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Chronic liver diseases impose a considerable global public health burden, yet available treatment options remain largely inadequate. The gut microbiota exerts a key modulatory effect on liver disease pathogenesis via the gut-liver axis. Among them, Lachnospiraceae, a dominant bacterial family in the healthy adult gut, has drawn growing interest in recent years. Lachnospiraceae exert protective functions by producing short-chain fatty acids, participating in secondary bile acid conversion, and synthesizing active metabolites such as N-acetyl-glutamic acid, thereby maintaining intestinal barrier integrity and regulating host metabolic and immune homeostasis. Extensive evidence indicates that in cirrhosis, alcohol-associated liver disease, and metabolic dysfunction-associated steatotic liver disease, Lachnospiraceae abundance is consistently and significantly reduced, and this decrease is closely correlated with disease severity and adverse prognosis. In hepatocellular carcinoma, however, different members of Lachnospiraceae exhibit functional divergence, with some butyrate-producing genera decreasing while other subgroups may become enriched and influence the tumor immune microenvironment. Live biotherapeutic products based on Lachnospiraceae have achieved clinical breakthroughs in recurrent Clostridioides difficile infection and metabolic syndrome, providing important references for their translational application in liver diseases. This review systematically synthesizes the abundance changes and mechanisms of Lachnospiraceae across major liver diseases, evaluates their biomarker and therapeutic target potential, and seeks to provide fresh perspectives for precision microbiome-modulating strategies in chronic liver disease management. Full article

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors comprising three isoforms—PPARα, PPARγ, and PPARβ/δ—that regulate hepatic lipid metabolism, glucose homeostasis, inflammation, bile acid synthesis, and fibrogenesis. Because liver diseases involve overlapping metabolic, inflammatory, cholestatic, and fibrotic pathways, PPAR agonists have emerged as a versatile therapeutic class across a spectrum of hepatic conditions. PPARα agonists (e.g., fenofibrate) promote fatty acid β-oxidation and suppress de novo lipogenesis; PPARγ agonists (e.g., pioglitazone) improve insulin sensitivity and exert anti-inflammatory and antifibrotic effects; and PPARδ agonists (e.g., seladelpar) regulate bile acid and cholesterol metabolism. Dual agonists (elafibranor [PPARα/δ] and saroglitazar [PPARα/γ]) and pan-PPAR agonists (lanifibranor [PPARα/γ/δ] and bezafibrate) aim to simultaneously address multiple pathogenic mechanisms. In primary biliary cholangitis (PBC), elafibranor and seladelpar received accelerated FDA approval in 2024 based on phase 3 trials (ELATIVE and RESPONSE, respectively), demonstrating significant biochemical response rates of 51% and 62% versus 4% and 20% with the placebo. Long-term open-label extension data from the ELATIVE trial have demonstrated sustained improvements in cholestatic biomarkers and stabilization of fibrosis markers over three years, with durable benefits on fatigue and pruritus. The ASSURE open-label study has confirmed the durability of seladelpar’s effects on biochemical response and pruritus through up to two years of treatment. Saroglitazar, a dual PPARα/γ agonist, has shown positive topline phase 3 results in the EPICS-III trial and received an FDA priority review designation. Bezafibrate has shown a survival benefit in large retrospective analyses and is used as a second-line therapy in Europe and Japan; notably, bezafibrate functions as a dual PPAR/pregnane X receptor (PXR) agonist, inducing CYP3A4 and efflux transporters that contribute to bile acid detoxification. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), pioglitazone remains the most extensively studied PPAR agonist, with meta-analytic evidence supporting MASH resolution and fibrosis reduction regardless of diabetes status. Lanifibranor demonstrated histological improvement in the phase 2b NATIVE trial and is currently in phase 3 development (NATiV3). PPAR agonists have also demonstrated therapeutic effects on liver fibrosis inhibition through direct modulation of hepatic stellate cell activation and suppression of fibrogenic signaling. This narrative review synthesizes the molecular pharmacology of PPAR isoforms; the available clinical and preclinical evidence for mono-, dual-, and pan-PPAR agonists; and their therapeutic applications across MASLD/MASH, alcohol-associated liver disease (ALD), PBC, primary sclerosing cholangitis (PSC), intestinal failure-associated liver disease (IFALD), and advanced chronic liver disease (ACLD). The evolution from single-isoform to multi-isoform PPAR agonism reflects the recognition that overlapping pathogenic mechanisms in liver diseases may require broader receptor coverage for optimal therapeutic efficacy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and poses a significant public health challenge. Allicin, a major bioactive organosulfur compound derived from garlic, has emerged as a promising candidate for MASLD prevention and management due to its antioxidant, anti-inflammatory, and metabolic regulatory properties. Despite its potential, evidence regarding allicin’s efficacy on MASLD remains limited and heterogeneous because existing studies have evaluated different garlic-derived interventions across diverse experimental settings. This review therefore distinguishes studies of purified allicin from those of raw garlic, garlic powder, aged garlic extract, black garlic, garlic essential oil, and individual garlic compounds. Preclinical studies using allicin suggest beneficial effects on hepatic steatosis, inflammation, glucose homeostasis, and lipid metabolism. Human studies, however, have evaluated raw garlic consumption or garlic powder supplementation rather than allicin alone. Findings from other garlic preparations and individual compounds are attributed only to the intervention tested, because differences in composition, stability, bioavailability, metabolism, and pharmacological activity preclude their attribution to allicin. Moreover, the available clinical trial evidence comprises five publications derived from only two randomized controlled trials conducted in Iran, both lasting 12–15 weeks. In addition, preclinical evidence most consistently supports regulation of hepatic lipid metabolism, particularly the AMP-activated protein kinase/sterol regulatory element-binding protein-1c-related signaling, as a potential mechanism underlying the anti-steatotic effects of allicin. Additional pathways may involve inflammatory signaling, oxidative stress, gut microbiota, and bile acid-related regulation, although the evidence for several of these mechanisms remains suggestive. Nevertheless, the precise molecular targets and signaling networks underlying these effects remain incompletely understood, and the relevance of allicin to aging-related MASLD is largely unexplored because previous studies have used young animals. Future studies should incorporate aged models and long-term randomized controlled trials across diverse populations to clarify the mechanisms, therapeutic potential, and safety of allicin in MASLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognised as a systemic disorder with clinically relevant extrahepatic manifestations. Pancreatic diseases have gained particular attention in this context, as they share key metabolic and inflammatory mechanisms with MASLD and may influence each other’s natural history and clinical outcomes. Beyond shared cardiometabolic risk factors, emerging evidence suggests that MASLD may actively contribute to pancreatic dysfunction and disease progression, supporting a bidirectional liver–pancreas relationship. Recognition of this association is essential to improve risk stratification, diagnostic assessment, and clinical management. This review summarises the current evidence linking MASLD with pancreatic disorders, focusing on acute and chronic pancreatitis, pancreatic cancer, and fatty pancreas. We examine shared pathophysiological pathways and discuss how these interactions may affect disease progression, nutritional status, diagnostic strategies, and therapeutic decision-making. We also address key clinical challenges, including alcohol assessment and MASLD–MetALD misclassification, highlight current knowledge gaps, and provide scenario-specific recommendations. Full article

Background and Objectives: To propose an integrated qualitative and quantitative US strategy for improving the diagnostic accuracy of hepatic steatosis (HS) grading. Materials and Methods: We retrospectively identified patients at a tertiary hospital who underwent B-mode US examination, attenuation imaging (ATI), hepatorenal index (HRI), and liver biopsy on the same day between 2023 and 2024. B-mode liver US images were independently reviewed by three radiologists with varying levels of experience. Each radiologist qualitatively assessed the degree of HS using a three-tier grading system: (1) no HS, (2) mild HS, and (3) moderate/severe HS. Median attenuation coefficient (AC) and HRI values were recorded. Liver biopsy pathology reports were used as the reference standard. We evaluated four strategies integrating qualitative assessment with ATI or HRI and compared their diagnostic performance. Results: Based on B-mode US, accuracies for detecting HS by the three radiologists were 87.0%, 87.0%, and 86.0%, respectively; for moderate/severe HS, the values were 79.0%, 76.0%, and 71.0%. ATI and HRI alone yielded diagnostic accuracies of 83.0% and 81.0%, respectively, for any HS and 67.0% and 53.0%, respectively, for moderate/severe HS. The highest accuracy was achieved using a strategy that retained the qualitative grade for one-grade discrepancies and assigning the intermediate grade only for two-grade discrepancies between the AC-based grade and the qualitative grade (93.0%, 87.0%, and 90.0% for any HS; 80.0%, 76.0%, and 74.0% for moderate/severe HS). Conclusions: The proposed integration strategy, which retained the qualitative grade for one-grade discrepancies and assigned the intermediate grade only for two-grade discrepancies, improved or maintained diagnostic performance, regardless of the radiologist’s level of experience. Full article

An abnormality of Ca²⁺ signaling may aggravate lipid accumulation in steatotic hepatocytes, leading to non-alcoholic fatty liver disease. However, the molecular identity of Ca²⁺-permeable channels and the mechanism of involvement of these channels in steatotic hepatocytes are not well-studied. In the present study, we investigated the role of a Ca²⁺-permeable channel TRPM2 in lipid metabolism in steatotic hepatocytes. A mouse model of non-alcoholic fatty liver disease was established by high-fat-diet feeding. Fat accumulation, fibrosis, lipophagic indexes, TFEB and lysosomal acid lipase in the liver tissue and/or hepatocytes were compared between TRPM2-knockout mice and wild-type mice. Knockout of the TRPM2 gene aggravated liver fat accumulation and fibrosis. Mechanistically, the TRPM2 knockout impaired the lipophagic process, decreased lysosomal abundance and attenuated lysosomal/autolysosomal acidification in mouse hepatocytes. Furthermore, the TRPM2 knockout reduced TFEB expression and its nuclear translation and also reduced the expression/activity of lysosomal acid lipase. These data demonstrate that TRPM2 deficiency may reduce lipophagy via its action on TFEB and lysosomal acid lipase, consequently contributing to liver steatosis and NAFLD under high-fat feeding conditions. Full article

Aim: To establish and validate a quantitative transporter-mediated imaging framework based on gadoxetic acid-enhanced T1 mapping for assessing liver functional reserve (LFR) and to investigate the physiological significance of the relative change in longitudinal relaxation rate (ΔR1%) as a quantitative imaging biomarker. Methods: Female C57BL/6J mice (6–8 weeks old) representing five experimental liver conditions (control, transporter-deficient Slco1b2/Slco1a5 double-knockout, carbon tetrachloride-induced fibrosis, methionine–choline-deficient diet-induced steatohepatitis, and alcohol-associated fatty liver disease; n = 6 per group) underwent serial Gd-EOB-DTPA-enhanced T1 mapping. Quantitative ΔR1% was calculated to characterize hepatobiliary enhancement kinetics. Liver functional reserve was independently evaluated using multispectral optoacoustic tomography of indocyanine green (ICG) pharmacokinetics and serum ICG retention assays, with histopathological and hepatocellular transporter analyses performed for mechanistic validation. Longitudinal data were analyzed using restricted maximum likelihood (REML)-based mixed-effects models. Intergroup comparisons were performed using one-way ANOVA or Kruskal–Wallis tests with appropriate post hoc analyses, and associations between imaging and functional parameters were evaluated using Spearman rank correlation analysis. A two-sided p < 0.05 was considered statistically significant. Results: Five experimental liver models exhibited distinct transporter-dependent hepatobiliary enhancement patterns. The transporter-deficient knockout mice showed minimal enhancement, whereas fibrosis and steatotic liver injury models demonstrated intermediate but clearly distinguishable functional profiles. Longitudinal mixed-effects analysis identified significant effects of time, experimental group, and time-by-group interaction on ΔR1% dynamics (all p < 0.0001). Although MRI-derived ΔR1% parameters were not significantly correlated with regional optoacoustic ICG kinetics, ΔR1% area under the curve showed a strong inverse correlation with serum ICG retention at 600 s (r = −0.729, p < 0.0001), indicating that MRI-derived ΔR1% and ICG-based measurements provide complementary rather than interchangeable assessments of liver function. Histological and molecular analyses further demonstrated marked heterogeneity in fibrosis, steatosis, and hepatobiliary transporter expression across models, whereas transporter abundance alone did not consistently predict imaging-derived functional performance. Conclusions: Quantitative Gd-EOB-DTPA-enhanced T1 mapping provides a transporter-mediated imaging framework for evaluating hepatic functional reserve across mechanistically distinct liver injury models. As a normalized quantitative imaging biomarker, ΔR1% captures the integrated functional consequences of hepatobiliary transport dysfunction and complements established liver function tests. These findings support the translational potential of quantitative T1 mapping as a standardized, noninvasive approach for assessing liver functional reserve. Full article

Background and Aims: The glucose metabolism pattern of the liver is closely related to liver diseases. In recent years, alcoholic hepatitis, viral hepatitis, fatty liver and other diseases have become important liver diseases that impact people’s lives. IL-33 (interleukin-33), as a member of the IL-1 cytokine family, and “alarmin” play a multi-dimensional regulatory role in various physiological and pathological processes of the liver. Methods: This study, by integrating transcriptomic data analysis and in vitro and in vivo experiments, expounds on new insights into the regulation of hepatocyte fate by IL-33 through metabolic reprogramming and reveals the potential, new role of IL-33 as a regulatory factor of metabolism. Conclusions: Our research further confirmed that IL-33, in addition to serving as an alarm hormone, is also a key checkpoint for liver metabolism, capable of promoting oxidative phosphorylation in hepatocytes and antagonizing acute liver injury induced by CCl₄. Full article

Background: We aimed to investigate the prevalence of HSD17B13 polymorphisms while evaluating the correlation between HSD17B13 gene variants and NASH prevalence in the Taiwanese population. Furthermore, we tried to identify the diagnostic value of liver enzymes as non-invasive biomarkers for NASH in morbidly obese patients. Methods: Severely obese patients with non-alcoholic fatty liver disease (NAFLD) who received liver biopsy during bariatric surgery and controls of liver donors who underwent donor hepatectomy were enrolled from 2016 to 2021. Genotyping was utilized in TaqMan PCR assays. For comparison of NAFLD severity, patients were divided into no NASH (NAFLD activity score, NAS 0–2), borderline NASH (NAS 3–4), and NASH (NAS 5–8). Results: The proportion of HSD17B13 rs72613567 TA allele carriers (T/TA and TA/TA genotypes) was 96% in both groups, corresponding to an estimated TA allele frequency of approximately 50% based on a standard allele-counting method. Among morbidly obese patients, T/TA and TA/TA genotypes were associated with lower odds of NASH prevalence compared with T/T genotype. For the non-invasive predictive factors of NASH, NASH group had significantly higher level of liver enzymes compared to “no NASH” and “borderline NASH” groups. Receiver operating characteristic curve analysis revealed there were moderate predictive values for NASH in AST (AUC = 0.71, p = 0.014) and ALT (AUC = 0.73, p = 0.007). Conclusions: Our study revealed a relatively high prevalence of the loss-of-function TA variant of HSD17B13 in this southern Taiwanese cohort, irrespective of body weight. This variant may contribute to the comparatively lower prevalence of NASH in the region. Additionally, AST and ALT may have potential predictive value for NASH prevalence. Given the single-center design, further larger, population-representative studies are warranted. Full article

Background: Alcohol-associated fatty liver disease (AFLD) is a major public health concern and remains one of the leading causes of chronic liver disease in the United States. Understanding the interplay between obesity, metabolic dysfunction, and lifestyle factors may help identify populations at increased risk for AFLD. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2013–2018. AFLD was operationally defined using elevated liver enzyme levels combined with risky alcohol consumption. Metabolic obesity phenotypes (MOPs) were characterized by combining body mass index categories with either metabolic health status or metabolic syndrome (MS). Results: The weighted prevalence of AFLD was 14% (95%CI: 12–16%). AFLD prevalence was significantly higher among males than females (17% vs. 10% respectively, p < 0.0001), and among Hispanics compared to Non-Hispanic Black participants (20% vs. 9% respectively, p < 0.0001). Compared with metabolically healthy normal-weight individuals, obese participants with MS demonstrated the strongest association overall AFLD association (adjusted PR: 6.73; 95% CI: 4.51–10.05). Furthermore, obese males with MS showed the highest odds of AFLD under both MOP schemes (MOP 1: OR: 8.19; 95% CI: 4.41–15.23; MOP 2: OR: 10.92; 95% CI: 6.86–17.37). Conclusions: Individuals with obesity and metabolic dysfunction demonstrated significantly higher AFLD prevalence compared with metabolically healthy normal-weight individuals. MOPs incorporating MS demonstrated stronger associations with AFLD than classifications based on metabolic health status alone. These findings support the importance of screening strategies that address both obesity and metabolic dysfunction in addition to alcohol use to better identify high-risk populations. Full article

Background and Objectives: Renal sinus fat accumulation affects many diabetic processes, including blood pressure. The aim of this study was to find out if there is a link between the amount of fat in the renal sinus and the blood pressure that changes throughout the day in adults with non-alcoholic fatty liver disease (NAFLD). Materials and Methods: This retrospective analysis involved 55 adult patients diagnosed with non-alcoholic fatty liver disease (NAFLD) based on abdominal computed tomography (CT) and who had undergone 24 h ambulatory blood pressure monitoring (ABPM). According to standard ABPM criteria, individuals whose night-time systolic blood pressure decreased by ≥10% compared to daytime values were classified as “dippers,” whereas those with a reduction of <10% were classified as “non-dippers”. Results: The non-dipper group had a significantly higher leukocyte count (p = 0.012). Renal sinus fat volume (RSFV) was significantly larger in the non-dipper group (6.41 ± 3 mL) than the dipper group (4.12 ± 2.26 mL; p = 0.005). In the ROC curve analysis showing the role of RSFV in predicting the non-dipper blood pressure pattern, the threshold value for RSFV in our cohort was determined as ≥3.7 mL with a positive predictive value of 72.2%. Conclusions: Our findings indicated that RSFV plays a significant role in predicting the non-dipper blood pressure profile among individuals diagnosed with NAFLD. Participants with an RSFV of 3.7 mL or more in our cohort were more likely to exhibit a non-dipping blood pressure pattern. Future studies are needed to validate these findings in larger cohorts. Full article

The ever-increasing disparity between lifespan and healthspan represents a challenging global issue, with metabolic dysregulation playing a central role in the initiation and progression of chronic non-communicable diseases (NCDs). This review highlights the importance of maintaining optimal redox homeostasis, with particular emphasis on reduced glutathione (GSH), for preserving metabolic health during aging. GSH participates in several physiological processes, including antioxidant defense, xenobiotic detoxification, redox signaling, and metabolic regulation. Diminished GSH levels are consistently reported in obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver, and cardiovascular diseases. Current evidence from human clinical studies indicates that foods rich in bioactive constituents can enhance GSH levels and stimulate GSH-dependent enzyme activity, with the Nrf2/Are signaling pathway being a central mechanistic link. Fasting may promote adaptive redox responses by inducing mild oxidative stress and activating the same molecular mechanism, although the effects on GSH-related antioxidant mechanisms remain heterogeneous across fasting protocols and study populations. Altogether, the available clinical evidence suggests that these nutritional and lifestyle interventions exhibit more consistent beneficial effects in individuals characterized by increased oxidative burden and underlying metabolic dysfunction. Interindividual differences in GSH responses further underscore the need for targeted, tailor-made approaches that account for genetic, epigenetic, and lifestyle factors. Collectively, targeting GSH homeostasis through nutritional and lifestyle interventions represents a promising strategy for improving metabolic health and may further contribute to healthy aging, positioning redox biology at the forefront of aging research and NCD prevention. Full article

Phase transition or phase separation occurs in cells and tissues in many physiological events, such as protein granules (P granules) in early C. elegans development. Inappropriate phase transition is often associated with pathologic processes such as RNA–protein complex (RNP) and FUS-mutation-associated diseases. Given its ubiquity, phase transition has been considered a new frontier for comprehending physiological processes and pathological diseases. However, molecular and cellular mechanisms of phase transition in situ remain poorly described. Combining histochemistry with polarization analysis and biochemical thin-layer chromatography, we identified a massive phase transition change during the development of Taihe fowl (Gallus gallus domesticus Brisson). During embryonic day 12 (E12), the livers of these Silkie chicken demonstrated a sudden massive transition from hepatic lipid droplets (HLD) into hepatic liquid crystal droplets (HLCDs). We identified these changes by characterizing the sudden appearance of birefringent Maltese crosses (MCs) typical to liquid crystals (LC) where non-birefringent lipid droplets used to reside within hepatic cells. LC status was confirmed by fluidity with shape-changing and in vitro thermal phase transition tests. These HLCDs were present consistently until the early postnatal days after hatching. Using thin-layer chromatography combined with X-ray diffraction analysis, we determined that these HLCDs were composed of cholesterol, cholesterol ester and lecithin, which are the same as the components of cytoplasmic membrane. There was no change in the quantity of lipid components during liver development to suggest a critical mass of components triggering these changes. However, expressions of membrane-associated autophagy markers LC3A and Beclin 1 increased dramatically during this HLD to HLCD transition. Increases in membrane-associated LC3A and Beclin 1 are localized with massive increases in membrane lipid components of HLCDs. Areas with enhanced LC3A and Beclin 1 signaling have been associated with liquid crystal MCs to the thickness of 69 Å (Bragg d value). These associations indicate the possible regulatory role autophagy plays during liquid crystal phase transition in embryonic liver development. Reactivation of this autophagy pathway may be a possible mechanism behind the development of non-alcoholic fatty liver disease in adulthood. Full article

Palmitic acid (PA) can be used as a substitute for fish oil in aquaculture; however, excessive intake can easily cause lipotoxic liver damage in animals, and the progression of non-alcoholic fatty liver disease (NAFLD) is closely associated with it. Adult zebrafish (Danio rerio) share a high degree of genetic homology with humans and possess conserved lipid metabolism pathways, making them ideal model organisms for studying hepatic lipotoxicity. This paper presents a comprehensive narrative review of studies on PA-induced hepatic lipotoxicity, with a primary focus on the adult zebrafish model: it elucidates the morphological and functional abnormalities in liver tissue caused by PA exposure; explains the molecular mechanisms by which PA induces metabolic disorders and cellular stress through upregulation of lipid synthesis and inhibition of β-oxidation, which further activates inflammatory signaling pathways such as NF-κB/JNK and may ultimately contribute to liver fibrosis; and summarizes intervention strategies targeting these mechanisms. Studies using embryonic or larval zebrafish are included only as supplementary mechanistic evidence where adult data are unavailable and are clearly distinguished throughout the text. To ensure transparency, the literature search and screening process are reported in detail, although formal systematic review methodologies (e.g., PRISMA, dual independent screening, and quantitative risk-of-bias assessment) were not applied. This study aims to refine the evaluation system for PA-induced hepatic lipotoxicity, providing both theoretical support for the scientific application of PA in aquaculture and important references for elucidating the pathogenesis of human NAFLD/NASH and developing preventive and therapeutic measures. Full article

Background/Objectives: Many HIV-positive (HIV+) males receiving highly active antiretroviral therapy (HAART) experience metabolic complications, including non-alcoholic fatty liver disease (NAFLD); lipodystrophy; and intestinal dysbiosis, often characterized by a Prevotella-rich enterotype. Gut microbial fermentation produces short-chain fatty acids (SCFAs), which play important roles in host metabolism. This study investigated the relationships among HAART, anthropometrics, diet, intestinal permeability, gut microbiota composition, and lipodystrophy in HIV+ males. Methods: Forty males aged 23–60 years were enrolled, including 19 HIV+ participants recruited from the East Tennessee State University (ETSU) Health Infectious Diseases Specialty Clinic and 20 HIV-negative (HIV−) controls recruited through standard methods. Participants provided a stool sample for 16S rRNA gene sequencing, SCFA analysis by gas chromatography, and proximate analysis, and completed a food frequency questionnaire. Lipodystrophy-related measures included body mass index (BMI), hip-to-waist ratio (H:W), and liver health assessment using FibroScan. Blood samples were collected by venipuncture. Serum markers of intestinal permeability, including Claudin-21, flagellin, and intestinal fatty acid-binding protein (IFABP), were quantified by enzyme-linked immunosorbent assay (ELISA). Results: HIV+ males exhibited significantly higher H:W ratios (p = 0.001) and hepatic steatosis (p = 0.0047) than HIV− controls (Welsh’s t-test). Concentrations of isobutyrate (p = 0.0024), isovalerate (p = 0.0008), and valerate (p = 0.0329) were elevated in HIV+ participants, whereas butyrate (p = 0.0014) and total acetate/propionate/butyrate (APB) (p = 0.0046) were higher in HIV− males (Welsh’s t-test). HIV+ participants also showed greater abundances of Prevotella and Lachnospiraceae (Analysis of Compositions of Microbiomes; ANCOM). Retrospective analysis revealed that all HIV+ participants were men who have sex with men (MSM). Conclusions: HIV+ males demonstrated distinct gut microbiome profiles, altered SCFA production, and markers of disrupted lipid metabolism. These findings provide a foundation for future investigations of microbiome-metabolism interactions in HIV+ MSM. Full article