Cell Metabolism

GLP-1 receptor agonists (GLP-1 RAs) effectively reduce weight in obesity, although significant weight regain typically follows discontinuation. Here, in a randomized clinical trial (ChiCTR2200066014), we found that GLP-1 RA (semaglutide) and a high-fibre diet achieved similar 12-week weight reduction, but semaglutide recipients exhibited significantly higher weight rebound at the 14th week after intervention cessation. Shotgun metagenomic sequencing revealed that semaglutide aggravated the proinflammatory signature in the gut microbiome, which contrasted with high-fibre diet intervention. The microbiota transplanted from semaglutide-treated subjects to germ-free mice induced gut barrier dysfunction, systemic inflammation and an increase in the bacterial antigen load in the liver and adipose tissue, which activated the NF-{kappa}B pathway to drive lipid accumulation. Using a diet-induced obesity mouse model, we found that semaglutide exacerbated gut microbiome dysbiosis by weakening host immune surveillance of the gut microbiota through downregulating IFN-{gamma} to reduce antimicrobial peptides expression and delaying gut transit time to shift microbial metabolism from saccharolysis towards proteolysis. Crucially, combining semaglutide with dietary fibre in mice mitigated microbiome dysbiosis and attenuated weight regain post-cessation. These findings suggest that GLP-1 RA-exacerbated gut microbiome dysbiosis in obesity as a key mediator of post-treatment weight rebound and propose adjunctive fibre supplementation as a strategy to sustain weight loss.

Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less defined. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a role for BAT in the clearance of circulating branched-chain amino acids and triglycerides, and also identify a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species (ROS) production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress. HIGHLIGHTSO_LIComprehensive analyses of BAT-linked circulating metabolome and lipidome in mice and humans. C_LIO_LIMulti-level metabolomics supports the role of BAT in circulating BCAA and triglyceride clearance. C_LIO_LICold-inducible 3-OHSA is secreted by BAT and signals to the liver. C_LIO_LI3-OHSA decreases hepatic oxidative stress by decreasing mitochondrial membrane potential. C_LI

Central carbon metabolism undergoes extensive remodeling in cancers, yet the extent to which the resulting network architectures and operating principles are conserved across species and oncogenic contexts in vivo remains unclear. Here, central carbon metabolism was evaluated in Hippo/Yki-driven Drosophila gut tumors, as Hippo-YAP/TAZ signaling links nutritional cues to metabolic state and contributes to epithelial tumorigenesis and therapy resistance. Using integrated steady-state metabolomics, transcriptomics and [U-13C6]glucose tracing, we defined how Hippo pathway activation reorganizes nutrient utilization and carbon flux in vivo and assessed how the resulting Yki-driven metabolic network aligns with mammalian cancer metabolism. Yki tumors exhibited a Warburg-like state with increased glycolytic throughput and enhanced conversion of glucose-derived carbon to lactate, accompanied by transcriptional upregulation of key glycolytic and lactate-production enzymes. Glucose carbon was also redirected into redox-supporting and anabolic nodes, including activation of the glycerol-3-phosphate shuttle and increased labeling of alanine and serine. Mitochondrial metabolism was reorganized into a non-canonical, segmented TCA network centered on -ketoglutarate, which accumulated and acted as a drain into glutamate/glutamine and 2-hydroxyglutarate rather than supporting complete oxidative turnover. Despite reduced abundance of pentose phosphate intermediates, non-oxidative PPP carbon rearrangements and ribose labeling were maintained, enabling robust glucose contribution to pyrimidine nucleotide pools, including strongly labeled dTTP. Together, these data establish a comprehensive map of Yki-driven central carbon partitioning in vivo and highlight conserved principles of tumor carbon allocation shared across oncogenic contexts and mammalian cancer metabolism.

Lethal sterile inflammatory diseases are linked to amino acid metabolism, but the role of serine remains unclear. Here, we show that dysregulated serine metabolism and reduced plasma serine levels correlate with disease severity of acute pancreatitis (AP) in patients and mouse models. Elevating serine levels via exogenous serine supplementation or pancreatic phosphoglycerate dehydrogenase (PHGDH) overexpression mitigates pancreatic injury, whereas a serine deprivation diet or pancreatic PHGDH knockdown exacerbates AP. Serine prevents cell death and oxidative stress in pancreatic acinar cells, human induced pluripotent stem cells-derived pancreatic organoids and mouse pancreatic tissue. Serine enhances cysteine and glutathione biosynthesis primarily by promoting solute carrier family 7 member 11 (SLC7A11)-dependent cystine uptake rather than by serving as a direct substrate. Mechanistically, the E3 ubiquitin ligase NEDD4 mediates ubiquitination and degradation of SLC7A11, whereas serine binds to NEDD4 and thereby inhibits SLC7A11 degradation. Similarly to serine, pharmacological inhibition of NEDD4 alleviates lipid peroxidation and pancreatic injury. These findings identify serine as a critical signaling regulator of SLC7A11 stability and oxidative stress, and provides a new therapeutic strategy for AP and associated sterile inflammatory disorders. HighlightsAcute pancreatitis (AP) is linked to abnormal serine metabolism and serine depletion. Serine prevents cell death in AP acinar cells, human pancreatic organoids and mice. Serine promotes SLC7A11-dependent cystine uptake and glutathione levels in acinar cells. Serine reduces NEDD4-mediated ubiquitination of SLC7A11. In briefSerine protects against cell death and pancreatic injury in acute pancreatitis by stabilizing SLC7A11 through disruption of NEDD4-mediated ubiquitination in acinar cells.

Dementia affects approximately 60 million people worldwide, yet molecular mechanisms linking early neuropathological changes to clinical progression remain poorly understood. We performed targeted and untargeted metabolomics in plasma and cerebrospinal fluid (CSF) from 166 memory clinic patients spanning no cognitive impairment, mild cognitive impairment due to Alzheimers disease (AD), AD dementia, and mixed AD-cerebrovascular dementia. Using a data-driven approach, we identified a CSF polyol signature characterized by elevated sorbitol, meso-erythritol, and d-glucose/erythritol ratio consistently associated with phosphorylated tau (pTau) and total tau (tTau), but not amyloid-{beta}. This association was validated in an independent CSF metabolomics (n=687) and proteomics (n=737) cohorts. Structural equation modelling confirmed that polyol metabolites predict tau burden, with less than 3% attenuation following genetic adjustment, establishing a non-genetic, metabolically driven mechanism. These findings define a tau-dominant, amyloid-independent metabolic axis in neurodegeneration, implicating the polyol pathway as a potentially modifiable therapeutic target.

Citrate is a central metabolite linking tricarboxylic acid (TCA) cycle activity to energy and lipid metabolism and supports the synthesis of inflammatory mediators, including itaconate, in macrophages. While citrate is primarily generated endogenously, extracellular citrate levels are elevated under pathological conditions such as citrate transporter disorder. Cells import extracellular citrate through SLC13 transporters, including the sodium-dependent citrate transporter NaCT (encoded by SLC13A5). However, whether macrophages take up extracellular citrate and how this affects metabolism and function remains unclear. Here, we combined mass spectrometry and tracing approaches to investigate the metabolic fate of citrate in human macrophage cell lines, primary, and iPSC-derived macrophages. We demonstrate that cells take up extracellular citrate, which was enhanced under metabolic stress conditions. Exogenous citrate was not substantially utilized as a carbon source but selectively altered glutamine metabolism and responses to bacterial infection with Salmonella enterica Typhimurium and Legionella pneumophila Corby. Our work identifies extracellular citrate as a context-dependent regulator in macrophages that decouples uptake from metabolic utilization. HighlightsO_LIMacrophages import extracellular citrate via SLC13 transporters C_LIO_LIExtracellular citrate accumulates under hypoxia and inflammatory activation C_LIO_LIExtracellular citrate does not fuel central carbon metabolism in human macrophages C_LIO_LICitrate modulates glutamine immunometabolism and modulates immune responses C_LI eTOC blurbVo{beta}-Willenbockel et al. demonstrate that human macrophages accumulate extracellular citrate without using it as a major carbon source. Instead, citrate modulates glutamine utilization, inflammatory responses, and host-pathogen interactions revealing a context-dependent regulatory role for extracellular metabolites in immune cell function.

Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal Glut2 knockout mice, which progressively lose Slc5a2 (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and instead oxidized mannose, while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, demonstrating dependence on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-driven metabolic program that preserves systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.

Neutrophils are the most abundant leukocytes in humans and play a central role in immune regulation. Although traditionally viewed as terminally differentiated cells with limited plasticity, growing evidence indicates that neutrophils exhibit substantial functional heterogeneity in response to stress. To date, however, most studies have focused on transcriptional and signaling changes, while metabolic heterogeneity, especially beyond central carbon metabolism, remains poorly characterized. Here, we systematically investigate metabolic reprogramming in neutrophils under three stress conditions: granulocyte colony-stimulating factor (G-CSF) treatment, hematopoietic stem cell transplantation (HSCT), and pancreatic ductal adenocarcinoma (PDAC). Using condition-specific genome-scale metabolic (GSM) models, we identify distinct metabolic vulnerabilities across neutrophil states. Vitamin metabolism emerged as a key differentiating feature between G-CSF- and HSCT-treated neutrophils, whereas PDAC-associated neutrophils displayed globally enhanced metabolic activity coupled with restricted metabolite exchange fluxes. Furthermore, solute carrier (SLC) family transporters were identified as major metabolic regulators underlying stress-induced neutrophil reprogramming. Together, our findings demonstrate that neutrophil heterogeneity extends beyond transcriptional programs to encompass profound metabolic specialization, highlighting metabolism as a critical dimension of neutrophil plasticity in health and disease.

Hepatocytes undergo extensive proliferation to facilitate liver repair after injury, yet early adaptive changes prior to proliferation remain unclear. Here, we report that during early acetaminophen (APAP)-induced liver injury, hepatocytes exhibit transient proliferation suppression, most pronounced in mid-zone hepatocytes due to zonal APAP metabolism. Using spatial transcriptomics (ST), immunohistochemistry, and functional studies, we identified a unique mid-zone stress-response program. Central to this adaptation is the Atf4-Chop axis, which actively suppresses proliferation via the cell cycle inhibitor Btg2, prioritizing cytoprotection over cell division. This transient arrest is a critical survival strategy: halting energy-intensive proliferation during peak injury allows mid-zone hepatocytes to redirect resources towards protection, enhancing their survival in early APAP-induced liver injury. Thus, Atf4-Chop-mediated quiescence preserves a hepatocyte reservoir necessary for subsequent regenerative proliferation and effective repair. Our findings reveal a key adaptive trade-off in mid-zone hepatocytes where transient proliferation arrest promotes early survival to enable repair.

The transition from metabolic health to type 2 diabetes unfolds through progressive insulin resistance (IR), yet the gold-standard hyperinsulinemic-euglycemic clamp is inapplicable at population scale and fasting insulin is not uniformly available. Several surrogate measures have been described in the literature, but whether these surrogates identify the same individuals, and whether continuous glucose monitoring (CGM) or NMR metabolomics carry information beyond conventional markers, remains unresolved. Here, we analyzed IR surrogates in 10,114 non-diabetic adults (35-75 y) from the Human Phenotype Project (HPP), integrated with 14-day CGM, dual x-ray absorptiometry (DEXA) body composition, liver and carotid ultrasound, sleep monitoring, and NMR metabolomics and established sex-specific, age-resolved reference ranges. IR surrogates were moderately inter-correlated but captured distinct metabolic facets. We next focused on DEXA-derived visceral adipose tissue (VAT), one of the strongest correlates of clamp-measured insulin resistance. Our analysis showed that VAT can be reliably predicted from anthropometric measurements alone (R{superscript 2} = 0.659). However, it is only modestly predicted by CGM features alone (R2 = 0.078). Among CGM-derived features, markers of glycemic variability were stronger predictors of VAT than conventional mean-glucose metrics. Residual-based analyses identified individuals whose visceral adiposity was substantially higher than expected given their BMI or HbA1c levels. Notably, 1.2% of adults in the HPP cohort exhibited elevated visceral adiposity despite having both a normal BMI (< 25 kg/m{superscript 2}) and normoglycemic HbA1c (< 5.7%). These discordant subpopulations harbored adverse profiles across lipid, hepatic, vascular, sleep, and metabolomic domains. NMR lipoprotein subfractions (VLDL, HDL) discriminated discordant phenotypes. A CGM variability-only model separated discordant individuals at AUC = 0.63, with negligible gain from adding mean glucose. Findings were validated in an independent cohort with available fasting insulin data. Together, these results establish normative IR surrogate reference ranges, quantify the fraction of metabolically at-risk individuals missed by conventional BMI and HbA1c screening, and highlight CGM variability metrics and NMR lipoprotein profiling as complementary tools for early metabolic risk stratification. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/26352290v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1f491a6org.highwire.dtl.DTLVardef@18660a9org.highwire.dtl.DTLVardef@133fa14org.highwire.dtl.DTLVardef@1675463_HPS_FORMAT_FIGEXP M_FIG C_FIG

Turning is a complex motor behavior that frequently triggers freezing of gait and falls in Parkinsons disease (PD), yet its neural dynamics in naturalistic settings remain unknown. Using chronic at-home intracranial recordings in four subjects with PD, we show that turning is marked by premotor cortical beta desynchronization driven by reduced burst rate. These findings identify a robust signature of ecological turning and implicate beta dynamics in adaptive motor transitions.

Environmental changes significantly impact the social behaviors of animals, yet individuals exhibit substantial variability in their responsiveness, known as environmental sensitivity. Understanding the biological basis of this individual variability is critical for elucidating vulnerability to stress-related and psychiatric disorders. To investigate the organism-wide physiological states linked to environmental sensitivity, we combined continuous, non-invasive RFID-based behavioral tracking with untargeted plasma metabolomics in group-housed mice undergoing spatial and social environmental restructuring. Following the environmental alteration, we observed heterogeneous behavioral shifts across individuals, enabling their operational classification into high-responsiveness mice (HRM) and low-responsiveness mice (LRM). Untargeted metabolomic profiling revealed distinct systemic metabolic signatures associated with these behavioral phenotypes. Specifically, HRM exhibited elevated levels of circulating essential and non-essential amino acids, as well as metabolites linked to one-carbon and energy metabolism. Exploratory co-variation analysis further identified plasma metabolic modules associated with individual behavioral metrics. These findings suggest that individual differences in behavioral adaptation are not solely neural phenomena but are coupled with coordinated, organism-wide metabolic adjustments. This study provides a framework for identifying candidate peripheral metabolic correlates of behavioral responsiveness to environmental and social change.

Dietary restriction extends lifespan across model organisms, but the plasma molecular changes mediating this effect remain incompletely characterized. We present a longitudinal multiomic analysis of 2,234 plasma samples from 960 Diversity Outbred mice subjected to intermittent fasting or caloric restriction and followed to natural death. Using mass spectrometry, we quantified 1,512 metabolites, lipids, and proteins and mapped their associations with diet, age and longevity. DR-induced molecular changes scale with caloric intake and modulate inflammatory, lipid catabolism, and oxidative stress pathways. Aging showed a biphasic signature with sharp acceleration beyond 85% of lifespan, demarcating terminal decline. Mediation and survival modeling both identified superoxide dismutase (SODE) and vascular cell adhesion molecule (VCAM1) as top lifespan predictors. Genetic analysis revealed 9,599 QTL, nine of which coincided with previously identified lifespan QTLs, and were largely related to immune regulation. These findings provide a rich multiomic and genetic resource for the aging research community.

Malonate is often described as an endogenous inhibitor of complex II of the electron transport chain. However, the cellular source of malonate is unclear, and current knowledge concerning its metabolism is limited to the action of a single enzyme, Acyl-CoA Synthetase Family Member 3 (ACSF3), which converts malonate to malonyl-CoA in the mitochondrial matrix. One potential route of malonate metabolism downstream of ACSF3 is its consumption by the mitochondrial fatty acid synthesis (mtFAS) pathway. However, studies examining the link between ACSF3 and mtFAS have yielded conflicting results. We developed a novel mass spectrometry approach to perform stable isotope tracing into products of mtFAS, and found that while malonate is in fact a carbon source for mtFAS, ACSF3 is not required for malonate incorporation into mtFAS products. Using this method to trace other nutrients into mtFAS, we also found evidence of acetyl-CoA carboxylase 1 (ACC1)-dependent malonate synthesis from glucose. We further show that ACC1 is required for optimal mtFAS activity, with downstream effects on oxidative phosphorylation. Together these findings establish the malonate as a regulated endogenous intermediate that supports mtFAS activity and mitochondrial oxidative function.

Mitochondrial protein homeostasis intersects with metabolic control, but the in vivo roles of specific mitochondrial co-chaperones remain unclear. The chaperone mtHSP70 plays a key role in import and folding of nuclear-encoded proteins targeted to mitochondrial matrix. Its protein folding cycle is regulated by the GrpE-like nucleotide exchange factor GRPEL1. Vertebrates also have a GRPEL2 paralog, postulated as the stress-sensitive counterpart, but its physiological relevance is not known. We show here that GRPEL2 is not essential for viability in mice, and its absence does not induce proteotoxic stress responses in stark contrast to GRPEL1. However, we find that GRPEL2 has a role in regulating body weight homeostasis. GRPEL2 knockout mice are protected from age- and diet-induced weight gain and maintain a better metabolic health and insulin sensitivity. Transcriptional profiling revealed minimal changes in liver and skeletal muscle, whereas white adipose tissue from Grpel2-deficient mice lacked the obesity-associated remodeling seen in controls. We propose that GRPEL2 fine-tunes metabolic setpoints without broadly perturbing mitochondrial protein import, thereby maintaining adipose tissue health during nutritional excess. These findings show that subtle alterations in mitochondrial chaperone systems reshape systemic metabolism and could suggest strategies to mitigate obesity and insulin resistance through targeted modulation of mitochondrial proteostasis.

The liver plays a central role in systemic metabolism, yet large-scale genetic studies of quantitative liver imaging phenotypes remain limited. Here, we applied deep learning-based segmentation and radiomics extraction to derive 200 well-defined liver MRI features across multiple categories and imaging contrasts in 43,176 UK Biobank participants. Association analyses revealed steatosis-independent radiomic signals predicting incident chronic liver disease beyond conventional risk factors. We conducted genome-wide association studies in 37,725 individuals and identified multiple heritable liver MRI features; joint genetic structure and pleiotropy analyses demonstrated that these radiomic traits capture complex genetic architecture beyond the extent of hepatic steatosis. These MRI features showed widespread genetic overlap with plasma proteins, metabolites, and cardiometabolic traits through shared genetic loci and genetic correlations independent of adiposity. We identified putative causal links between liver MRI traits and cardiometabolic and liver-related outcomes, as well as evidence for pathway-specific imaging biomarkers to track activity of hepatically-influenced therapeutics.

Fatty acid biosynthesis is a central metabolic process required for membrane formation, organelle maintenance, and cellular proliferation, yet its broader relationship with stress responses and cellular aging remains incompletely understood. Here, we combined human and yeast interactome analyses with transcriptomic profiling and chronological lifespan assays to investigate the systems-level organization of fatty acid metabolic pathways and their relationship to cellular longevity. Integrated interactome mapping of mammalian fatty acid metabolic regulators, including ACACA, FASN, SCD, ACSL, ELOVL, and SLC27 family proteins, together with conserved yeast orthologs including ACC1, FAS1/FAS2, ELO1-3, OLE1, FAA1-4, ACS1/ACS2, and FAT1 revealed strong enrichment of anabolic growth regulation, membrane organization, vesicle trafficking, proteostasis, and endoplasmic reticulum (ER)-associated stress pathways. In yeast, fatty acid metabolic networks segregated into distinct anabolic and membrane-associated functional modules. Pharmacological inhibition of fatty acid synthesis using cerulenin suppressed cellular proliferation while extending chronological lifespan and induced broad downregulation of translation-associated anabolic pathways together with activation of stress-associated and membrane lipid remodeling programs. ER-associated interactome analyses of DPAGT1 and ALG7 further identified strong enrichment of membrane trafficking and unfolded protein response (UPR)-associated pathways, while pharmacological ER stress induction using tunicamycin also promoted enhanced chronological longevity. Collectively, our findings support a conserved model in which perturbation of fatty acid metabolic pathways remodels anabolic growth and ER-associated stress responses to promote cellular longevity.

Can we decode Alzheimers disease (AD) heterogeneity into a few portable axes that capture how amyloid-{beta}, tau and neurodegeneration (A-T-N) spatially co vary in vivo? To answer this question, we built a pipeline that harmonizes longitudinal amyloid-{beta}/tau PET and T1 MRI (gray matter) from ADNI cohort (12,430 images) with mixed effects modeling and then derived stage specific multimodal axes (mVCs) using linked component analysis, with robustness tested in simulations and external validation in the OASIS cohort (4,958 images). We identified a small set of multimodal axes that (i) recapitulate early tau weighted variation in cognitively unimpaired (CU) individuals, AD like A-T-N coupling in cognitively impaired (CI) individuals and atypical CU and CI participants with posterior (precuneus/occipitoparietal) and fronto insular/frontal weighted patterns, (ii) map onto domain specific cognition, APOE e4, and blood/CSF biomarkers of neurodegeneration, neuroaxonal injury and astrocyte activation, (iii) predict clinical transitions, (iv) generalize in an independent cohort, and (v) demonstrate modelling robustness to missing data, high dimensionality, and cross-cohort variability, enabling direct application of the extracted axes to new datasets for biomarker discovery and stratification. Multimodal axes provide a portable, interpretable layer for quantifying amyloid-{beta}-tau-neurodegeneration coupling at the individual level, complementing current biomarker-based staging frameworks based on A-T-N status and tau PET topography, and can be computed on new datasets to aid clinical assessment and trial enrichment.

The gut microbiota produces metabolites that circulate to host tissues and are increasingly linked to metabolic health, yet the mechanisms by which individual microbial products regulate liver glucose metabolism remain poorly defined. Here, we identify the tryptophan-derived microbial metabolite indole-3-propionic acid (IPA) as a direct modulator of hepatic glucose production. In primary hepatocytes, a focused screen of indole metabolites revealed that several indole-containing compounds suppress glucagon-stimulated glucose output, with IPA emerging as a physiologically relevant candidate. IPA selectively reduced glucose production from mitochondrial-dependent gluconeogenic substrates while largely preserving glycerol-supported glucose production, suggesting that it does not simply shut down gluconeogenesis but instead alters how hepatocytes use metabolic fuels. Mechanistic analyses showed that IPA redirects lactate-derived carbon away from glucose production and reshapes mitochondrial metabolism, including redox balance, ATP availability, and urea cycle-linked metabolic activity. These effects occurred without detectable disruption of proximal insulin or glucagon signaling, supporting a model in which IPA acts primarily through intracellular metabolic remodeling. In mice, endogenous IPA levels varied with nutritional state, and short-term IPA administration improved fasting glycemia and glucose handling in Western diet-fed animals. Finally, microbiome-depleted mice colonized with IPA-producing Clostridium sporogenes displayed increased circulating IPA and improved glucose tolerance compared with mice colonized with an IPA-deficient mutant C. Sporogenes strain. Together, these findings identify IPA as a microbial metabolite that directly connects gut tryptophan metabolism to hepatic mitochondrial function and systemic glucose regulation, highlighting a mechanistic gut-liver pathway with potential therapeutic relevance to metabolic disease.

Parkinsons disease (PD) is the fastest-growing neurologic disease and a leading cause of disability worldwide. PD affects the body and mind, is progressive, and there is no prevention or cure. Gut microbiome, a recently recognized contributing factor in PD, offers new leads for understanding the underlying pathobiology and devising new treatments. Here, we present the most comprehensive study of the PD gut microbiome to date, comprising three large datasets with a sample size of 1,006 PD and 544 neurologically healthy controls, generated with uniform methodology from subject recruitment to data analysis, and characterized using deep shotgun metagenome sequencing, genome-wide genotypes, and metadata. We begin by describing the gut dysbiosis at the species, gene, pathway, and functional level. Next, we find that PD-associated genetic variants at the SNCA gene region are associated with increased abundance of opportunistic pathogens and depletion of fiber degraders in the PD gut. We show that the presence of opportunistic pathogens at high levels in the gut increases the penetrance of SNCA variants for PD risk, raising the GWAS-derived odds ratio from less than 1.5 to over 8. The genetic variants identified here control splicing of the SNCA transcripts into alpha-synuclein isoforms with varying affinity for pathological aggregation. These data suggest pathogens are triggers for disease in the setting of genetic susceptibility, and the link to the genome implicates the microbes in the causation of PD. Finally, shifting focus to translation, we show that not all PD patients have the same dysbiotic features, and propose a conceptual framework to identify microbiome-based biomarkers to select appropriate patients for targeted microbiome-based clinical trials and personalized treatment.