growth of H78 strain. Lon protease decreases the abundance and stability of the two-component system response regulator GacA and thus participates in the abovementioned Gac/Rsm cascade and negatively regulates Plt biosynthesis. Similarly, Lon protease also decreases the abundance and stability of transcriptional activator PltR. PltR protein can be directly degraded by the Lon protease but not by a mutated form of Lon protease with an amino acid replacement of S674 -A. In summary, Lon protease negatively regulates Plt biosynthesis via both the Gac/Rsm-mediated global regulatory pathway and the direct degradation of the transcriptional activator PltR in P. protegens H78.

Tale of Three Phosphate Additives for Stabilizing NCM811/Graphite Pouch Cells: Significance of Molecular Structure-Reactivity in Dictating Interphases and Cell Performance.

Electrolyte additives have been extensively used as an economical approach to improve Li-ion battery (LIB) performances; however, their selection has been conducted on an Edisonian trial-and-error basis, with little knowledge about the relationship between their molecular structure and reactivity as well as the electrochemical performance. In this work, a series of phosphate additives with systematic structural variation were introduced with the purpose of revealing the significance of additive structure in building a robust interphase and electrochemical property in LIBs. By comparing the interphases formed by tripropyl phosphate (TPPC1), triallyl phosphate (TPPC2), and tripropargyl phosphate (TPPC3) containing alkane, alkene, and alkyne functionalities, respectively, theoretical calculations and comprehensive characterizations reveal that TPPC3 and TPPC2 exhibit more reactivity than TPPC1, and both can preferentially decompose both reductively and oxidatively, forming dense and protective interphases on both the cathode and anode, but they lead to different long-term cycling behaviors at 55 °C. We herein correlate the electrochemical performance of the high energy Li-ion cells to the molecular structure of these additives, and it is found that the effectiveness of TPPC1, TPPC2, and TPPC3 in preventing gas generation, suppressing interfacial resistance growth, and improving cycling stability can be described as TPPC3 > TPPC2 > TPPC1, i.e., the most unsaturated additive TPPC3 is the most effective additive among them. The established correlation between structure-reactivity and interphase-performance will doubtlessly construct the principle foundation for the rational design of new electrolyte components for future battery chemistry.

Lycium ruthenicum Anthocyanins Attenuate High-Fat Diet-Induced Colonic Barrier Dysfunction and Inflammation in Mice by Modulating the Gut Microbiota.

SCOPE: Gut barrier dysfunction and inflammation originating from a dysbiotic gut microbiota (GM) are strongly associated with a high-fat diet (HFD). Anthocyanins from Lycium ruthenicum (ACs) show antiobesity effects through modulating the GM. However, the mechanism linking the antiobesity effects of ACs and GM modulation remains obscure. METHODS AND RESULTS: To investigate the ameliorative effects of ACs on colonic barrier dysfunction and inflammation, mice are fed an HFD with or without ACs at doses of 50, 100, and 200 mg kg-1 for 12 weeks. AC supplementation reduced weight gain, enriched short-chain fatty acid (SCFA)-producing bacteria (e.g., Ruminococcaceae, Muribaculaceae, Akkermansia, Ruminococcaceae_UCG-014, and Bacteroides) and SCFA content, depleted endotoxin-producing bacteria (e.g., Helicobacter and Desulfovibrionaceae), and decreased endotoxin (i.e., lipopolysaccharide) levels. SCFAs substantially activated G protein-coupled receptors (GPRs), inhibited histone deacetylases (HDAC), increased intestinal tight junction mRNA and protein expression levels, reduced intestinal permeability, and protected intestinal barrier integrity in HFD-induced mice. These effects mitigate intestinal inflammation by inhibiting the LPS/NF-κB/TLR4 pathway. CONCLUSION: These data indicates that ACs can mitigate colonic barrier dysfunction and inflammation, induce SCFA production and inhibit endotoxin production by modulating the GM in HFD-fed mice. This finding provides a clue for understanding the antiobesity effects of ACs.

Comprehensive treatments of tungsten slags in China: A critical review.

As a critical and strategic metal, tungsten is widely used in the fields of machinery, mining and military industry. With most of the tungsten resources reserves in the world, China is the largest producer and exporter of tungsten. This has resulted in the generation of a huge amount of tungsten slag (slag) stored in China. This slag always contains not only valuable elements, such as tungsten (W), scandium (Sc), tin (Sn), niobium (Nb) and tantalum (Ta), but also toxic elements, such as arsenic (As), lead (Pb), chromium (Cr) and mercury (Hg). Due to a lack of developed technologies, most of these slags cannot be treated safely, which results in a waste of resources and serious environmental and ecological risks. In this review we briefly describe the distribution and proportion of tungsten deposits in China, the tungsten extraction process and the properties of tungsten slag. We also mainly discuss the comprehensive treatments for the valuable and toxic slag, including the amounts of valuable metal elements that can be recovered and the stabilization of toxic elements. These aspects are summarized in a comparison of their advantages and disadvantages. In particular, we focus on the efforts to analyze the relationship between the existing processes and attempts to establish a comprehensive technology to treat tungsten slag and also suggest areas for future research.

Health beneficial effects of resistant starch on diabetes and obesity via regulation of gut microbiota: a review.

Resistant starch (RS) is well known to prevent type 2 diabetes mellitus (T2DM) and obesity. Recently, attention has been paid to gut microbiota which mediates the RS's impact on T2DM and obesity, while a mechanistic understanding of how RS prevents T2DM and obesity through gut microbiota is not clear yet. Therefore, this review aims at exploring the underlying mechanisms of it. RS prevents T2DM and obesity through gut microbiota by modifying selective microbial composition to produce starch-degrading enzymes, promoting the production of intestinal metabolites, and improving gut barrier function. Therefore, RS possessing good functional features can be used to increase the fiber content of healthier food. Furthermore, achieving highly selective effects on gut microbiota based on the slight differences of RS's chemical structure and focusing on the effects of RS on strain-levels are essential to manipulate the microbiota for human health.

Predicting circRNA-Disease Associations Based on circRNA Expression Similarity and Functional Similarity.

Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs that have well-conserved sequences. Emerging evidence has shown that circRNAs can be novel biomarkers or therapeutic targets for many diseases and play an important role in the development of various pathological conditions. Therefore, identifying potential disease-related circRNAs is helpful in improving the efficiency of finding therapeutic targets for diseases. Here, we propose a computational model (PreCDA) to predict potential circRNA-disease associations. First, we calculated the circRNA expression similarity based on circRNA expression profiles. The circRNA functional similarity is calculated based on cosine similarity, and the disease similarity is used as the dimension of each circRNA vector. The associations between circRNAs and diseases are defined based on the circRNA functional similarity and expression similarity. We constructed a disease-related circRNA association network and used a graph-based recommendation algorithm (PersonalRank) to sort candidate disease-related circRNAs. As a result, PreCDA has an average area under the receiver operating characteristic curve value of 78.15% in predicting candidate disease-related circRNAs. In addition, we discuss the factors that affect the performance of this method and find some unknown circRNAs related to diseases, with several common diseases used as case studies. These results show that PreCDA has good performance in predicting potential circRNA-disease associations and is helpful for the diagnosis and treatment of human diseases.

A seminaphthorhodafluor-based near-infrared fluorescent probe for hydrazine and its bioimaging in living systems.

Hydrazine (N2H4) has been classified as a potential carcinogen with its high toxicity, which can be readily absorbed through the skin or via breathing directly. Although some fluorescent probes have been developed for imaging of N2H4, very little can be used for imaging of N2H4 in vivo because of its short emission wavelength. In this study, a new colorimetric and near-infrared (NIR) fluorescent probe CF-1 based on a seminaphthorhodafluor dye was successfully designed and used for hydrazine determination. Upon reaction with N2H4, probe CF-1 showed obvious off-on NIR emission spectrum centered at 657 nm, as well as a distinct color change that can be distinguished by the naked eye. The results of fluorescence spectrum experiments indicated that probe CF-1 has high selectivity and low detection limitation (40.6 nM in the solution). Probe CF-1 has low cytotoxicity and was applied to imaging hydrazine in mitochondria of HeLa cells and in zebrafish.

A Pipeline for Reconstructing Somatic Copy Number Alternation's Subclonal Population-Based Next-Generation Sequencing Data.

State-of-the-art next-generation sequencing (NGS)-based subclonal reconstruction methods perform poorly on somatic copy number alternations (SCNAs), due to not only it needs to simultaneously estimate the subclonal population frequency and the absolute copy number for each SCNA, but also there exist complex bias and noise in the tumor and its paired normal sequencing data. Both existing NGS-based SCNA detection methods and SCNA's subclonal population frequency inferring tools use the read count on radio (RCR) of tumor to its paired normal as the key feature of tumor sequencing data; however, the sequencing error and bias have great impact on RCR, which leads to a large number of redundant SCNA segments that make the subsequent process of SCNA's subclonal population frequency inferring and subclonal reconstruction time-consuming and inaccurate. We perform a mathematical analysis of the solution number of SCNA's subclonal frequency, and we propose a computational algorithm to reduce the impact of false breakpoints based on it. We construct a new probability model that incorporates the RCR bias correction algorithm, and by stringing it with the false breakpoint filtering algorithm, we construct a whole SCNA's subclonal population reconstruction pipeline. The experimental result shows that our pipeline outperforms the existing subclonal reconstruction programs both on simulated data and TCGA data. Source code is publicly available as a Python package at https://github.com/dustincys/msphy-SCNAClonal.

Microbiome-Metabolomics Analysis of the Impacts of Long-Term Dietary Advanced-Glycation-End-Product Consumption on C57BL/6 Mouse Fecal Microbiota and Metabolites.

Thermally processed diets are widely consumed, although advanced-glycation end products (AGEs) are unavoidably formed. AGEs, clusters of protein-cross-linking products, become less digestible because they impair intestinal peptidase proteolysis. We characterized the impacts of dietary AGEs on gut microbiota through a microbiome-to-metabolome association study. C57BL/6 mice were fed a heat-treated diet (high-AGE diet, H-AGE) or a standard AIN-93G diet (low-AGE diet, L-AGE) for 8 months. Fecal-microbiota composition was examined by 16S rDNA sequencing, and fecal-metabolome profile was evaluated by gas chromatography-tandem time-of-flight mass spectrometry (GC-TOF-MS). Reduced α-diversity and altered microbiota composition with elevated Helicobacter levels were found in the H-AGE group, and among the 57 perturbed metabolites, protein-fermentation products (i.e., p-cresol and putrescine) were increased. Major dysfunctional metabolic pathways were associated with carbohydrate and amino acid metabolism in two groups. Moreover, high correlations were found between fluctuant gut microbiota and metabolites. These findings might reveal the underlying mechanisms of the detrimental impacts of dietary AGEs on host health.