The metabolic landscape of connective tissue diseases: Applications and discoveries in metabolomics research.

The Gut Microbiome in Health and Disease

Gut microbiota is expected to coevolve with the host's physiology and may play a role in adjusting the host's energy metabolism to suit the host's environment. To evaluate the effects of both evolved host metabolism and the environmental context in shaping the gut microbiota, we used a unique combination of (1) experimental evolution to create selection lines for a fast metabolism and (2) a laboratory-to-field translocation study. Mature bank voles Myodes glareolus from lines selected for high aerobic capacity (A lines) and from unselected control (C lines) were released into large (0.2 ha) outdoor enclosures for longitudinal monitoring. To examine whether the natural environment elicited a similar or more pronounced impact on the gut microbiota of the next generation, we also sampled the field-reared offspring. The gut microbiota were characterized using 16S rRNA amplicon sequencing of fecal samples. The artificial selection for fast metabolism had minimal impact on the gut microbiota in laboratory conditions but in field conditions, there were differences between the selection lines (A lines vs. C lines) in the diversity, community, and resilience of the gut microbiota. Notably, the selection lines differed in the less abundant bacteria throughout the experiment. The lab-to-field transition resulted in an increase in alpha diversity and an altered community composition in the gut microbiota, characterized by a significant increase in the relative abundance of Actinobacteria and a decrease of Patescibacteria. Also, the selection lines showed different temporal patterns in changes in microbiota composition, as the average gut microbiota alpha diversity of the C lines, but not A lines, was temporarily reduced during the initial transition to the field. In surviving young voles, the alpha diversity of gut microbiota was significantly higher in A-line than C-line voles. These results indicate that the association of host metabolism and gut microbiota is context-specific, likely mediated by behavioral or physiological modifications in response to the environment.

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.

The gut microbiota is integral to the health and adaptability of wild herbivores. Interactions with soil microbiota can shape the composition and function of the gut microbiota, thereby influencing the hosts' adaptive strategies. As a result, soil microbiota plays a pivotal role in enabling wild herbivores to thrive in extreme environments. However, the influence of soil microbiota from distinct regions on host's gut microbiota has often been overlooked. We conducted the first comprehensive analysis of the composition and diversity of gut and soil microbiota in goitered gazelles across six regions in the Qaidam Basin, utilizing source tracking and ecological assembly process analyses. Significant differences were observed in the composition and diversity of soil and gut microbiota among the six groups. Source tracking analysis revealed that soil microbiota in the GangciGC (GC) group contributed the highest proportion to fecal microbiota (8.94%), while the Huaitoutala (HTTL) group contributed the lowest proportion (1.80%). The GC group also exhibited the lowest α-diversity in gut microbiota. The observed differences in gut microbial composition and diversity among goitered gazelles from six regions in the Qaidam Basin were closely tied to their adaptive strategies. Ecological assembly process analysis indicated that the gut microbiota were primarily influenced by stochastic processes, whereas deterministic processes dominated most soil microbial groups. Both the differences and commonalities in gut and soil microbiota play essential roles in enabling these gazelles to adapt to diverse environments. Notably, the utilization pattern of soil microbiota by gut microbiota did not align with regional trends in gut microbial α-diversity. This discrepancy may be attributed to variations in environmental pressures and the gut's filtering capacity, allowing gazelles to selectively acquire microbiota from soil to maintain homeostasis. This study highlights the significant regional variation in gut and soil microbiota diversity among goitered gazelle populations in the Qaidam Basin and underscores the critical role of soil-derived microbiota in their environmental adaptation.

Shaping the future of gastrointestinal cancers through metabolic interactions with host gut microbiota

To characterize the impact of gut microbiota on host metabolism, we investigated the multicompartmental metabolic profiles of a conventional mouse strain (C3H/HeJ) (n=5) and its germ-free (GF) equivalent (n=5). We confirm that the microbiome strongly impacts on the metabolism of bile acids through the enterohepatic cycle and gut metabolism (higher levels of phosphocholine and glycine in GF liver and marked higher levels of bile acids in three gut compartments). Furthermore we demonstrate that (1) well-defined metabolic differences exist in all examined compartments between the metabotypes of GF and conventional mice: bacterial co-metabolic products such as hippurate (urine) and 5-aminovalerate (colon epithelium) were found at reduced concentrations, whereas raffinose was only detected in GF colonic profiles. (2) The microbiome also influences kidney homeostasis with elevated levels of key cell volume regulators (betaine, choline, myo-inositol and so on) observed in GF kidneys. (3) Gut microbiota modulate metabotype expression at both local (gut) and global (biofluids, kidney, liver) system levels and hence influence the responses to a variety of dietary modulation and drug exposures relevant to personalized health-care investigations.

The gut microbiota is considered a relevant factor in obesity and associated metabolic diseases, for which postmenopausal women are particularly at risk. Increasing physical activity has been recognized as an efficacious approach to prevent or treat obesity, yet the impact of physical activity on the microbiota remains under-investigated. We examined the impacts of voluntary exercise on host metabolism and gut microbiota in ovariectomized (OVX) high capacity (HCR) and low capacity running (LCR) rats. HCR and LCR rats (age = 27wk) were OVX and fed a high-fat diet (45% kcal fat) ad libitum and housed in cages equipped with (exercise, EX) or without (sedentary, SED) running wheels for 11wk (n = 7-8/group). We hypothesized that increased physical activity would hinder weight gain, increase metabolic health and shift the microbiota of LCR rats, resulting in populations more similar to that of HCR rats. Animals were compared for characteristic metabolic parameters including body composition, lipid profile and energy expenditure; whereas cecal digesta were collected for DNA extraction. 16S rRNA gene-based amplicon Illumina MiSeq sequencing was performed, followed by analysis using QIIME 1.8.0 to assess cecal microbiota. Voluntary exercise decreased body and fat mass, and normalized fasting NEFA concentrations of LCR rats, despite only running one-third the distance of HCR rats. Exercise, however, increased food intake, weight gain and fat mass of HCR rats. Exercise clustered the gut microbial community of LCR rats, which separated them from the other groups. Assessments of specific taxa revealed significant (p<0.05) line by exercise interactions including shifts in the abundances of Firmicutes, Proteobacteria, and Cyanobacteria. Relative abundance of Christensenellaceae family was higher (p = 0.026) in HCR than LCR rats, and positively correlated (p<0.05) with food intake, body weight and running distance. These findings demonstrate that exercise differentially impacts host metabolism and gut microbial communities of female HCR and LCR rats without ovarian function.

Gut microbiota play key roles in host nutrition and metabolism. However, little is known about the relationship between host genetics, gut microbiota and metabolic profiles. Here, we used high-throughput sequencing and gas chromatography/mass spectrometry approaches to characterize the microbiota composition and the metabolite profiles in the gut of five cyprinid fish species with three different feeding habits raised under identical husbandry conditions. Our results showed that host species and feeding habits significantly affect not only gut microbiota composition but also metabolite profiles (ANOSIM, p ≤ 0.05). Mantel test demonstrated that host phylogeny, gut microbiota, and metabolite profiles were significantly related to each other (p ≤ 0.05). Additionally, the carps with the same feeding habits had more similarity in gut microbiota composition and metabolite profiles. Various metabolites were correlated positively with bacterial taxa involved in food degradation. Our results shed new light on the microbiome and metabolite profiles in the gut content of cyprinid fishes, and highlighted the correlations between host genotype, fish gut microbiome and putative functions, and gut metabolite profiles.

Nonalcoholic fatty liver disease is the most prevalent chronic liver disease worldwide. It is now updated as metabolic dysfunction-associated steatotic liver disease (MASLD). The progression of MASLD to hepatocellular carcinoma (HCC) involves complex mechanisms, with the gut microbiota (GM) and its metabolites playing a pivotal role in this transformation through the "gut-liver axis." This review systematically summarizes the characteristics of GM dysbiosis in patients with MASLD and the regulatory mechanisms of its metabolites (e.g., short-chain fatty acids, secondary bile acids, trimethylamine N-oxide, and lipopolysaccharides) in the progression from MASLD to HCC. Short-chain fatty acids exert protective effects in the early stages by enhancing the intestinal barrier and modulating immune and metabolic responses. However, metabolic disturbances, such as the "paradoxical effect" of butyrate and the lipogenic effect of acetate, may promote the formation of a tumor microenvironment in the later stages. Secondary bile acids (e.g., deoxycholic acid) exacerbate liver fibrosis and carcinogenesis by activating inflammatory pathways (nuclear factor-κB and mitogen-activated protein kinase), inducing oxidative stress, and inhibiting foresaid X receptor signaling. Trimethylamine N-oxide directly drives HCC progression by activating the mitogen-activated protein kinase/nuclear factor-κB pathway, promoting epithelial-mesenchymal transition, and creating an immunosuppressive microenvironment. Lipopolysaccharide accelerates fibrosis and metabolic reprogramming through toll-like receptor 4-mediated chronic inflammation and hepatic stellate cell activation. This review highlights that the dynamic changes in GM metabolites are closely associated with MASLD-HCC progression. Specific monitoring of these metabolites may serve as potential biomarkers for early detection. Furthermore, gut-targeted therapies (e.g., fecal microbiota transplantation) have shown translational potential. Future studies are needed to further validate their clinical value and develop precise prevention and treatment strategies.

Objective To determine the prevalence of echocardiographic findings and their change over time in patients with connective tissue diseases (CTDs) and to analyse which findings were associated with escalation of immunosuppressive therapy. Method We conducted a retrospective cohort study of consecutive hospitalized patients from a tertiary rheumatology referral centre who received transthoracic echocardiography between 1 January 2006 and 31 December 2015. We tested for associations between echocardiographic findings and treatment escalation via Fisher’s exact test; p < 0.05 was considered significant. Escalation of therapy was defined by dosage of glucocorticoids and type of disease-modifying anti-rheumatic drug. The clinical relevance of echocardiographic findings concerning change in immunosuppressive therapy was recorded. Results In total, 1004 patients were included (865 females), with a total of 1660 echocardiographic examinations. The most frequent findings were mitral, tricuspid, and aortic valve regurgitation (found in 36.7%, 25.4%, and 17.7% of all patients), aortic valve sclerosis (20.1%), left ventricular dysfunction (21.5%), and left atrial dilatation (19.2%). Only pericardial effusions were more frequent in cases with treatment escalation (10.9% of cases with escalated therapy vs 6.9% of cases without, p = 0.007). In 314 patients who received follow-up examinations, echocardiographic findings were found to change between examinations. Only 73 of all 1660 examinations were discussed in depth considering the treatment strategy in the hospital discharge letter. Conclusion Patients with CTDs exhibited a wide, dynamically changing spectrum of echocardiographic abnormalities. Most findings neither reflected disease activity nor appeared to influence the therapeutic regimen.

Dioxin-like polychlorinated biphenyl 126 (PCB126) disrupts gut microbiota-host metabolic dysfunction in mice via aryl hydrocarbon receptor activation

Alzheimer's disease, a progressively degenerative neurological disorder, is the most common cause of dementia in the elderly. While its precise etiology remains unclear, researchers have identified diverse pathological characteristics and molecular pathways associated with its progression. Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease. These non-coding RNAs regulate several biological processes critical to the advancement of the disease, offering promising potential as therapeutic targets and diagnostic biomarkers. Therefore, this review aims to investigate the underlying mechanisms of Alzheimer's disease onset, with a particular focus on microRNAs, long non-coding RNAs, and circular RNAs associated with the disease. The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs. It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease, as well as how these non-coding RNAs influence the disease's progression by regulating gene expression and protein functions. For example, miR-9 targets the UBE4B gene, promoting autophagy-mediated degradation of Tau protein, thereby reducing Tau accumulation and delaying Alzheimer's disease progression. Conversely, the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA, promoting the generation of amyloid-β and accelerating Alzheimer's disease development. Additionally, circular RNAs play significant roles in regulating neuroinflammatory responses. By integrating insights from these regulatory mechanisms, there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease. This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs, potentially paving the way for early detection and novel treatment strategies.

Dioxin-like PCB 126 increases intestinal inflammation and disrupts gut microbiota and metabolic homeostasis

Epithelial ovarian cancer (EOC) is a deadly disease with limited diagnostic biomarkers and therapeutic targets. Here we conduct a comprehensive proteomic profiling of ovarian tissue and plasma samples from 813 patients with different histotypes and therapeutic regimens, covering the expression of 10,715 proteins. We identify eight proteins associated with tumor malignancy in the tissue specimens, which are further validated as potential circulating biomarkers in plasma. Targeted proteomics assays are developed for 12 tissue proteins and 7 blood proteins, and machine learning models are constructed to predict one-year recurrence, which are validated in an independent cohort. These findings contribute to the understanding of EOC pathogenesis and provide potential biomarkers for early detection and monitoring of the disease. Additionally, by integrating mutation analysis with proteomic data, we identify multiple proteins related to DNA damage in recurrent resistant tumors, shedding light on the molecular mechanisms underlying treatment resistance. This study provides a multi-histotype proteomic landscape of EOC, advancing our knowledge for improved diagnosis and treatment strategies.

Recent studies have made significant advances in understanding the mechanisms of gut microbiota involved in human health and disease [1,2].Now the gut microbiota has been recognized as a key player in a broad spectrum of human diseases from obesity associated liver and cardiovascular diseases to mental development and psychiatric diseases [3,4].Accordingly, modulations of gut microbial diversity and composition are expected to improve human health and to provide novel therapeutic modalities for human disease.The gut microbial modulators can be simply specific diets and drinks, natural tea and Chinese herbs, or specialized prebiotics and probiotics.In this special issue, authors presented a number of very interesting studies on changes of gut microbiota in digestive diseases.These review and original articles of research and clinical studies cover a range of topics, including the pathogenesis of alcoholic and nonalcoholic fatty liver diseases (NAFLD), the outcome of intestinal bacterial translocation in advanced cirrhosis, the gut microbiota changes in an animal colitis model after treatment with a monoclonal antibody, and fecal microbiota transplantation (FMT) in elderly patients with refractory Clostridium difficile infection.In these articles, authors have described mechanisms of disease development as well as therapeutic effects of specific antibodies, probiotics, and FMT.While we know the simple cause of alcoholic fatty liver disease (AFLD), its pathogenesis is complicated and it