Microbial genome-wide association studies (GWAS) have uncovered numerous host genetic variants associated with gut microbiota. However, links between host genetics, the gut microbiome and specific cellular contexts remain unclear. Here we use a computational framework, scBPS (single-cell Bacteria Polygenic Score), to integrate existing microbial GWAS and single-cell RNA-sequencing profiles of 24 human organs, including the liver, pancreas, lung and intestine, to identify host tissues and cell types relevant to gut microbes. Analysing 207 microbial taxa and 254 host cell types, scBPS-inferred cellular enrichments confirmed known biology such as dominant communications between gut microbes and the digestive tissue module and liver epithelial cell compartment. scBPS also identified a robust association between Collinsella and the central-veinal hepatocyte subpopulation. We experimentally validated the causal effects of Collinsella on cholesterol metabolism in mice through single-nuclei RNA sequencing on liver tissue to identify relevant cell subpopulations. Mechanistically, oral gavage of Collinsella modulated cholesterol pathway gene expression in central-veinal hepatocytes. We further validated our approach using independent microbial GWAS data, alongside single-cell and bulk transcriptomic analyses, demonstrating its robustness and reproducibility. Together, scBPS enables a systematic mapping of the host-microbe crosstalk by linking cell populations to their interacting gut microbes.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

We evaluated the impact of sex and mitochondrial-haplotype on the age-related changes in the fecal gut microbiome of the genetically heterogeneous rodent model, the OKC-HETB/W rat. The age-related changes in the microbiome differed markedly between male and female rats. Five microbial species changed significantly with age in male rats compared to nine microbial species in female rats. Only three of these microbes changed with age in both male and female rats. The mitochondrial-haplotype of the rats also affected how aging altered the microbiome. Interestingly, most of the microbial species that changed significantly with age were mitochondrial-haplotype and sex specific, i.e., changing in one sex and not the other. We also discovered that sex and mitochondrial-haplotype significantly affected the age-related variations in content of fecal short-chain fatty acids and plasma metabolites that influence or are regulated by the microbiome, e.g., tryptophan derived metabolites and bile acids. This study demonstrates that the host's sex plays a significant role in how the gut microbiome evolves with age, even within a genetically diverse background. Importantly, this is the first study to show that the mitochondrial-haplotype of a host impacts the age-related changes in the microbiome.

Nonalcoholic fatty liver disease (NAFLD) is closely related to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for treating NAFLD. However, the therapeutic effects and potential molecular mechanisms of Lanzhou Lily polysaccharides (LLP) on NAFLD remains unclear. Therefore, the alleviating effects of LLP on NAFLD induced by high-fat diet (HFD) were investigated. LLP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFD-induced NAFLD mice, as evidenced by decreased serum levels of TG, TC, HDL-C and LDL-C. Furthermore, LLP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. LLP also inhibited the TNF-α and IL-1β expression, thereby reducing levels of hepatic proinflammatory cytokines. Furthermore, LLP restored gut microbiota dysbiosis (up-regulated Bacteroidota, Proteobacteria, Alistipes and Lachnospiraceae abundances, down-regulated Firmicutes, Verrucomicrobiota, Desulfobacterota and Turicibacter abundances), and regulated microbial metabolic pathways such as primary bile acid biosynthesis and amino acid metabolism. In addition, the resultes of Spearman's correlation analysis found that some key metabolites in these metabolic pathways were associated with intestinal microorganisms such as Desulfobacterota, Prevotellaceae-UCG-001, Colidextribacter and Alistipes. Therefore, our study suggests that LLP may has potential applications in the treatment of NAFLD by regulating gut microbiota and its metabolite profile.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent type of liver disease worldwide. The exact pathophysiology behind MASLD remains unclear; however, it is thought that a combination of factors or "hits" act as precipitants for disease onset and progression. Abundant evidence supports the roles of diet, genes, metabolic dysregulation, and the intestinal microbiome in influencing the accumulation of lipids in hepatocytes and subsequent progression to inflammation and fibrosis. Currently, there is no cure for MASLD, but lifestyle changes have been the prevailing cornerstones of management. Research is now focusing on the intestinal microbiome as a potential therapeutic target for MASLD, with the spotlight shifting to probiotics, antibiotics, and fecal microbiota transplantation. In this review, we provide an overview of how intestinal microbiota interact with the immune system to contribute to the pathogenesis of MASLD and metabolic dysfunction-associated steatohepatitis (MASH). We also summarize key microbial taxa implicated in the disease and discuss evidence supporting microbial-targeted therapies in its management.

Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected by the gut microbiota. However, studies on the interplay between gut microbiota and tryptophan metabolites in patients undergoing dialysis are lacking. This study aimed to identify the gut microbiota, the indole pathway in tryptophan metabolism, and significant functional differences in ESRD patients with regular hemodialysis. We performed the shotgun metagenome sequencing of stool samples from 85 hemodialysis patients. Using the linear discriminant analysis effect size (LEfSe), we examined the composition of the gut microbiota and metabolic features across varying concentrations of tryptophan and indole metabolites. Higher tryptophan levels promoted tyrosine degradation I and pectin degradation I metabolic modules; lower tryptophan levels were associated with glutamate degradation I, fructose degradation, and valine degradation modules. Higher 3-indoxyl sulfate concentrations were characterized by alanine degradation I, anaerobic fatty acid beta-oxidation, sulfate reduction, and acetyl-CoA to crotonyl-CoA. Contrarily, lower 3-indoxyl sulfate levels were related to propionate production III, arabinoxylan degradation, the Entner-Doudoroff pathway, and glutamate degradation II. The present study provides a better understanding of the interaction between tryptophan, indole metabolites, and the gut microbiota as well as their gut metabolic modules in ESRD patients with regular hemodialysis.

The present systematic review and meta-analysis aimed to summarize the associations between gut microbiota composition and non-alcoholic fatty liver disease. To compare the differences between individuals with or without NAFLD, the standardized mean difference and 95% confidence interval were computed for each α-diversity index and relative abundance of gut microbes. The β-diversity indices were summarized in a qualitative manner. A total of 54 studies with 8894 participants were included. Overall, patients with NAFLD had moderate reduction in α-diversity indices including Shannon (SMD = -0.36, 95% CI = [-0.53, -0.19], p < 0.001) and Chao 1 (SMD = -0.42, 95% CI = [-0.68, -0.17], p = 0.001), but no significant differences were found for Simpson, observed species, phylogenetic diversity, richness, abundance-based coverage estimator, and evenness (p ranged from 0.081 to 0.953). Over 75% of the included studies reported significant differences in β-diversity. Although there was substantial interstudy heterogeneity, especially for analyses at the phylum, class, and family levels, the majority of the included studies showed alterations in the depletion of anti-inflammatory microbes (i.e., Ruminococcaceae and Coprococcus) and the enrichment of proinflammatory microbes (i.e., Fusobacterium and Escherichia) in patients with NAFLD. Perturbations in gut microbiota were associated with NAFLD, commonly reflected by a reduction in beneficial species and an increase in the pathogenic species.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease globally, yet no therapies are approved. The effects of Escherichia coli Nissle 1917 expressing aldafermin, an engineered analog of the intestinal hormone FGF19, in combination with dietary change were investigated as a potential treatment for MASLD.

MASLD was induced in C57BL/6J male mice by American lifestyle-induced obesity syndrome diet and then switched to a standard chow diet for seven weeks. In addition to the dietary change, the intervention group received genetically engineered E. coli Nissle expressing aldafermin, while control groups received either E. coli Nissle vehicle or no treatment. MASLD-related plasma biomarkers were measured using an automated clinical chemistry analyzer. The liver steatosis was assessed by histology and bioimaging analysis using Fiji (ImageJ) software. The effects of the intervention in the liver were also evaluated by RNA sequencing and liquid-chromatography-based non-targeted metabolomics analysis. Pathway enrichment studies were conducted by integrating the differentially expressed genes from the transcriptomics findings with the metabolites from the metabolomics results using Ingenuity pathway analysis.

After the intervention, E. coli Nissle expressing aldafermin along with dietary changes reduced body weight, liver steatosis, plasma aspartate aminotransferase, and plasma cholesterol levels compared to the two control groups. The integration of transcriptomics with non-targeted metabolomics analysis revealed the downregulation of amino acid metabolism and related receptor signaling pathways potentially implicated in the reduction of hepatic steatosis and insulin resistance. Moreover, the downregulation of pathways linked to lipid metabolism and changes in amino acid-related pathways suggested an overall reduction of oxidative stress in the liver.

These data support the potential for using engineered microbial therapeutics in combination with dietary changes for managing MASLD.

Non-alcoholic fatty liver disease (NAFLD) is considered the most common chronic liver disease worldwide, affecting nearly 25% of the global adult population. Increasing evidence suggests that functional and compositional changes in the gut microbiota may contribute to the development and promote the progression of NAFLD. 16S rRNA gene next-generation sequencing is widely used to determine specific features of the NAFLD microbiome, but a complex system such as the gut microbiota requires a comprehensive approach. We used three different approaches: MALDI-TOF-MS of bacterial cultures, qPCR, and 16S NGS sequencing, as well as a wide variety of statistical methods to assess the differences in gut microbiota composition between NAFLD patients without significant fibrosis and the control group. The listed methods showed enrichment in Collinsella sp. and Oscillospiraceae for the control samples and enrichment in Lachnospiraceae (and in particular Dorea sp.) and Veillonellaceae in NAFLD. The families, Bifidobacteriaceae, Lactobacillaceae, and Enterococcaceae (particularly Enterococcus faecium and Enterococcus faecalis), were also found to be important taxa for NAFLD microbiome evaluation. Considering individual method observations, an increase in Candida krusei and a decrease in Bacteroides uniformis for NAFLD patients were detected using MALDI-TOF-MS. An increase in Gracilibacteraceae, Chitinophagaceae, Pirellulaceae, Erysipelatoclostridiaceae, Muribaculaceae, and Comamonadaceae, and a decrease in Acidaminococcaceae in NAFLD were observed with 16S NGS, and enrichment in Fusobacterium nucleatum was shown using qPCR analysis. These findings confirm that NAFLD is associated with changes in gut microbiota composition. Further investigations are required to determine the cause-and-effect relationships and the impact of microbiota-derived compounds on the development and progression of NAFLD.

Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease. Gut dysbiosis is considered a significant contributing factor in disease development. Increased intestinal permeability can be induced by gut dysbiosis, followed by the entry of lipopolysaccharide into circulation to reach peripheral tissue and result in chronic inflammation. We reviewed how microbial metabolites push host physiology toward MAFLD, including short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites. The effects of SCFAs are generally reported as anti-inflammatory and can improve intestinal barrier function and restore gut microbiota. Gut microbes can influence intestinal barrier function through SCFAs produced by fermentative bacteria, especially butyrate and propionate producers. This is achieved through the activation of free fatty acid sensing receptors. Bile is directly involved in lipid absorption. Gut microbes can alter bile acid composition by bile salt hydrolase-producing bacteria and bacterial hydroxysteroid dehydrogenase-producing bacteria. These bile acids can affect host physiology by activating farnesoid X receptor Takeda G protein-coupled receptor 5. Gut microbes can also induce MAFLD-associated symptoms by producing tryptophan metabolites kynurenine, serotonin, and indole-3-propionate. A summary of bacterial genera involved in SCFAs production, bile acid transformation, and tryptophan metabolism is provided. Many bacteria have demonstrated efficacy in alleviating MAFLD in animal models and are potential therapeutic candidates for MAFLD.

Acinetobacter infections have high rates of mortality due to an increasing incidence of infections by multidrug-resistant (MDR) and extensively-drug-resistant (XDR) strains. Therefore, new therapeutic strategies for the treatment of Acinetobacter infections are urgently needed. Acinetobacter spp. are Gram-negative coccobacilli that are obligate aerobes and can utilize a wide variety of carbon sources. Acinetobacter baumannii is the main cause of Acinetobacter infections, and recent work has identified multiple strategies A. baumannii uses to acquire nutrients and replicate in the face of host nutrient restriction. Some host nutrient sources also serve antimicrobial and immunomodulatory functions. Hence, understanding Acinetobacter metabolism during infection may provide new insights into novel infection control measures. In this review, we focus on the role of metabolism during infection and in resistance to antibiotics and other antimicrobial agents and discuss the possibility that metabolism may be exploited to identify novel targets to treat Acinetobacter infections.

The frequency of non-alcoholic fatty liver disease (NAFLD) has intensified, creating diagnostic challenges and increasing the need for reliable non-invasive diagnostic tools. Due to the importance of the gut-liver axis in the progression of NAFLD, studies attempt to reveal microbial signatures in NAFLD, evaluate them as diagnostic biomarkers, and to predict disease progression. The gut microbiome affects human physiology by processing the ingested food into bioactive metabolites. These molecules can penetrate the portal vein and the liver to promote or prevent hepatic fat accumulation. Here, the findings of human fecal metagenomic and metabolomic studies relating to NAFLD are reviewed. The studies present mostly distinct, and even contradictory, findings regarding microbial metabolites and functional genes in NAFLD. The most abundantly reproducing microbial biomarkers include increased lipopolysaccharides and peptidoglycan biosynthesis, enhanced degradation of lysine, increased levels of branched chain amino acids, as well as altered lipid and carbohydrate metabolism. Among other causes, the discrepancies between the studies may be related to the obesity status of the patients and the severity of NAFLD. In none of the studies, except for one, was diet considered, although it is an important factor driving gut microbiota metabolism. Future studies should consider diet in these analyses.

Increasing evidence has suggested the mitigatory efficacy of prebiotic inulin on nonalcoholic fatty liver disease (NAFLD), nevertheless, its action mechanisms remain elusive. Herein, inulin consumption effectively ameliorated high-sucrose diet-induced hepatic steatosis and inflammation, and rehabilitated liver lipogenesis regulators, including carbohydrate response element-binding protein, stearoyl-CoA desaturase-1 and peroxisome proliferator-activated receptor alpha. Furthermore, inulin supplementation restored the intestinal barrier integrity and function by up-regulating expressions of tight junction proteins (zonula occludens-1, claudin-1 and occludin). High-throughput sequencing demonstrated that inulin administration regulated the gut microbiota composition, wherein abundance of short-chain fatty acid (SCFA)-producers, including Bifidobacterium, Phascolarctobacterium and Blautia, was significantly enhanced in the inulin-treated rats, conversely, opportunistic pathogens, such as Acinetobacter and Corynebacterium_1, were suppressed. SCFA quantitative analysis showed that dietary inulin suppressed faecal acetate levels, but improved propionate and butyrate concentrations in rats with NAFLD. Functional prediction showed that tryptophan metabolism was one of the key metabolic pathways affected by gut microbiota changes. A targeted metabolomics profiling of tryptophan metabolism demonstrated that inulin intervention up-regulated faecal contents of indole-3-acetic acid and kynurenic acid, whereas down-regulated levels of kynurenine and 5-hydoxyindoleacetic acid in NAFLD rats. Therefore, this study demonstrated that inulin intake alleviated hepatic steatosis likely by regulating the gut microbiota composition and function and restoring the intestinal barrier integrity, which may provide a novel notion for the prevention and treatment of NAFLD in future.

Tryptophan (TRP) is an essential dietary amino acid that, unless otherwise committed to protein synthesis, undergoes metabolism via the Tryptophan-Kynurenine (TRP-KYN) pathway in vertebrate organisms. TRP and its metabolites have key roles in diverse physiological processes including cell growth and maintenance, immunity, disease states and the coordination of adaptive responses to environmental and dietary cues. Changes in TRP metabolism can alter the availability of TRP for protein and serotonin biosynthesis as well as alter levels of the immune-active KYN pathway metabolites. There is now considerable evidence which has shown that the TRP-KYN pathway can be influenced by various stressors including glucocorticoids (marker of chronic stress), infection, inflammation and oxidative stress, and environmental toxicants. While there is little known regarding the role of TRP metabolism following exposure to environmental contaminants, there is evidence of linkages between chemically induced metabolic perturbations and altered TRP enzymes and KYN metabolites. Moreover, the TRP-KYN pathway is conserved across vertebrate species and can be influenced by exposure to xenobiotics, therefore, understanding how this pathway is regulated may have broader implications for environmental and wildlife toxicology. The goal of this narrative review is to (1) identify key pathways affecting Trp-Kyn metabolism in vertebrates and (2) highlight consequences of altered tryptophan metabolism in mammals, birds, amphibians, and fish. We discuss current literature available across species, highlight gaps in the current state of knowledge, and further postulate that the kynurenine to tryptophan ratio can be used as a novel biomarker for assessing organismal and, more broadly, ecosystem health.