Fusobacterium nucleatum (Fn) has been implicated in various diseases, including colorectal cancer (CRC). This study elucidates Fn's contribution to cholesterol synthesis and the underlying link with CRC, as well as butyrate's counteracting effects in this process. Cells and mouse models were treated with Fn followed/accompanied by butyrate treatments to investigate the interplay between butyrate and Fn's oncogenic properties. Transcriptomics analysis pinpointed Fn's profound impact on cholesterol biosynthesis genes and pathways. Fn treatment upregulated the expression of genes involved in cholesterol synthesis (FDPS, FDFT1, and SQLE) and increased SREBF2 activity in cells and mouse intestines, elevating cholesterol levels in cells, intestines, and sera. Fn upregulated miR-130a-3p, identified through transcriptomics and target prediction, through nuclear factor-κB activation. miR-130a-3p subsequently downregulated AMPKα/β1 expression to activate SREBF2 and upregulate cholesterol biosynthesis genes. These effects were predominantly mitigated by butyrate. Notably, analysis of TCGA data revealed that fusobacterial abundance correlated significantly with the expression of FDPS, FDFT1, SQLE, and AMPKα/β1 in CRC. Fn abundance and miRNA expression in human stools were quantified using qPCR and RT-qPCR. Fecal miR-130a-3p levels increased progressively from normal subjects through adenoma patients to CRC patients, correlating significantly with fecal Fn abundance. Additionally, heightened fecal Fn abundance was associated with an increased incidence of hypercholesterolemia in CRC patients. Fn promotes cholesterol biosynthesis by upregulating miR-130a-3p, which downregulates AMPK proteins and activates SREBF2. This study highlights the influence of gut bacteria on host cholesterol synthesis. Targeted modulation of gut microbiota to reduce cholesterol may represent a promising preventive strategy for CRC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide. The liver communicates with the intestine, in large part through the gut microbiota. Microbial enzymes are key mediators that affect the progression of MASLD and the more severe metabolic dysfunction-associated steatohepatitis (MASH). These enzymes contribute to the metabolism or biosynthesis of steroids, fatty acids, amino acids, ethanol, choline, and intestinal hormones that contribute to disease progression. Additionally, dysbiosis and functional alterations in the microbiota compromise the intestinal barrier, increasing its permeability to bacterial metabolites and liver exposure to microbial-associated molecular patterns (MAMPs), thereby exacerbating liver inflammation and fibrosis. Furthermore, functional alterations in the gut microbiota can modulate intestinal signaling pathways through metabolites or gut hormones, subsequently affecting hepatic metabolism. A deeper understanding of the roles of the gut microbiota and microbial enzymes in MASH will facilitate the development of personalized treatments targeting specific gut microbes or functional enzymes.

Cholesterol serves as a fundamental molecule in various structural and biochemical pathways; however, high cholesterol levels are linked to cardiovascular diseases. Some selected strains of Lactobacilli are known for modulating cholesterol levels. However, the molecular mechanism underlying cholesterol transformation by lactobacilli has remained elusive. This study describes the discovery and function of a microbial 3β-OH-Δ5-6-cholesterol-5β-reductase (5βChR) from Limosilactobacillus fermentum NKN51, which directly converts cholesterol to coprostanol, thereby unraveling this longstanding mystery. Protein engineering of the reductase enzyme identified the cholesterol and NADPH interacting amino acid residues, detailing the catalytic mechanism of 5βChR. Phylogenetic analyses highlight the prevalence of 5βChRs in gut commensal lactobacilli, which share a common evolutionary origin with plant 5β reductases. Meta-analysis of microbiomes from healthy individuals underscores the importance of 5βChR homologs, while a cohort study demonstrates an inverse association between 5βChR abundance and diabetes. The discovery of the 5βChR enzyme and its molecular mechanism in cholesterol metabolism paves the way for a better understanding of the gut-associated microbiome and the design of practical applications to ameliorate dyslipidemia.

Background/Objectives: The gut microbiota plays a pivotal role in host physiology through metabolite production, with lipids serving as essential biomolecules for cellular structure, metabolism, and signaling. This review aims to elucidate the interactions between gut microbiota and lipid metabolism and their implications for enhancing swine production. Methods: We systematically analyzed current literature on microbial lipid metabolism, focusing on mechanistic studies on microbiota-lipid interactions, key regulatory pathways in microbial lipid metabolism, and multi-omics evidence (metagenomic/metabolomic) from swine models. Results: This review outlines the structural and functional roles of lipids in bacterial membranes and examines the influence of gut microbiota on the metabolism of key lipid classes, including cholesterol, bile acids, choline, sphingolipids, and fatty acids. Additionally, we explore the potential applications of microbial lipid metabolism in enhancing swine production performance. Conclusions: Our analysis establishes a scientific framework for microbiota-based strategies to optimize lipid metabolism. The findings highlight potential interventions to improve livestock productivity through targeted manipulation of gut microbial communities.

As immune cells, neutrophils serve as the first line of defense against infections; however, the mechanism by which neutrophils regulate lipid metabolism is unknown. The neutrophil depletion group was treated with 100 μg InVivoMAb anti-mouse Ly6G 6 times, whereas the control group mice were intraperitoneally injected with the same quantity of InVivoMAb rat IgG2a. Body fat content, triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) in the jejunum and ileum, as well as 9 long-chain fatty acids (LCFAs) in the intestinal contents were significantly decreased. Furthermore, genes involved in the absorption of lipids in each segment of the intestine also showed decreased expression. Neutrophil-depletion and control models were administered 25 μCi of 3H-cholesterol by gavage. The distribution of 3H cholesterol in the intestinal segment, heart, liver, serum, and feces was not altered by anti-Ly6G antibodies. Metagenomics was applied to investigate uncultured microorganisms in the intestinal contents to identify bacteria containing lipid metabolism genes. At the species level, 12 bacteria were involved in unsaturated LCFA synthesis, among which 2 increased and 10 decreased. The overall relative abundance of these bacteria decreased from 3.102% to 0.734%. Many genes involved in lipid metabolism were also reduced as a result, such as fatty acid synthase and peroxisome proliferator-activated receptor γ. In conclusion, neutrophil depletion does not affect intestinal lipid absorption in the diet but leads to a decrease in the overall relative abundance of gut bacteria involved in unsaturated LCFA synthesis. Consequently, intestinal lipid synthesis and absorption are reduced.

The oral and gastrointestinal (GI) tract microbiota in humans is susceptible to geographical influences and represents vital factors impacting healthy aging. The northeastern region of China, characterized by distinct dietary and climatic conditions, significantly influences the human microbiome composition. However, the microbial structure of the entire long-lived population in this area has not been evaluated. This study recruited a cohort of 142 individuals aged 55-102 residing in Northeast China, and their oral and gut microbiota were evaluated using full-length 16S rRNA gene amplicon sequencing. The results indicate that the oral and GI tract microbiota of long-lived individuals showed reduced microbial taxonomic richness and evenness compared to sub-longevity individuals. With aging, the core species experience a gradual decline in abundance, while subordinate species show an increase. The long-lived population exhibited a heightened ability to enrich beneficial bacteria including Akkermansia, Alistipes, Parabacteroides, and Eubacterium coprostanoligenes in the GI tract, which are associated with host metabolism and have the potential to act as probiotics, reducing the risks of unhealthy aging in the northeast population. Bifidobacterium sp. and Lactobacillus salivarius have been found to coexist in both the oral cavity and the GI tract of long-lived individuals. We hypothesize that beneficial bacterial taxa from the oral cavity colonize the GI tract more extensively in long-lived individuals compared to those with a shorter lifespan. These findings pave the way for identifying probiotic strains that can promote healthy aging in Northeast China.

Ischemic stroke (IS) is a cerebrovascular disease that predominantly affects middle-aged and elderly populations, exhibiting high mortality and disability rates. At present, the incidence of IS is increasing annually, with a notable trend towards younger affected individuals. Recent discoveries concerning the "gut-brain axis" have established a connection between the gut and the brain. Numerous studies have revealed that intestinal microbes play a crucial role in the onset, progression, and outcomes of IS. They are involved in the entire pathophysiological process of IS through mechanisms such as chronic inflammation, neural regulation, and metabolic processes. Although numerous studies have explored the relationship between IS and intestinal microbiota, comprehensive analyses of specific microbiota is relatively scarce. Therefore, this paper provides an overview of the typical changes in gut microbiota following IS and investigates the role of specific microorganisms in this context. Additionally, it presents a comprehensive analysis of post-stroke microbiological therapy and the relationship between IS and diet. The aim is to identify potential microbial targets for therapeutic intervention, as well as to highlight the benefits of microbiological therapies and the significance of dietary management. Overall, this paper seeks to provide key strategies for the treatment and management of IS, advocating for healthy diets and health programs for individuals. Meanwhile, it may offer a new perspective on the future interdisciplinary development of neurology, microbiology and nutrition.

The recent observational studies have unveiled the correlation between the composition and dynamic alterations of the gut microbiome and aging; however, the causal relationship remains uncertain.

The objective of this study is to investigate the causal relationship between the gut microbiome and accelerated aging as well as frailty, from a genetic perspective.

We obtained data on the gut microbiome, intrinsic epigenetic age acceleration, and Frailty Index from published large-scale genome-wide association studies. A two-sample Mendelian randomization analysis was conducted primarily using inverse variance weighting model. We utilized the MR-Egger intercept analysis, IVW method, the Cochran Q test, and the leave-one-out analysis to assess the robustness of the results.

IVW analysis indicated a potential association between Peptococcus (OR: 1.231, 95% CI 1.013-1.497, P = 0.037), Dialister (OR: 1.447, 95% CI 1.078-1.941, P = 0.014) and Subdoligranulum (OR: 1.538, 95% CI 1.047-2.257, P = 0.028) with intrinsic epigenetic age acceleration; while Prevotella 7 (OR: 0.792, 95% CI 0.672-0.935, P = 0.006) was associated with a potential protective effect. Allisonella (OR: 1.033, 95% CI 1.005-1.063, P = 0.022), Howardella (OR: 1.026, 95% CI 1.002-1.050, P = 0.031) and Eubacterium coprostanoligenes (OR: 1.037, 95% CI 1.001-1.073, P = 0.042) were associated with an increased risk of frailty; conversely, Flavonifractor (OR: 0.954, 95% CI 0.920-0.990, P = 0.012) and Victivallis (OR: 0.984, 95% CI 0.968-1.000, P = 0.049) appeared to exhibit a potential protective effect against frailty.

The findings of this study provide further evidence for the genetic correlation between gut microbiota and accelerated aging as well as frailty, enhancing the understanding of the role of gut microbiota in aging-related processes. However, the underlying mechanisms and potential clinical applications require further investigation before any targeted interventions can be developed.

Sterols and bile acids are vital signaling molecules that play key roles in systemic functions, influencing the composition of the human gut microbiota, which maintains a symbiotic relationship with the host. Additionally, gut microbiota-encoded enzymes catalyze the conversion of sterols and bile acids into various metabolites, significantly enhancing their diversity and biological activities. In this review, we focus on the microbial transformations of sterols and bile acids in the gut, summarize the relevant bacteria, genes, and enzymes, and review the relationship between the sterols and bile acids metabolism of gut microbiota and human health. This review contributes to a deeper understanding of the crucial roles of sterols and bile acids metabolism by gut microbiota in human health, offering insights for further investigation into the interactions between gut microbiota and the host.

The catalytic conversion of chiral alcohols and corresponding carbonyl compounds by carbonyl reductases (alcohol dehydrogenases), which are NAD(P) or NAD(P)H-dependent oxidoreductases, has attracted considerable attention. However, existing carbonyl reductases are insufficient to meet the demands of diverse industrial applications; hence, new enzymes with functions that can expand the toolbox of biocatalysts are urgently required. Developing precisely controlled chiral biocatalysts is of great significance for the efficient development of a broad spectrum of active pharmaceutical ingredients via biosynthesis. In this review, we summarized methods for discovering novel natural carbonyl reductases from various perspectives. Furthermore, advances in protein engineering, utilizing known sequence and structural information as well as catalytic dynamics mechanisms to improve potential functions, are also addressed. The exponential growth in data-driven tools over the past decade has made it possible to de novo design carbonyl reductases. Additionally, various applications of these high-performance carbonyl reductases and different strategies for coenzyme regeneration involving photocatalysis during the reaction process were reviewed. These advancements will bring new opportunities and challenges to the fields of green chemistry and biosynthesis in the future.

Gut microbiome, the group of commensals residing within the intestinal tract, is closely associated with dietary patterns by interacting with food components. The gut microbiome is modifiable by the diet, and in turn, it utilizes the undigested food components as substrates and generates a group of small molecule-metabolites that addressed as "meta-metabolome" in this review. Profiling and mapping of meta-metabolome could yield insightful information at higher resolution and serve as functional readouts for precision nutrition and formation of personalized dietary strategies. For assessing the meta-metabolome, sample preparation is important, and it should aim for retrieval of gut microbial metabolites as intact as possible. The meta-metabolome can be investigated via untargeted and targeted meta-metabolomics with analytical platforms such as nuclear magnetic resonance spectroscopy and mass spectrometry. Employing flux analysis with meta-metabolomics using available database could further elucidate metabolic pathways that lead to biomarker discovery. In conclusion, integration of gut microbiome and meta-metabolomics is a promising supplementary approach to tailor precision dietary intervention. In this review, relationships among diet, gut microbiome, and meta-metabolome are elucidated, with an emphasis on recent advances in alternative analysis techniques proposed for nutritional research. We hope that this review will provide information for establishing pipelines complementary to traditional approaches for achieving precision dietary intervention.

Cholesterol gallstones (CGS) still lack effective noninvasive treatment. The etiology of experimentally proven cholesterol stones remains underexplored. This cross-sectional study aims to comprehensively evaluate potential biomarkers in patients with gallstones and assess the effects of microbiome-targeted interventions in mice. Microbiome taxonomic profiling was conducted on 191 samples via V3-V4 16S rRNA sequencing. Next, 60 samples (30 age- and sex-matched CGS patients and 30 controls) were selected for metagenomic sequencing and fecal metabolite profiling via liquid chromatography-mass spectrometry. Microbiome and metabolite characterizations were performed to identify potential biomarkers for CGS. Eight-week-old male C57BL/6J mice were given a lithogenic diet for 8 weeks to promote gallstone development. The causal relationship was examined through monocolonization in antibiotics-treated mice. The effects of short-chain fatty acids such as sodium butyrate, sodium acetate (NaA), sodium propionate, and fructooligosaccharides (FOS) on lithogenic diet-induced gallstones were investigated in mice. Gut microbiota and metabolites exhibited distinct characteristics, and selected biomarkers demonstrated good diagnostic performance in distinguishing CGS patients from healthy controls. Multi-omics data indicated associations between CGS and pathways involving butanoate and propanoate metabolism, fatty acid biosynthesis and degradation pathways, taurine and hypotaurine metabolism, and glyoxylate and dicarboxylate metabolism. The incidence of gallstones was significantly higher in the Clostridium glycyrrhizinilyticum group compared to the control group in mice. The grade of experimental gallstones in control mice was significantly higher than in mice treated with NaA and FOS. FOS could completely inhibit the formation of gallstones in mice. This study characterized gut microbiome and metabolome alterations in CGS. C. glycyrrhizinilyticum contributed to gallstone formation in mice. Supplementing with FOS could serve as a potential approach for managing CGS by altering the composition and functionality of gut microbiota.

Omega-3 fatty acids are believed to show anti-fibrotic effects by lowering inflammation and regulating the gut microflora. Marine microalgae are an alternative, sustainable source of omega-3 fatty acids to the conventionally used fish oil. Microalgae N. oceanica is a promising source of EPA, one of the essential omega-3 PUFAs. Current study investigates the inhibitory effects of EPA rich N. oceanica biomass against CCl4 induced liver fibrosis in rats. Here, we studied the anti-fibrotic effects in N. oceanica biomass fed groups: T1 - Low dose (4.16 mg/kg EPA), T2 - Medium dose (8.33 mg/kg EPA) and T3 - High dose (16.66 mg/kg EPA), when compared to fish oil fed group (FO - 16.66 mg/kg EPA) as a positive control. The elevated levels of serum liver biomarker enzymes and cholesterol induced by CCl4 showed a significant reduction in T3. Histopathological analysis showed the protective effects of biomass feeding on inflammation and hepatocyte degeneration. In addition, the abundance of the SCFA producing bacteria like Blautia argi, Romboutsia ilealis, Romboutsia timonensis, Stomatobaculum longum and Limosilactobacillus reuteri markedly increased in the PUFA fed groups. The cholesterol metabolising bacteria Eubacterium coprostanoligenes showed a noteworthy increase upon PUFA administration. Overall results indicate that the ameliorative effects observed upon administration of N. oceanica biomass were comparable to FO in a dose dependent manner. Therefore, we can conclude that N. oceanica biomass supplementation is associated with the alleviation of liver fibrosis in rats.

Surgical intervention is currently the primary treatment for hepatolithiasis; however, some patients still experience residual stones and high recurrence rates after surgery. Cholesterol metabolism seems to play an important role in hepatolithiasis pathogenesis. A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis. Therefore, regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery. Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepatolithiasis. This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis, as well as food intake and targeted therapeutic drugs.

Lipids are essential for life and serve as cell envelope components, signaling molecules, and nutrients. For lipids to achieve their required functions, they need to be correctly localized. This requires the action of transporter proteins and an energy source. The current understanding of bacterial lipid transporters is limited to a few classes. Given the diversity of lipid species and the predicted existence of specific lipid transporters, many more transporters await discovery and characterization. These proteins could be prime targets for modulators that control bacterial cell proliferation and pathogenesis. One overarching goal of our research is to understand the molecular mechanisms of bacterial metabolite trafficking, including lipids, and to leverage that understanding to identify or engineer inhibitory ligands. In recent years, our work has revealed two novel lipid transport systems in bacteria: bacterial sterol transporters (Bst) A, B, and C in Methylococcus capsulatus and the TatT proteins in Enhygromyxa salina and Treponema pallidum. Both systems are composed of transporters bioinformatically identified as being involved in the transport of other metabolites, but substrates were never revealed. However, the genetic colocalization of the genes encoding BstABC with sterol biosynthetic enzymes in M. capsulatus suggested that they might recognize sterols as substrates. Also, homologues of TatTs are present in diverse bacteria but are overrepresented in bacteria deficient in de novo lipid synthesis or residing in nutrient-poor environments; we reasoned that these proteins might facilitate the transport of lipids. Our efforts to reveal the substrate scope of two TatT proteins revealed their engagement with long-chain fatty acids. Enabling the discovery of the BstABC system and the TatT proteins were bioinformatic analyses, quantitative measurements of protein-ligand equilibrium affinities, and high-resolution structural studies that provided remarkable insights into ligand binding cavities and the structural basis for ligand interaction. These approaches, in particular our bioinformatics and structural work, highlighted the diversity of protein sequence and structures amenable to lipid engagement. These observations allowed the hypothesis that lipid handling proteins, in general and especially so in the bacterial domain, can have diverse amino acid compositions and three-dimensional structures. As such, bioinformatics geared at identifying them in poorly characterized genomes is likely to miss many candidates that diverge from well-characterized family members. This realization spurred efforts to understand the unifying features in all of the lipid handling proteins we have characterized to date. To do this, we inspected the ligand binding sites of the proteins: they were remarkably hydrophobic and sometimes displayed a dichotomy of hydrophobic and hydrophilic amino acids, akin to the ligands that they accommodate in those cavities. Because of this, we reasoned that the physicochemical features of ligand binding cavities could be accurate predictors of a protein's propensity to bind lipids. This finding was leveraged to create structure-based lipid-interacting pocket predictor (SLiPP), a machine-learning algorithm capable of identifying ligand cavities with physico-chemical features consistent with those of known lipid binding sites. SLiPP is especially useful in poorly annotated genomes (such as with bacterial pathogens), where it could reveal candidate proteins to be targeted for the development of antimicrobials.

This review summarizes the intricate relationship between the microbiome and cancer initiation and development. Microbiome alterations impact metabolic pathways, immune responses, and gene expression, which can accelerate or mitigate cancer progression. We examine how dysbiosis affects tumor growth, metastasis, and treatment resistance. Additionally, we discuss the potential of microbiome-targeted therapies, such as probiotics and fecal microbiota transplants, to modulate cancer metabolism. These interventions offer the possibility of reversing or controlling cancer progression, enhancing the efficacy of traditional treatments like chemotherapy and immunotherapy. Despite promising developments, challenges remain in identifying key microbial species and pathways and validating microbiome-targeted therapies through large-scale clinical trials. Nonetheless, the intersection of microbiome research and cancer initiation and development presents an exciting frontier for innovative therapies. This review offers a fresh perspective on cancer initiation and development by integrating microbiome insights, highlighting the potential for interdisciplinary research to enhance our understanding of cancer progression and treatment strategies.

Since the discovery of statins and the Scandinavian Simvastatin Survival Study (4S) results three decades ago, remarkable advances have been made in the treatment of dyslipidaemia, a major risk factor for atherosclerotic cardiovascular disease. Safe and effective statins remain the cornerstone of therapeutic approach for this indication, including for children with genetic dyslipidaemia, and are one of the most widely prescribed drugs in the world. However, despite the affordability of generic statins, they remain underutilised worldwide. The use of ezetimibe to further decrease plasma LDL cholesterol and the targeting of other atherogenic lipoproteins, such as triglyceride-rich lipoproteins and lipoprotein(a), are likely to be required to further reduce atherosclerotic cardiovascular disease events. Drugs directed at these lipoproteins, including gene silencing and editing methods that durably suppress the production of proteins, such as PCSK9 and ANGPTL3, open novel therapeutic options to further reduce the development of atherosclerotic cardiovascular disease.

In this study, we investigated the influence of the inclusion of Tenebrio molitor (TM) larvae meal in the diet on the diversity and structure of the bacterial community in the caecal content of Barbary partridges. A total of 36 partridges, selected randomly for slaughter from 54 animals, were divided equally into three treatment groups, including the control group (C) with a diet containing corn-soybean meal and two experimental groups, in which 25% (TM25) and 50% (TM50) of the soybean meal protein was replaced by the meal from TM larvae. After slaughtering, the bacterial community of the 30 caecal samples (10 samples per each experimental group) was analysed by high-throughput sequencing using the V4-V5 region of the 16 S rRNA gene. Alpha diversity showed a higher diversity richness in the TM50 group. Beta diversity showed statistical dissimilarities among the three groups. Firmicutes was the dominant phylum regardless of the diet, with the predominant families Ruminococcaceae and Lachnospiraceae. Clostridia and Faecalibacterium were decreased in both TM groups, Lachnospiraceae was suppressed in the TM50 group, but still this class, genus and family were abundantly present in all samples. Several potentially beneficial genera, such as Bacillus, Ruminococcaceae UCG-009, Oscillibacter and UC1-2E3 (Lachnospiraceae) were increased in the TM50 group. The results showed a beneficial effect of the T. molitor larvae meal on the caecal microbiota of Barbary partridges, particularly in the TM50 group, which showed an increase in bacterial diversity.

Metalloenzymes play central roles in the anaerobic metabolism of human gut microbes. They facilitate redox and radical-based chemistry that enables microbial degradation and modification of various endogenous, dietary, and xenobiotic nutrients in the anoxic gut environment. In this review, we highlight major families of iron-sulfur (Fe-S) cluster-dependent enzymes and molybdenum cofactor-containing enzymes used by human gut microbes. We describe the metabolic functions of 2-hydroxyacyl-CoA dehydratases, glycyl radical enzyme activating enzymes, Fe-S cluster-dependent flavoenzymes, U32 oxidases, and molybdenum-dependent reductases and catechol dehydroxylases in the human gut microbiota. We demonstrate the widespread distribution and prevalence of these metalloenzyme families across 5000 human gut microbial genomes. Lastly, we discuss opportunities for metalloenzyme discovery in the human gut microbiota to reveal new chemistry and biology in this important community.

Antibiotics are safe, effective drugs and continue to save millions of lives and prevent long-term illness worldwide. A large body of epidemiological, interventional and experimental evidence shows that exposure to antibiotics has long-term negative effects on human health. We reviewed the literature data on the links between antibiotic exposure, gut dysbiosis, and chronic disease (notably with regard to the "developmental origins of health and disease" ("DOHaD") approach). Molecular biology studies show that the systemic administration of antibiotic to infants has a rapid onset but also often a long-lasting impact on the microbial composition of the gut. Along with other environmental factors (e.g., an unhealthy "Western" diet and sedentary behavior), antibiotics induce gut dysbiosis, which can be defined as the disruption of a previously stable, functionally complete microbiota. Gut dysbiosis many harmful long-term effects on health. Associations between early-life exposure to antibiotics have been reported for chronic diseases, including inflammatory bowel disease, celiac disease, some cancers, metabolic diseases (obesity and type 2 diabetes), allergic diseases, autoimmune disorders, atherosclerosis, arthritis, and neurodevelopmental, neurodegenerative and other neurological diseases. In mechanistic terms, gut dysbiosis influences chronic disease through direct effects on mucosal immune and inflammatory pathways, plus a wide array of direct or indirect effects of short-chain fatty acids, the enteric nervous system, peristaltic motility, the production of hormones and neurotransmitters, and the loss of intestinal barrier integrity (notably with leakage of the pro-inflammatory endotoxin lipopolysaccharide into the circulation). To mitigate dysbiosis, the administration of probiotics in patients with chronic disease is often (but not always) associated with positive effects on clinical markers (e.g., disease scores) and biomarkers of inflammation and immune activation. Meta-analyses are complicated by differences in probiotic composition, dose level, and treatment duration, and large, randomized, controlled clinical trials are lacking in many disease areas. In view of the critical importance of deciding whether or not to prescribe antibiotics (especially to children), we suggest that the DOHaD concept can be logically extended to "gastrointestinal origins of health and disease" ("GOHaD") or even "microbiotic origins of health and disease" ("MOHaD").

The gut microbiome is a vast, variable, and largely unexplored component of human biology that sits at the intersection of heritable and environmental factors, and represents a rich source of novel chemistry that is already known to be compatible with the human body. This alone would make it a promising place to search for new therapeutics, but recent work has also identified gut microbiome abnormalities in patients with a number of psychiatric disorders, including anxiety disorders-suggesting that not only treatments, but cures may lie therein. Here, we'll discuss two known "para-endogenous" anxiolytics-γ-hydroxybutyrate and the neurosteroid allopregnanolone-which have recently been discovered to be produced by the microbiome.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH.

Diet is a major determinant of gut microbiome composition, and variation in diet-microbiome interactions may contribute to variation in their health consequences. To mechanistically understand these relationships, here we map interactions between ∼150 small-molecule dietary xenobiotics and the gut microbiome, including the impacts of these compounds on community composition, the metabolic activities of human gut microbes on dietary xenobiotics, and interindividual variation in these traits. Microbial metabolism can toxify and detoxify these compounds, producing emergent interactions that explain community-specific remodeling by dietary xenobiotics. We identify the gene and enzyme responsible for detoxification of one such dietary xenobiotic, resveratrol, and demonstrate that this enzyme contributes to interindividual variation in community remodeling by resveratrol. Together, these results systematically map interactions between dietary xenobiotics and the gut microbiome and connect toxification and detoxification to interpersonal differences in microbiome response to diet.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health concern that is exacerbated by the obesity pandemic. Dietary interventions have the potential to alleviate obesity-associated MASLD through variable mechanisms, including optimizing the gut microbiota. Previously, we reported that soy protein concentrate (SPC) with low or high levels of isoflavone (LIF or HIF) protected young obese Zucker rats from developing liver steatosis. The current study was designed to test whether SPC-LIF and SPC-HIF diets would reverse liver steatosis and alter fecal microbial composition in adult obese Zucker rats with existing steatosis.

Six-week-old male obese Zucker rats (n = 26) were fed a casein control diet (CAS) for 8 weeks and 7 rats were randomly selected and sacrificed to confirm liver steatosis. The remaining rats were randomly assigned to receive CAS, SPC-LIF, or SPC-HIF diet (n = 6-7/group) for an additional 10 weeks.

Compared to CAS diet, feeding SPC-LIF and SPC-HIF diets resulted in significantly lower liver weight, liver steatosis score, and liver microvesicular score (p < 0.05), but did not lead to difference in body weight, liver macrovesicular score, serum ALT, or serum AST. Isoflavone levels (e.g., LIF vs. HIF) did not affect any of these measurements except in the SPC-HIF group, which had an additional decrease in liver weight (p < 0.05) compared to the SPC-LIF group. The SPC-HIF group also had significantly higher levels of the aglycone forms of daidzein, genistein, and equol as well as the total levels of daidzein, genistein, and equol compared to SPC-LIF or CAS diet fed rats (p < 0.05). The distribution of microbial communities based on measures of beta diversity of both SPC-LIF and SPC-HIF groups were significantly different to that of the CAS group (p ≤ 0.005). Alpha-diversity did not differ between any of the groups.

Taken together, dietary soy protein can reverse liver steatosis in adult Zucker rats, and the reversal of steatosis is accompanied by alterations in gut microbial composition.

Biological aging is linked to altered body composition and reduced neuroactive steroid hormones like dehydroepiandrosterone sulfate (DHEAS), which can stimulate the GABA signaling pathway via gut microbiota. Our study examined the association of gut microbiota with lifespan in mice through comprehensive analysis of its composition and functional involvement in cholesterol sulfate, a precursor of DHEAS, metabolism. We used 16S rRNA and metagenomic sequencing, followed by metabolic pathway prediction and thin layer chromatography and MALDI-TOF cholesterol sulfate identification. Significant increases in bacteria such as Bacteroides, typical for long-lived and Odoribacter and Colidextribacter, specific for short-lived mice were detected. Furthermore, for males (Rikenella and Alloprevotella) and females (Lactobacillus and Bacteroides), specific bacterial groups emerged as predictors (AUC = 1), highlighting sex-specific patterns. Long-lived mice showed a strong correlation of Bacteroides (0.918) with lipid and steroid hormone metabolism, while a negative correlation of GABAergic synapse with body weight (-0.589). We found that several Bacteroides species harboring the sulfotransferase gene and gene cluster for sulfonate donor synthesis are involved in converting cholesterol to cholesterol sulfate, significantly higher in the feces of long-lived individuals. Overall, we suggest that increased involvement of gut bacteria, mainly Bacteroides spp., in cholesterol sulfate synthesis could ameliorate aging through lipid metabolism.

Berberine (BBR) is used to treat diarrhea clinically. However, its reproductive toxicity is unclear. This study aims to investigate the impact of BBR on the male reproductive system. Intragastric BBR administration for 14 consecutive days results in a significant decrease in the serum testosterone concentration, epididymal sperm concentration, mating rate and fecundity of male mice. Testicular treatment with testosterone propionate (TP) partially reverses the damage caused by BBR to the male reproductive system. Mechanistically, the decrease in Muribaculaceae abundance in the gut microbiota of mice is the principal cause of the BBR-induced decrease in the sperm concentration. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment demonstrate that Muribaculaceae is necessary for spermatogenesis. The intragastric administration of Muribaculaceae intestinale to BBR-treated mice restores the sperm concentration and testosterone levels. Metabolomic analysis reveals that BBR affects arginine and proline metabolism, of which ornithine level is downregulated. Combined analysis via 16S rRNA metagenomics sequencing and metabolomics shows that Muribaculaceae regulates ornithine level. The transcriptomic results of the testes indicate that the expressions of genes related to the low-density lipoprotein receptor (LDLR)-mediated testosterone synthesis pathway decrease after BBR administration. The transcriptional activity of the Ldlr gene in TM3 cells is increased with increased ornithine supplementation in the culture media, leading to increased testosterone synthesis. Overall, this study reveals an association between a BBR-induced decrease in Muribaculaceae abundance and defective spermatogenesis, providing a prospective therapeutic approach for addressing infertility-related decreases in serum testosterone triggered by changes in the gut microbiota composition.

Gut microbiota plays a vital role in host metabolism; however, the influence of gut microbes on polyamine metabolism is unknown. Here, we found germ-free models possess elevated polyamine levels in the colon. Mechanistically, intestinal Lactobacillus murinus-derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by targeting the expression of enzymes in polyamine metabolism. In addition, Lactobacillus murinus delays recovery of dextran sodium sulfate-induced colitis by reducing polyamine levels in mice. Notably, a decline in the abundance of small RNAs was observed in the colon of mice with colorectal cancer (CRC) and human CRC specimens, accompanied by elevated polyamine levels. Collectively, our study identifies a specific underlying mechanism used by intestinal microbiota to modulate host polyamine metabolism, which provides potential intervention for the treatment of polyamine-associated diseases.

The understanding that changes in microbiome composition can influence chronic human diseases and the efficiency of therapies has driven efforts to develop microbiota-centred therapies such as first and next generation probiotics, prebiotics and postbiotics, microbiota editing and faecal microbiota transplantation. Central to microbiome research is understanding how disease impacts microbiome composition and vice versa, yet there is a problematic issue with the term 'dysbiosis', which broadly links microbial imbalances to various chronic illnesses without precision or definition. Another significant issue in microbiome discussions is defining 'healthy individuals' to ascertain what characterises a healthy microbiome. This involves questioning who represents the healthiest segment of our population-whether it is those free from illnesses, athletes at peak performance, individuals living healthily through regular exercise and good nutrition or even elderly adults or centenarians who have been tested by time and achieved remarkable healthy longevity.This review advocates for delineating 'what defines a healthy microbiome?' by considering a broader range of factors related to human health and environmental influences on the microbiota. A healthy microbiome is undoubtedly linked to gut health. Nevertheless, it is very difficult to pinpoint a universally accepted definition of 'gut health' due to the complexities of measuring gut functionality besides the microbiota composition. We must take into account individual variabilities, the influence of diet, lifestyle, host and environmental factors. Moreover, the challenge in distinguishing causation from correlation between gut microbiome and overall health is presented.The review also highlights the resource-heavy nature of comprehensive gut health assessments, which hinders their practicality and broad application. Finally, we call for continued research and a nuanced approach to better understand the intricate and evolving concept of gut health, emphasising the need for more precise and inclusive definitions and methodologies in studying the microbiome.

The metabolism of steroids by the gut microbiome affects hormone homeostasis, impacting host development, mental health, and reproductive functions. In this study, we identify the Δ4-3-ketosteroid 5β-reductase, 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, and Δ6-3-ketosteroid reductase enzyme families encoded by common human gut bacteria. Through phylogenetic reconstruction and mutagenesis, We show that 5β-reductase and Δ6-3-ketosteroid reductase have evolved to specialize in converting diverse 3-keto steroid hormones into their 5β- and Δ6-reduced derivatives. We also find that the novel 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase is fused with 5β-reductase in multiple species, streamlining the multi-step conversion of pregnenolone, a steroid hormone precursor, into epipregnanolone. Through metagenomic analysis, we reveal that these enzymes are prevalent in healthy populations, being enriched in females over males. These findings provide the molecular basis for studying microbial steroid metabolism in the gut, offering insights into its potential impact on hormonal health in hosts, especially in the context of women's health.

Evidence indicates that both vitamin D and the gut microbiome are involved in the process of colon carcinogenesis. However, it is unclear what effects supplemental vitamin D3 has on the gut microbiome and its metabolites in healthy adults. We conducted a double-blind, randomized, placebo-controlled trial to identify the acute and long-term microbiota structural and metabolite changes that occur in response to a moderate dose (4,000 IU) of vitamin D3 for 12 weeks in healthy adults. Our results demonstrated a significant increase in serum 25-hydroxy-vitamin D (25(OH)D) in the treatment group compared to placebo (P < 0.0001). Vitamin D3 significantly increased compositional similarity (P < 0.0001) in the treatment group, and enriched members of the Bifidobacteriaceae family. We also identified a significant inverse relationship between the percent change in serum 25(OH)D and microbial stability in the treatment group (R = -0.52, P < 0.019). Furthermore, vitamin D3 supplementation resulted in notable metabolic shifts, in addition to resulting in a drastic rewiring of key gut microbial-metabolic associations. In conclusion, we show that a moderate dose of vitamin D3 among healthy adults has unique acute and persistent effects on the fecal microbiota, and suggest novel mechanisms by which vitamin D may affect the host-microbiota relationship.

Preventative measures to reduce the rise in early-onset colorectal cancer are of critical need. Both vitamin D, dietary and serum levels, and the gut microbiome are implicated in the etiology of colorectal cancer. By understanding the intimate relationship between vitamin D, the gut microbiome, and its metabolites, we may be able to identify key mechanisms that can be targeted for intervention, including inflammation and metabolic dysfunction. Furthermore, the similarity of vitamin D to cholesterol, which is metabolized by the gut microbiome, gives precedence to its ability to produce metabolites that can be further studied and leveraged for controlling colorectal cancer incidence and mortality.

The interactions between dietary cholesterol and intestinal microbiota strongly affect host health. Sulfonation is a major conjugating pathway responsible for regulating the chemical and functional homeostasis of endogenous and exogenous molecules. However, the role of cholesterol sulfonation metabolism in the host remains unclear. This work was designed to profile cholesterol-specific host-microbe interaction and conversion focusing on cholesterol sulfonation metabolism. Results indicated that the serum and fecal cholesterol sulfate (CHS) levels were significantly higher than those of total bile acid (TBA) levels in hypercholesterolemic mice. Deletion of the gut microbiota by antibiotics could dramatically increase total cholesterol (TC) levels but it decreased CHS levels in a pseudo-germ-free (PGF) mouse host. 16S rRNA gene sequencing assay and correlation analysis between the abundance of various intestinal bacteria (phylum and class) and the CHS/TC ratio showed that the intestinal genera Bacteroides contributed essentially to cholesterol sulfonation metabolism. These results were further confirmed in an in situ and ex vivo mouse intestinal model, which indicated that the sulfonation metabolism rate of cholesterol could reach 42% under high cholesterol conditions. These findings provided new evidence that the sulfonation metabolic pathway dominated cholesterol metabolism in hypercholesterolemic mice and microbial conversion of cholesterol-to-CHS was of vital importance for cholesterol-lowering by Bacteroides. This suggested that the gut microbiota could regulate cholesterol metabolism and that it was feasible to reduce cholesterol levels by dietary interventions involving the gut microbiota.

Despite recent advances, severe acute pancreatitis (SAP) remains a lethal inflammation with limited treatment options. Here, we provide compelling evidence of GV-971 (sodium oligomannate), an anti-Alzheimer's medication, as being a protective agent in various male mouse SAP models. Microbiome sequencing, along with intestinal microbiota transplantation and mass cytometry technology, unveil that GV-971 reshapes the gut microbiota, increasing Faecalibacterium populations and modulating both peripheral and intestinal immune systems. A metabolomics analysis of cecal contents from GV-971-treated SAP mice further identifies short-chain fatty acids, including propionate and butyrate, as key metabolites in inhibiting macrophage M1 polarization and subsequent lethal inflammation by blocking the MAPK pathway. These findings suggest GV-971 as a promising therapeutic for SAP by targeting the microbiota metabolic immune axis.

Gut bacteria are related to colorectal cancer (CRC) and its clinicopathologic characteristics.

To develop gut bacterial subtypes and explore potential microbial targets for CRC.

Stool samples from 914 volunteers (376 CRCs, 363 advanced adenomas, and 175 normal controls) were included for 16S rRNA sequencing. Unsupervised learning was used to generate gut microbial subtypes. Gut bacterial community composition and clustering effects were plotted. Differences of gut bacterial abundance were analyzed. Then, the association of CRC-associated bacteria with subtypes and the association of gut bacteria with clinical information were assessed. The CatBoost models based on gut differential bacteria were constructed to identify the diseases including CRC and advanced adenoma (AA).

Four gut microbial subtypes (A, B, C, D) were finally obtained via unsupervised learning. The characteristic bacteria of each subtype were Escherichia-Shigella in subtype A, Streptococcus in subtype B, Blautia in subtype C, and Bacteroides in subtype D. Clinical information (e.g., free fatty acids and total cholesterol) and CRC pathological information (e.g., tumor depth) varied among gut microbial subtypes. Bacilli, Lactobacillales, etc., were positively correlated with subtype B. Positive correlation of Blautia, Lachnospiraceae, etc., with subtype C and negative correlation of Coriobacteriia, Coriobacteriales, etc., with subtype D were found. Finally, the predictive ability of CatBoost models for CRC identification was improved based on gut microbial subtypes.

Gut microbial subtypes provide characteristic gut bacteria and are expected to contribute to the diagnosis of CRC.

Persistent colonization and outgrowth of potentially pathogenic organisms in the intestine can result from long-term antibiotic use or inflammatory conditions, and may perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, although an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5-7. Here we isolated and down-selected commensal bacterial consortia from stool samples from healthy humans that could strongly and specifically suppress intestinal Enterobacteriaceae. One of the elaborated consortia, comprising 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby re-establishing colonization resistance and alleviating Klebsiella- and Escherichia-driven intestinal inflammation in mice. Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection.

The role of the gut microbiota in host physiology has been previously elucidated for some marine organisms, but little information is available on their metabolic activity involved in transformation of environmental pollutants. This study assessed the metabolic profiles of the gut microbial cultures from grouper (Epinephelus coioides), green mussel (Perna viridis) and giant tiger prawn (Penaeus monodon) and investigated their transformation mechanisms to typical plastic additives. Community-level physiological profiling analysis confirmed the utilization profiles of the microbial cultures including carbon sources of carbohydrates, amines, carboxylic acids, phenolic compounds, polymers and amino acids, and the plastic additives of organophosphate flame retardants, tetrabromobisphenol A derivates and bisphenols. Using in vitro incubation, triphenyl phosphate (TPHP) was found to be rapidly metabolized into diphenyl phosphate by the gut microbiota as a representative ester-containing plastic additive, whereas the transformation of BPA (a representative phenol) was relatively slower. Interestingly, all three kinds of microbial cultures efficiently transformed the hepatic metabolite of BPA (BPA-G) back to BPA, thereby increasing its bioavailability in the body. The specific enzyme analysis confirmed the ability of the gut microbiota to perform the metabolic reactions. The results of 16S rRNA sequencing and network analysis revealed that the genera Escherichia-Shigella, Citrobacter, and Anaerospora were functional microbes, and their collaboration with fermentative microbes played pivotal roles in the transformation of the plastic additives. The structure-specific transformations by the gut microbiota and their distinct bioavailability deserve more attention in the future.

Consumption of whole grains is associated with a reduction in chronic diseases and offers benefits for cardiovascular health and metabolic regulation. The relationship between whole-grain corn and corn bran with the gut microbiota (GM) remains an area of growing interest, particularly regarding their influence on cardiometabolic health.

To investigate the effects of different corn flours on cardiometabolic outcomes and GM changes in adults with elevated low-density lipoprotein cholesterol (LDL cholesterol) concentrations.

In this crossover study, 36 adults with LDL cholesterol above 110 mg/dL consumed 48 g/d of 3 corn flour types for 4 wk: whole-grain corn meal, refined corn meal (RCM), and a blend of RCM and corn bran (RCM + B). We assessed the impact on cardiometabolic markers [LDL cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), total cholesterol, and triglycerides)] and GM composition and estimated function. Statistical analyses included mixed-effects modeling and responder (>5% decrease in LDL cholesterol) analysis to evaluate changes in GM related to lipid profile improvements.

Of the 3 corn flour types, only RCM + B significantly decreased LDL cholesterol over time (-10.4 ± 3.6 mg/dL, P = 0.005) and marginally decreased total cholesterol (-9.2 ± 3.9 mg/dL, P = 0.072) over time. There were no significant effects on HDL cholesterol or triglyceride concentrations. No significant changes were observed in GM alpha diversity, whereas beta diversity metrics indicated individual variability. Two genera, unclassified Lachnospiraceae and Agathobaculum (Padj ≤ 0.096), differed significantly by treatment, but only Agathobaculum remained significantly elevated in the whole-grain corn meal, compared to RCM and RCM + B, after adjustment for multiple comparisons.

The type of corn flour, particularly RCM + B, notably influenced LDL cholesterol concentrations in adults with elevated LDL cholesterol. This study suggests that incorporating milled fractions (e.g., bran) of whole-grain corn with refined corn flour may be a viable alternative to supplementing manufactured grain products with isolated or synthetic fibers for improved metabolic health. This trial was registered at clinicaltrials.gov as NCT03967990.