The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed an unprecedented global health crisis, resulting in over 776.8 million confirmed COVID-19 cases and over 7 million confirmed deaths worldwide (1, 2). While the acute phase of the infection has been extensively characterized, a significant portion of convalescent individuals develop a debilitating post-viral syndrome known as Long COVID (LC), which affects an estimated 65 million people globally and manifests as heterogeneous symptoms including persistent fatigue, cognitive impairment, and respiratory issues (3, 4). Among this population, patients with end-stage renal disease (ESRD) on maintenance dialysis represent a particularly vulnerable subgroup because pre-existing immune dysfunction, chronic inflammation and profound metabolic disturbances jointly predispose them to severe acute COVID-19 and a higher burden of LC (5, 6). Elucidating the mechanisms that link SARS-CoV-2 infection to disease severity and long-term sequelae in this high-risk population is therefore a critical public health and clinical priority.

The clinical trajectory of COVID-19 is increasingly understood to be heavily influenced by the host's metabolic state, with perturbations in amino acid, energy, and lipid metabolism closely linked to disease severity and outcomes (7, 8). Metabolomics has emerged as a pivotal tool for uncovering these pathological shifts and identifying potential biomarkers (9). A particularly promising yet underexplored metabolic interface in COVID-19 is the gut-lung axis, with the gut microbiota and its functional output playing a crucial immunomodulatory role (10). Notably, short-chain fatty acids (SCFAs) depletion has been documented in both chronic kidney disease (CKD) populations and in individuals following COVID-19, suggesting a potential link to immune dysregulation and adverse clinical courses (11, 12). Straight-chain SCFAs primarily arise from the microbial fermentation of dietary carbohydrates, whereas branched-chain short-chain fatty acids (BCFAs) are mainly derived from the fermentation of branched-chain amino acids (BCAAs) (13). Despite these advances, critical knowledge gaps persist specifically concerning the dialysis population. The pre-existing uraemic milieu, characterized by gut dysbiosis, accumulation of uremic toxins and dialysis-related metabolic stress, likely creates a distinct metabolic landscape that interacts with SARS-CoV-2 differently from the general population (14, 15). However, the specific changes in gut microbiota–derived metabolites such as SCFAs and the accompanying systemic metabolic shifts after COVID-19 in dialysis patients remain largely undefined. Against this background, the present study sought to characterize fecal SCFAs profiles and serum metabolomic signatures in dialysis patients with and without acute COVID-19, and to explore their evolution in relation to LC, in order to provide a metabolic framework for risk stratification and targeted follow-up in this high-risk population.

COVID-19 superimposed on end-stage kidney disease produced a characteristic pattern of gut and systemic metabolic disruption in this cohort of dialysis patients. Fecal profiles showed a marked loss of microbiota-derived SCFAs, while serum metabolomics revealed extensive reprogramming of amino acid, energy and carbohydrate metabolism during acute infection, and a persistent amino-acid–centered signature among patients who subsequently developed LC. Notably, pathway enrichment analysis suggested significant changes in pathways annotated as essential amino acid biosynthesis, including valine, leucine and isoleucine biosynthesis as well as phenylalanine, tyrosine and tryptophan biosynthesis. Because the end products of these pathways are essential amino acids that humans cannot synthesize de novo, enrichment signals assigned to these biosynthetic pathways in serum are unlikely to represent host-intrinsic biosynthetic activity. Instead, they more plausibly reflect altered metabolic functions of the gut microbiota and microbial contributions to the circulating amino acid pool. This interpretation is consistent with prior work showing that the gut microbiota can synthesize and metabolize essential amino acids, and that COVID-19 is associated with marked shifts in the gut microbiota and related metabolites, including branched-chain and aromatic amino acids (33, 34). This inference is further supported by the pronounced disruption of the fecal SCFA profile observed in our patients. Because SCFAs are key indicators of commensal microbial homeostasis, their depletion points to substantial perturbation of the gut ecosystem. Together, these observations suggest that SARS-CoV-2 infection may further remodel an already vulnerable gut ecosystem in dialysis patients, thereby contributing to systemic serum metabolomic signatures. Correlation analysis further linked these metabolic derangements to inflammatory burden, nutritional status and immune cell counts, highlighting tight coupling between the metabolic and clinical phenotype in this highly vulnerable population. Amino acids and energy-supporting intermediates, including glutamine, aspartate, methionine, cystine, and taurine, were inversely associated with CRP, leukocyte and neutrophil counts, and AST, and positively associated with albumin, potassium, and lymphocyte or eosinophil counts. In contrast, purine degradation products and selected organic acids, including uric acid, hypoxanthine, pyruvate, and glycolate, showed the opposite pattern. These associations are cross-sectional and do not establish causality or directionality. however, they align with immunometabolic frameworks in which sustained inflammatory signaling increases the demand for amino acids that support biosynthesis, redox balance, and energetic needs, while immune activation and cellular stress are frequently accompanied by altered glycolytic flux and increased purine turnover (35, 36). In the context of uremia-related metabolic inflexibility, such infection-associated reprogramming may have amplified clinical consequences.

Dialysis patients generally exhibit an inherent “immune paralysis” state, characterized by lymphocyte depletion and impaired T-cell function, leading to a weakened immune response to viral infections and increased susceptibility to pathogens such as SARS-CoV-2 (37, 38). Once an infection occurs, these patients often experience an excessive inflammatory response due to the imbalance in immune regulation, which is consistent with the clinical data from this study (blood routine and CRP) (39). Additionally, dialysis patients typically have gut dysbiosis and impaired intestinal barrier function, contributing to a mild but persistent chronic inflammatory state (40). The SARS-CoV-2 virus can invade the intestinal mucosa through its receptor, angiotensin-converting enzyme 2 (ACE2), further exacerbating gut microbiota dysbiosis and profoundly affecting the composition of gut microbiota metabolites (41, 42). SCFAs are important metabolites produced by gut microbiota fermentation of dietary fibers, playing a central role in regulating host immune responses and inflammatory reactions (43). Their anti-inflammatory mechanisms include: first, as histone deacetylase (HDAC) inhibitors, especially butyrate, which can promote the differentiation and function of regulatory T cells (Treg) with anti-inflammatory functions, thereby maintaining immune homeostasis (44). Second, by activating G protein-coupled receptors (GPCRs), SCFAs inhibit the activation of inflammation pathways such as nuclear factor kappa B (NF-κB), thus reducing the production of key pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), alleviating the inflammatory response (43, 45). Third, butyrate, propionate, and other SCFAs are the primary energy sources for colonic epithelial cells, crucial for maintaining the integrity of the intestinal epithelial barrier and enhancing tight junction functions (46). In this study, the substantial reduction in SCFAs (notably propionate and butyrate) in COVID-19-infected dialysis patients likely impairs these protective mechanisms, increasing intestinal permeability, facilitating lipopolysaccharide (LPS) translocation, inducing metabolic endotoxemia, and triggering a self-amplifying cytokine cascade that exacerbates systemic inflammation and worsens clinical outcomes (47, 48). In contrast, BCFAs, which are mainly generated from BCAA fermentation by proteolytic anaerobes, are comparatively less well characterized than straight-chain SCFAs, and the evidence for their immunomodulatory benefits appears more context dependent across studies (49). In COVID-19, SARS-CoV-2–associated gut dysbiosis has been consistently reported across cohorts, featuring reduced microbial diversity and broad taxonomic and functional shifts that relate to disease severity (50–52). In uremic states, pre-existing disruption of the gut–kidney axis and microbially derived metabolite remodeling in CKD can further constrain beneficial fermentation outputs and amplify inflammatory tone (53). Collectively, these findings indicate that microbiota-derived SCFA loss in uremic patients removes a critical restraint on mucosal and systemic inflammation, synergistically exacerbating SARS-CoV-2 pathology.

The profound depletion of fecal SCFAs observed during the acute phase in our study may set a pathological trajectory for post-COVID-19 metabolic sequelae. Although we did not longitudinally track fecal SCFA levels, emerging multi-omics evidence suggests that such gut microbiome dysbiosis often persists long after viral clearance (54). Specifically, studies have shown that the loss of SCFA-producing bacteria in COVID-19 patients is concurrently associated with impaired microbial biosynthesis of essential amino acids, particularly L-isoleucine, and these alterations correlate with systemic inflammation and disease severity (55). This provides a plausible mechanistic explanation for our serum metabolomics findings in the Long COVID cohort, where we observed persistent perturbations in valine, leucine and isoleucine biosynthesis pathways despite the resolution of acute infection. In dialysis patients, who already suffer from uremic dysbiosis, the acute loss of SCFAs may remove a critical restraint on gut permeability and inflammation, making the gut ecosystem difficult to recover (56). The resulting inability of the microbiome to synthesize sufficient essential amino acids and provide energy substrates likely contributes to the metabolic malnutrition state. This aligns with the clinical symptoms of fatigue and muscle weakness prevalent in our LC patients. Therefore, even without direct fecal sampling in the follow-up period, the acute SCFA crash we observed signals a need for early gut-targeted interventions to potentially prevent these long-term metabolic deficits.

The metabolic reprogramming induced by COVID-19 is likely exacerbated in dialysis patients because it is superimposed on pre-existing uremic malnutrition and metabolic inflexibility (57). In our cohort, non-targeted serum metabolomics identified 54 key differential metabolites, with pathway enrichment analyses indicating that amino acid metabolism was most prominently and extensively perturbed. Notably, glutamine and aspartate—central precursors for purine and pyrimidine nucleotide synthesis—were markedly reduced, consistent with intense utilization to support both viral replication and proliferating immune cells (58, 59). At the same time, tryptophan and sulfur-containing amino acids such as methionine and cysteine were depleted, changes that are expected to promote immunoregulatory kynurenine pathway activity and to limit glutathione synthesis, thereby weakening antiviral immunity and antioxidant defenses (60–62). In parallel, the accumulation of purine degradation products and organic acids suggests enhanced purine catabolism and a shift toward glycolytic energy metabolism in the setting of systemic inflammation and tissue hypoxia. Together, these COVID-19–driven metabolic changes, acting on the background of chronic protein–energy wasting in dialysis patients, likely create a synergistic disturbance that contributes to more severe inflammatory states and poorer clinical outcomes.

This study compared the serum metabolomics between the LC group and the non-LC group, revealing a more persistent metabolic dysregulation pattern. Interestingly, LC patients also exhibited disruptions in amino acid metabolism pathways, including arginine biosynthesis and tyrosine metabolism, with significant reductions in the levels of glutamine, aspartate, and tyrosine in their serum. These metabolic features were highly similar to those observed in the dialysis infection group. This suggests that the onset of LC is not coincidental but results from an imbalance in the amino acid metabolism homeostasis in the patients, which has not recovered in parallel with the alleviation of clinical symptoms. Importantly, this specific imbalance in amino acid metabolism provides a potential metabolic mechanism to explain typical LC symptoms, such as memory decline and susceptibility to fatigue. Specifically, glutamine, as an important energy substrate in the brain and a precursor of the neurotransmitters glutamate and γ-aminobutyric acid (GABA), may lead to mental fatigue and cognitive decline when deficient, as it affects neuronal energy metabolism (63). N-Methyl-D-aspartate (NMDA) receptors, crucial for synaptic plasticity and learning and memory, rely on aspartate, which is involved in the urea cycle and serves as a precursor for NMDA receptor agonists. The depletion of aspartate may impair memory formation (64). Tyrosine, an essential precursor for the synthesis of dopamine and norepinephrine, plays a central role in maintaining attention, alertness, and working memory (65). A deficiency of tyrosine in LC patients can limit the synthesis of these neurotransmitters, directly leading to fatigue and memory impairment. Recent LC multi-omics studies in the general population (66, 67) have also identified persistent disturbances in amino acid and energy metabolism that associate with fatigue, reduced exercise tolerance and neurocognitive complaints, suggesting that our findings in dialysis patients reflect a broader pathophysiological pattern.

In light of the marked depletion of fecal SCFAs (particularly propionate and butyrate) and perturbations in amino acid metabolism observed in our cohort, targeted modulation of the gut microbiota–SCFAs axis and optimization of amino acid and energy metabolism represent conceptually promising adjunctive strategies for dialysis patients with COVID-19 or long COVID. In the context of kidney diseases reduced SCFA production due to gut dysbiosis is linked to aggravated systemic inflammation, immune dysregulation, oxidative stress, and progression of renal injury; conversely, restoration or supplementation of SCFAs has demonstrated renoprotective potential in preclinical models of CKD, diabetic nephropathy, acute kidney injury, and hypertensive nephropathy (68). Direct clinical evidence in maintenance hemodialysis patients further supports feasibility: a pilot study showed that oral sodium propionate supplementation significantly reduced pro-inflammatory markers (CRP, IL-2, IL-17), oxidative stress, gut-derived uremic toxins (indoxyl sulfate, p-cresyl sulfate), and improved insulin resistance, iron metabolism, and quality of life (69). These effects align with the known actions of SCFAs and may be particularly relevant for mitigating COVID-19-associated cytokine dysregulation, metabolic endotoxemia, and uremic amplification in dialysis patients (70). Nevertheless, important challenges persist. No studies have specifically assessed SCFA supplementation in dialysis patients during or after SARS-CoV-2 infection. Potential concerns include gastrointestinal tolerability, optimal dosing to prevent excessive acidification or metabolic overload in the setting of impaired renal clearance, and altered SCFA handling in uremia. Similarly, targeted amino acid optimization (e.g., glutamine or branched-chain amino acids) could theoretically counteract catabolic stress and support immune/neurotransmitter functions, but carries risks of exacerbating uremic toxicity, acid-base imbalance, or hyperammonemia in this population, with currently only indirect evidence available.

In conclusion, modulation of the gut microbiota–SCFAs axis holds translational promise, underpinned by mechanistic and preclinical insights in kidney diseases and preliminary clinical data in hemodialysis. Future randomized controlled trials are essential to determine its safety, efficacy, optimal formulations, timing, and dosing in dialysis patients recovering from COVID-19, thereby translating these metabolic findings into targeted interventions to attenuate acute severity and long-term sequelae in this high-risk group.

First, although 81 maintenance dialysis patients were enrolled, the effective sample size for omics analyses was modest, and the fecal and serum biospecimen sets were only partially overlapping. This may have reduced statistical power and limited the depth of microbiome–metabolome integration. Second, while the enrichment of essential amino acid pathways strongly suggests a microbial contribution to the serum metabolome, the mechanisms by which COVID-19 perturbs the metabolic milieu of dialysis patients are likely to be highly complex. The direct causal flux from gut microbiota to circulating metabolites remains to be fully clarified. Future studies should therefore integrate multi-omics and experimental approaches, expand to multicenter cohorts with larger sample sizes, and incorporate longitudinal sampling at multiple time points. Such efforts will be essential to delineate how COVID-19 influences metabolism in dialysis patients, to define the causal roles of key metabolites in disease progression, and to rigorously assess their translational potential.

This study demonstrates that COVID-19 infection significantly exacerbates metabolic disturbances in dialysis patients mediated by a disrupted gut-kidney axis, particularly highlighted by the comprehensive depletion of SCFAs and widespread disruption of serum amino acid metabolic pathways. The reduction in SCFAs may weaken their anti-inflammatory and barrier protective functions, thus intensifying systemic inflammation. Meanwhile, the reprogramming of amino acid metabolism provides the necessary material foundation for viral replication while further impairing the host's immune response. Together, these factors interact with the pre-existing metabolic imbalance in dialysis patients, creating a “synergistic effect” that ultimately leads to more severe inflammatory states and adverse clinical outcomes. This study reveals the disrupted characteristics of dialysis patients after COVID-19 infection at the metabolite level, offering a new metabolic perspective on understanding their pathogenesis. Some patients continue to experience persistent amino acid metabolism imbalance after recovery, forming the metabolic basis for LC symptoms. These findings comprehensively uncover the pathological continuity from acute infection to LC in dialysis patients from a metabolic perspective, providing new insights into understanding the clinical heterogeneity of this population and developing targeted intervention strategies focused on restoring gut homeostasis and metabolic balance.