Main

The immune system responds to harmful stimuli such as infections and cellular damage1, playing a critical role in regulating inflammatory signaling required to combat exogenous infections or elicit an initial antitumor response at the presence of malignancy2,3. A remarkable feature of the immune system is its capacity to form a long-term adaptive response enabling a rapid recall to future re-challenges termed immune memory4, providing specific immunity that can span over decades5. Yet, this principally advantageous plasticity actively specializing the immune system throughout life comes at the cost of reduced responsiveness to novel antigens which is highlighted by attenuated responses to vaccines and increased vulnerability to novel infectious diseases6,7. Immune aging describes the global remodeling of the immune system that is characterized by reduced thymic output and an increase in memory populations with concomitant reduction in naive T cell populations8,9. These changes cumulate in a chronic low-grade inflammatory state termed inflammaging10,11 that is characterized by increased concentrations of pro-inflammatory mediators favoring the development of heart disease and cancer12,13.

The emerging field of immunometabolism has highlighted the critical role of metabolic dependencies of immune cells and their organelles in regulating immune fate and function14. Mitophagy is a selective form of autophagy aimed at degrading damaged and dysfunctional mitochondria, with impaired mitophagy capacities constituting a defining characteristic of a variety of chronic conditions15. Indeed, inhibition of autophagy and impaired mitochondrial function constitute two of the hallmarks of aging16. Mitochondrial quality control also critically affects immune fate and function, in turn affecting systemic inflammaging17. T cells with dysfunctional mitochondrial dynamics provoke systemic senescence via pathological cytokine secretion18, thereby placing them at the center of age-associated multimorbidity. In cancer, exhausted tumor-infiltrating leukocytes accumulate dysfunctional mitochondria caused by impairment of mitophagy19 and repression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis20. Improving mitochondrial quality control therefore possesses great hypothetical potential for improving immune function and positively influencing aging-associated diseases characterized by a dysfunctional immune response. Yet, interventions aimed at improving immune health are currently restricted to generalized lifestyle interventions such as physical exercise[21](https://www.nature.com/articles/s43587-025-00996-x#ref-CR21 “Duggal, N. A, Pollock, R. D., Lazarus, N. R., Harridge, S. & Lord, J. M. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17, https://doi.org/10.1111/acel.12750

(2018)“) or caloric restriction22, as hypothetical therapeutic approaches exhibit long-term safety concerns[23](https://www.nature.com/articles/s43587-025-00996-x#ref-CR23 “Borgoni, S., Kudryashova, K. S., Burka, K. & de Magalhães, J. P. Targeting immune dysfunction in aging. Ageing Res. Rev. 70, 101410, https://doi.org/10.1016/j.arr.2021.101410

(2021).“).

Urolithin A (UA) is a postbiotic metabolite derived from ellagitannins, of which pomegranates constitute a rich source24. UA potently induces mitophagy in humans and rodents25,26, whereas clinical trials have demonstrated improved physical performance upon UA supplementation27,28. We have recently shown that UA directly regulates CD8+ (cluster of differentiation 8-positive) T cell fate, leading to the expansion of T memory stem cells (TSCM) and naive-like T cells (TN) with potent anti-tumor memory in mice via mitophagy-elicited activation of Wnt signaling and T cell factor 1 (TCF1) induction29. We found that exposure to UA confers a beneficial T cell state on human chimeric antigen receptor (CAR) T cells ex vivo29. Therefore, we hypothesized that oral UA supplementation could trigger a similar effect associated with improved immune function in humans.

Results

The present study was designed as a randomized, double-blind, placebo-controlled proof-of-concept trial to investigate the effect of short-term (4 weeks) UA supplementation on immune health and systemic inflammation in a study cohort of 50 healthy middle-aged adults (MitoImmune, NCT05735886). Primary end points were changes in T cell subpopulations, as well as changes in mitochondrial activity in CD3+ T cells compared to placebo. A 1 month intervention period was chosen according to the average lifespan of human effector and memory T cell populations30. We screened n = 79 study participants out of whom 50 successfully met all screening inclusion and exclusion criteria (Fig. 1). Participants were deemed healthy by a study physician as determined by their medical history, anthropometric measurements, physical examination, vital signs, and laboratory parameters. Randomization was performed based on age, gender, and body mass index (BMI), and participants were allocated to the treatment groups 1:1. Therefore, baseline characteristics of participants were similar (Table 1). Overall, there were more female participants (60% female versus 40% male) who were equally distributed to both groups. Vital signs did not differ between both groups at baseline (Table 1). Also, baseline levels of metabolic markers, kidney function parameters, and liver enzymes did not differ between the two groups (Extended Data Table 1).

Fig. 1: CONSORT diagram of participant inclusion.

The MitoImmune trial was a single-center, randomized, double-blind, placebo-controlled, investigator-initiated interventional trial performed with healthy adults aged 45–70 years. Fifty participants (n = 50) met the inclusion and exclusion criteria and were subsequently included into the trial and then randomized to a daily intervention of single-dose (1,000 mg) UA or placebo based on age, gender, and BMI in a 1:1 ratio. The total study duration was 28 days. One participant did not complete the allocated trial product intake (n = 1 dropout) but provided samples for end point analysis. No participant was therefore excluded for the final analysis. Fourty-nine participants reported >90% intake compliance as assessed via questionaires and completed scheduled visits (n = 49).

Biochemical safety analysis and adverse event recording

Previously, long-term UA oral administration over 4 months was found to be safe and well tolerated in a cohort of middle-aged adults27. In line with this, only a total of nine adverse events were recorded during the 28 day study period in both groups (Extended Data Table 2). Four were reported in the UA group, whereas five were reported in the placebo group. Most adverse events (n = 6) were upper respiratory tract infections, of which three (n = 3) constituted SARS-CoV2 infections. One participant in the placebo group (n = 1) discontinued intake upon a major depressive episode which was deemed unrelated to the intervention. By protocol, no participants were excluded from final analysis, and analysis was performed by the original assigned group. No other differences in adverse events were reported between the two groups, confirming safety and tolerance of UA supplementation in aged adults without prior conditions. No significant changes were observed in kidney function parameters or liver enzymes after the 28 days of either UA or placebo (Extended Data Table 1). The intake of UA led to high plasma levels of parent UA and its conjugated form, UA glucuronide (Extended Data Fig. 1a,b), confirming its bioavailability.

Primary outcome: CD3+ immune subpopulations

The primary aim of the present study was to assess the effect of UA on CD3+ T cell subpopulations. In addition to growing evidence from recent omics-based studies supporting the notion of aging-associated remodeling of immune populations31,32, initial observations have highlighted the correlation of a reduced lymphocyte count in the peripheral blood with age33. We therefore performed clinical hemocytometry to first categorize circulating immune cells, comparing immune composition at baseline and upon the last study visit (Extended Data Fig. 1c). After 28 days participants in the UA group displayed significantly more circulating lymphocytes (Extended Data Fig. 1d) compared to baseline levels, a change which was not observed in the placebo group. Other immune populations, such as eosinophils, neutrophils, monocytes, and total leukocytes did not show marked alterations upon any intervention (Extended Data Fig. 1e–h).

We then performed broad spectral cytometry (Fig. 2a) to identify cell surface markers and transcription factors (Supplementary Fig. 1). The number of total CD3+ αβ, CD8+, and CD4+ T cells (Fig. 2b–d) among total peripheral blood mononuclear cells (PBMCs) did not change upon taking UA. Yet, we observed a significant change of naive CD8+ T cells (TN) after 28 days of UA intake. (Fig. 2e). The percentage of TSCM remained unaltered (Fig. 2f) in contrast to our previous in vitro observations29. Other CD8+ T cell subsets, such as central memory cells (TCM), effector memory cells (TEM), terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA) or recently characterized “virtual memory” cells, which arise with a memory-like phenotype without prior foreign antigen challenge34, remained unaffected in both cohorts (Extended Data Fig. 2a–d). Total CD8+ T cells in the UA group displayed more antigen Kiel 67 (Ki-67) (Fig. 2g) after the completion of the last study visit, a marker of cellular proliferation and T cell reinvigoration that predicts pathological complete response to immune checkpoint blockade (ICB) in patients with triple-negative breast cancer35. Programmed cell death protein 1 (PD-1) expression was unaltered in both groups (Extended Data Fig. 2e). We also observed a reduction in thymocyte selection associated high mobility group box (TOX) expression (Fig. 2h), the master regulator of T cell exhaustion that marks aging-associated T cells36 and promotes CD8+ T cell dysfunction in cancer37,38. There was no difference in prominent senescence markers such as p16 and p21, or KLRG1 and CD57 (Extended Data Fig. 2f–i). Thus, UA altered the CD8+ T cell phenotype suggestive of a more naive-like, less exhausted global state. By stark contrast, UA did not affect the phenotype of CD4+ T cells in terms of TN, TEM, TCM, TSCM or TEMRA populations (Extended Data Fig. 2h–l) in our human cohort. There were also no changes in CD4+ T helper 1 (Th1) cells (marked by T-bet expression), Gata3+ T helper 2 (Th2) cells, FoxP3+ T regulatory (Treg) cells, circulating T follicular helper cells (Tfh1, identified via Bcl-6), or γδ T cells (Extended Data Fig. 2m–p). Collectively, UA supplementation instigates phenotypical changes in circulating T cells, with expansion of lymphocyte populations and an emphasis on naive-like, less exhausted CD8+ state.

Primary outcome: metabolic reprogramming

The immune system exhibits a striking metabolic plasticity while metabolic reprogramming critically instructs but also defines immune fate and function14. For instance, different metabolic needs are met by diverging mitochondrial ultrastructures in T cells17, which we expected to undergo change upon UA supplementation. A co-primary outcome therefore constituted changes in metabolic dependencies of immune (primarily T cell) populations. To further characterize the metabolic profile of immune cells on a single-cell resolution, we used single-cell energetic metabolism by profiling translation inhibition (SCENITH), a flow-cytometry-based strategy that uses incorporation of puromycin to infer metabolic dependencies39. We first modeled mitochondrial dependence, glucose dependence, glycolytic capacity, and fatty acid oxidation (FAO) and amino acid oxidation (AAO) capacity in CD8+ T cell subsets of all participants at baseline. In line with previous results using SCENITH, the expression of CD45RA, mostly present in naive T cells, is indicative of strong dependence on oxidative phosphorylation (OXPHOS) (Extended Data Fig. 3a,b)40,41. After strong metabolic activation of T cells upon antigen encounter14, memory T cells rewire their metabolism toward a more quiescent but metabolically primed state, shifting toward catabolic processes of generating energy. Correspondingly, we found both elevated glycolytic capacity and FAO and AAO capacity in TCM (Extended Data Fig. 3c,d). Indeed, TCM were significantly less dependent on glucose (Extended Data Fig. 3a), consistent with their induction and maintenance of mitochondrial biogenesis that reflects their ability to create energy via OXPHOS42. Thus, our approach faithfully detects metabolic dependencies of immune cell subsets, enabling us to study intervention-related effects.

We next assessed whether UA supplementation provokes changes in immune metabolism. After the 28 day intervention period, CD8+ T cells of the UA group displayed reduced glucose dependence and increased FAO and AAO capacity, whereas it did not elicit changes in mitochondrial dependence or glycolytic capacity (Fig. 3a–d). The capacity to use FAO and AAO was most strongly elevated in naive CD8+ T cells (Fig. 3e and Extended Data Fig. 3e–g). Also, natural killer (NK) cells displayed enhanced FAO and AAO capacity and concomitantly reduced glucose dependence (Extended Data Fig. 3h), while we observed a similar trend in nonclassical monocytes (Fig. 3f and Extended Data Fig. 3i). No statistically significant changes were observed in CD4+ T cells (Fig. 3h and Extended Data Fig. 3k) or B cells (Extended Data Fig. 3h–l). The strong glycolytic phenotype of classical monocytes remained unaltered (Extended Data Fig. 3m,n). Altogether, daily intake of UA resulted in reduced glucose dependence and pronounced capacity to meet bioenergetic needs via the mitochondrial oxidation of fatty acids and amino acids in the lymphoid compartment, consistent with their phenotypical remodeling.

Fig. 3: Primary end point—UA induces metabolic reprogramming of human immune cells.

a–d, Metabolic profiling of CD8+ cells using SCENITH. Truncated violin plots of glucose dependence (a), fatty acid and amino acid oxidation capacity (FAO and AAO capacity) (b), mitochondrial dependence (c), and glycolytic capacity (d) are shown. Data shown from UA- and placebo-treated participants at baseline (d0) and after the 28 day supplementation period (d28) depicting percentage. Mean (solid line) and 25th/75th quartiles (dotted lines) are shown. N = 25 per group. P values for treatment effects were calculated using a repeated measures mixed-effects model. e–h, Truncated violin plots depicting fatty acid and amino acid oxidation (FAO and AAO) capacity from several immune subpopulations as assessed by SCENITH. Data from TN (e), CD56dimCD16hi NK cells (f), nonclassical monocytes (g), and CD4+ cells (h) are shown from UA- and placebo-treated participants at baseline (d0) and after the 28 day supplementation period (d28). Depicted are mean (solid line) and 25th/75th quartiles (dotted lines), n = 25 per group. P values for treatment effects were calculated using a repeated measures mixed-effects model. All statistical tests were two-sided. No adjustments for multiple comparisons were made.

Secondary outcomes: effect of UA on other immune populations and mitochondrial remodeling

A secondary outcome constituted shifts in circulating immune cells frequencies apart from the T cell population.

In addition to the pronounced changes observed in the CD8+ compartment, other peripheral immune populations were also affected by UA supplementation. CD56dimCD16bright NK cells, the most common NK subset in human blood, were expanded among total PBMCs in the UA group (Fig. 4a), while we did not observe a change in the expression of their inhibitory receptors such as NKG2A, KIR, or KLRG1 (Extended Data Fig. 4a–c). Furthermore, we found that the percentage of nonclassical monocytes (defined as CD14loCD16hi cells) in PBMCs was increased after 28 days of UA compared to placebo (Fig. 4b), whereas the relative frequency of intermediate monocytes and classical monocytes did not differ between the two groups (Extended Data Fig. 4d,e). Yet, classical monocytes exhibited less human leukocyte antigen-DR isotype (HLA-DR) in participants of the UA group at the final study visit (Fig. 4c), indicative of a less inflammatory phenotype43. Circulating dendritic cells (DCs) and innate lymphoid cells did not change upon either intervention (Fig. 4d and Extended Data Fig. 4f), and also, the percentage of total B cells, plasma cells, plasmablasts, or specific B cell subsets was not different between the two intervention groups (Fig. 4e and Extended Data Fig. 4g–j). Collectively, UA supplementation instigates phenotypical changes extending beyond CD8+ immunity.

Fig. 4: Secondary end point—UA alters peripheral immune frequencies and mitochondrial remodeling.

a, Absolute change in percentage of CD56dimCD16hi NK cells in PBMCs after 28 days. Data are mean ± 95% CI, n = 25 per group. P value for treatment effects was calculated using a two-sided repeated measures mixed-effects model. b, Absolute change in percentage of nonclassical monocytes (CD14−CD16+) within PBMCs after 28 days. Data are mean ± 95% CI, n = 25 per group. P value for treatment effect was calculated using a two-sided repeated measures mixed-effects model. c, Absolute change in HLA-DRhi cells within classical monocytes after 28 days of UA or placebo supplementation. Data are mean ± 95% CI, n = 25 per group. P value for treatment effect was calculated using a two-sided repeated measures mixed-effects model. d,e, Absolute change in percentage of DCs (d) and B cells (e) within PBMCs after 28 days. Data are mean ± 95% CI, n = 25 per group. P values for treatment effect were calculated using a two-sided repeated measures mixed-effects model. f,g, Expression of PGC-1α in CD8+ cells before (d0) and after (d28) UA and placebo supplementation, respectively. Assessed by flow cytometry, data shown as mean fluorescence intensity (MFI). Representative histograms are shown in (f), data depicted in (g). Data are mean ± 95% CI, n = 12 per group. P value for treatment effect was calculated using a two-sided repeated measures mixed-effects model. No adjustments for multiple comparisons were made.

Considering the well-established yet rapid impact of UA on mitophagy25 and the association between mitochondrial plasticity and immune fate17,29,44, which we have previously extended to the notion of UA-elicited mitophagy altering T cell function in mice29, we next assessed whether UA supplementation elicits mitochondrial remodeling in the immune compartment of humans. To this end, we used MitoTrackerGreen, a fluorescent dye that stains mitochondria independent of mitochondrial membrane potential (MMP). Neither CD8+ or CD4+ cells of UA-treated participants exhibited a change in mitochondrial mass after 28 days (Extended Data Fig. 5a–d). Mitochondrial biogenesis and mitophagy are closely interlinked15 to guarantee sustained replacement of dysfunctional mitochondria and maintain adequate mitochondrial mass. PGC-1α is considered the master regulator of mitochondrial biogenesis45. We have previously shown that UA elicits mitophagy quickly in T cells ex vivo, which is followed by PGC-1α-mediated mitochondrial biogenesis29. We therefore hypothesized that an unchanged mitochondrial mass in T cells of UA-treated participants may be due to compensatory mitochondrial biogenesis upon mitophagy induction. Indeed, UA-exposed CD8+ T cells displayed stronger expression of PGC-1α after the intervention period (Fig. 4f,g), whereas no such change was detected after intake of placebo. Consistent with no alterations in the CD4+ phenotype, no significant induction of PGC-1α was seen in CD4+ T cells (Extended Data Fig. 5e). Given that hyperpolarized mitochondria can be a source of reactive oxygen species which can potentiate senescence46, we finally assessed MMP, where we found no difference in MMP in both CD8+ T cells and CD4+ T cells in the UA group compared to placebo (Extended Data Fig. 5f–h). As we hypothesized that mitophagy induction might have occurred before our follow-up visits, we performed additional ex vivo experiments from PBMCs derived from healthy donors that were not included in the trial. Here, incubation with UA at 25 µM led to quick hypopolarization of mitochondria, followed by lysosome formation, reduction of MitoTracker staining, and mtDNA/nuDNA (mitochondrial DNA to nuclear DNA) ratio, as well as stabilization of Pink1/Parkin levels (Extended Data Fig. 6a–f). This is consistent with rapid mitophagy induction that we have also observed in mice29. In summary, our data indicate that the mitophagy inducer UA supplementation affects mitochondria in CD8+ cells in vivo, possibly via PGC-1α-mediated mitochondrial biogenesis.

Secondary outcome: systemic inflammation and activation-induced immune response

Considering the effects of UA on immune polarization and the observation that aging-associated metabolic failure profoundly contributes to the phenotype of inflammaging18, we next investigated whether circulating cytokine plasma levels are affected by UA supplementation. Sample limitation allowed the measurement of up to n = 20 cytokine levels per group. Here, while administration of UA led to significantly lower levels of IL-2, there was no pathological induction of several pro-inflammatory cytokines (Fig. 5a).

Fig. 5: Secondary end point—UA alters inflammatory immune response.

a, Plasma cytokine measurements. Fold change compared to baseline plasma levels of the indicated cytokines of UA- and placebo-treated participants are shown. Data are mean ± 95% CI, n = 15/19/20/20/19/19/19/18/20/20 of matched samples per cytokine. P values for treatment effects were calculated by a two-sided repeated measures mixed-effects model. No adjustments for multiple comparisons were made. b, PBMC stimulation overview. Thawed PBMCs from UA- and placebo-treated individuals were stimulated with anti-CD3/anti-CD28 beads for a duration of 4 days, followed by functional readouts. c,d, Expression of TNF in CD8+ cells before (d0) and after (d28) UA and placebo supplementation, respectively. Cells were stimulated as depicted in b. Assessed by flow cytometry, data shown as MFI. Representative histograms are shown in c, data is depicted in d. Data are mean ± 95% CI, n = 25 per group. P value for treatment effects was calculated by a two-sided repeated measures mixed-effects model. e, Percentage of IL-4hi cells within CD8+ cells after 4 days of PBMC stimulation as depicted in a. Data are mean ± 95% CI, n = 25 per group. P value for treatment effects was calculated by a two-sided repeated measures mixed-effects model. f, E. coli uptake of monocytes from UA- and placebo-treated participants before (d0) and after the supplementation period (d28), respectively. Data are mean ± 95% CI, n = 25 per group. P value for treatment effects was calculated by a two-sided repeated measures mixed-effects model. No adjustments for multiple comparisons were made. Schematic in b created using BioRender.com.

A recent single-cell atlas of healthy human blood has indicated an aging-associated bias toward type 2 immunity that is uncovered in healthy participants upon antigen challenge, but not at steady state32. We therefore next focused on cytokine expression of stimulated T cells to detect potential differences in the context of immune response which could constitute a potential predisposition to conditions that may only manifest when specifically triggered (such as a pathological type 2 reaction observed in fibrotic conditions). To this end, PBMCs from both intervention groups were incubated in the presence of anti-CD3/anti-CD28 stimulation beads for a total of 4 days (Fig. 4b). Intriguingly, challenged CD8+ T cells of UA-treated participants more readily produced TNF while not pathologically enhancing IL-4 secretion, whereas placebo intake did not elicit any changes (Fig. 4c–e). Taken together, our results indicate that UA treatment improves an activation-induced type 1 response, while not influencing inflammatory conditioning at steady state.

Expanding on our functional findings in CD8+ T cells, we next assessed myeloid function after UA. The immunosenescent phenotype is considered responsible for an increased susceptibility to infections in older adults6. Given the established role of UA in instructing macrophage polarization in vitro47 in addition to here suggesting altered circulating monocyte composition, we lastly performed a phagocytosis assay to assess whether UA impacts monocyte phagocytotic capabilities of Gram-negative bacteria. Monocytes from UA-exposed participants markedly enhanced phagocytosis of Escherichia coli particles ex vivo when compared with the placebo cohort (Fig. 5f), hinting at superior uptake and clearance of Gram-negative bacteria. Collectively, our data support the notion that apart from profound phenotypic and metabolic changes in the human immune system, UA supplementation results in changes in immune function that potentially carries systemic consequences.

Exploratory outcome: single-cell RNA sequencing

To further profile the immune compartment upon UA intake, we performed explorative single-cell RNA sequencing (scRNA-seq) from five participants before and after both interventions. After quality control filtering, we profiled a total of 231,079 cells with >1,000 genes per cell (Extended Data Fig. 7a). For population clustering, a hierarchical approach was used32 incorporating Azimuth48 to define subpopulations (Extended Data Fig. 7b). A total of 89 genes were differentially expressed in CD8+ T cells (52 up, 37 down) after 28 days of UA compared to placebo (Extended Data Fig. 7c). Consistent with previous in vitro data29 and our findings of UA eliciting a naive-like state in T cells (Fig. 2), we found upregulation of the Wnt-associated stemness transcription factors TCF7 and LEF1, as well as induction of IL7R. Among downregulated genes, several genes associated with T cell exhaustion, suppression, and hypofunction (NR4A2, CREM, TGFB1, METRNL)49,50,51,[52](https://www.nature.com/articles/s43587-025-00996-x#ref-CR52 “Jackson, C. M., et al. The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function. Immunity https://doi.org/10.1016/j.immuni.2024.07.003

(2024).“) were identified. Canonical pathway analysis revealed activation of T cell receptor (TCR) signaling and several pathways associated with cytoskeleton remodeling, adhesion, and cellular motility (Extended Data Fig. 7d) in UA-exposed CD8+ T cells. Likewise, Gene Ontology enrichment analysis using EnrichR53 confirmed similar tendency toward cytoskeletal reorganization programs (Extended Data Fig. 7e). Among downregulated canonical pathways, both protein kinase A (PKA) signaling and other immune inhibitory pathways were shown to be strongly inhibited (Extended Data Fig. 7f). Indeed, recent findings suggest G-protein coupled receptors (GPCRs) and Gαs signaling as an immune checkpoint in human cancer that drives a hyporesponsive state, thereby resulting in immunotherapy failure54. Consistently, predicted upstream regulators suggested a reduced role of several components of the GPCR–Gαs–PKA axis, such as G protein-coupled receptor 174 (GPR174), guanine nucleotide binding protein (G protein), alpha stimulating (GNAS), and cyclic adenosine monophosphate (cAMP; Extended Data Fig. 7g). Other transcription factors central to T cell exhaustion and blunted tumor infiltration such as interferon regulatory factor (IRF4; ref. 55), signal transducer and activator of transcription 6 (STAT6) and yes-associated protein 1 (YAP1) were also among predicted inhibited pathways. These findings extended to the TEM subset where we also observed downregulation of the transcription factor ‘cAMP-responsive element modulator’ (CREM; Extended Data Fig. 7h,i). Gene Ontology enrichment analysis confirmed an upregulation of cytoskeletal and adhesion-associated programs, while revealing downregulation of GPCR–Gαs–PKA-associated pathways and its ligand PGE2 in TEM as well. Among naive T cells, several components of the electron transport chain (MT-ND5, MT-CO1, MT-CO2) were induced upon UA intake (Extended Data Fig. 7j). Collectively, the transcriptomic findings support our experimental evidence of altered mitochondrial activity and reduced CD8+ T cell suppression upon UA intake.

Changes in the NK cell compartment in UA-treated individuals were characterized by reduction of several well-known immediate-early genes56 (Extended Data Fig. 8a) including NR4A2, DUSP1, FOS, JUN, and NFKBIA. These constitute primary response genes that are induced rapidly after stimulation and generally do not require de novo protein synthesis57. Consistently, other downregulated genes belonged to inflammatory TNF and interferon pathways, while NK cells of UA-treated participants also displayed reduction of the activation markers CD69 and CXCR4 (Extended Data Fig. 8a). Such transcriptional profile is in line with less “inflamed” NK subsets that were recently described56. Furthermore, NK cells also displayed an upregulation