Post-acute COVID-19 gastrointestinal sequelae: Mechanisms of persistent dysbiosis, intestinal barrier dysfunction, and emerging long-COVID phenotypes

Abstract

Post-acute coronavirus disease 2019 (COVID-19) syndrome (long COVID) affects 10%-30% of survivors and commonly presents with prolonged gastrointestinal symptoms, including chronic diarrhea, irritable bowel syndrome-like symptoms, and functional dyspepsia that may persist beyond 12 months. Gut dysbiosis-the depletion of short-chain fatty acid (SCFA)-producing commensals, such as Faecalibacterium prausnitzii and the enrichment of proinflammatory taxa, such as Ruminococcus gnavus-has been proposed as a central mechanism alongside intestinal barrier dysfunction, mucosal immune dysregulation, and persistent systemic inflammation. Severe acute respiratory syndrome coronavirus 2 infects intestinal epithelial cells via high ACE2 expression, with prolonged fecal shedding independent of respiratory clearance, potentially establishing dysbiosis that persists through SCFA depletion, reduced tryptophan metabolism, and barrier disruption, as reflected by elevated serum zonulin and I-FABP levels. These disturbances are associated with low-grade endotoxemia due to bacterial translocation and loss of immune tolerance, which may contribute to gastrointestinal and systemic manifestations via the gut-brain and gut-lung axes. Microbiota-targeted strategies, such as probiotics, synbiotics, and fecal microbiota transplantation, have shown preliminary benefits in early trials, although the evidence remains heterogeneous, and larger randomized trials are needed. This review synthesizes the current mechanistic insights, emerging biomarkers, and therapeutic implications to guide clinical management and future research.

Key Words: Long COVID; Gut dysbiosis; Intestinal barrier dysfunction; Short-chain fatty acids; Microbiota-targeted therapy

Core Tip: Long-coronavirus disease gastrointestinal manifestations affect 10%-30% of survivors, but remain overlooked. Persistent dysbiosis-the loss of beneficial bacteria and pathogenic enrichment-drives symptoms through barrier dysfunction, immune dysregulation, and endotoxemia. Dysbiosis has been implicated as a potential contributor to short-chain fatty acid depletion and impaired tryptophan metabolism; however, current human evidence is largely observational, and causality remains unproven. Clinical biomarkers (zonulin, I-FABP, and dysbiotic signatures) enable patient stratification. Microbiota-targeted interventions (probiotics, synbiotics, fecal microbiota transplantation, and postbiotics) offer rational therapeutic approaches. This review establishes dysbiosis as a central therapeutic target and provides an evidence-based framework for its clinical management.

INTRODUCTION

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major cause of long-term morbidity worldwide. A substantial proportion of infected persons experience chronic symptoms lasting weeks to months after disease onset, a condition referred to as post-acute COVID-19 or long-COVID, affecting an estimated 10%-30% of COVID-19 survivors and imposing a significant burden on healthcare systems, occupational capacity, and quality of life[1-3]. However, systemic symptoms, such as fatigue, cognitive impairment, and dyspnea, have predominated the long-COVID literature, whereas gastrointestinal manifestations remain underappreciated despite their clinical relevance and impact on patient function.

Gastrointestinal involvement in acute COVID-19 is common, with reported symptoms (diarrhea, nausea, vomiting, and abdominal pain) in 15%-39% of hospitalized patients[4]. SARS-CoV-2 directly infects the gastrointestinal epithelium through high ACE2 receptor expression, which is detected in fecal specimens weeks after respiratory symptom resolution and facilitates prolonged viral shedding and associated complications[4]. Nevertheless, the mechanisms underlying persistent gastrointestinal dysfunction after acute COVID-19 remain unclear.

Recent observational studies have identified a subgroup of patients with persistent or emergent gastrointestinal symptoms, including chronic diarrhea, bloating, constipation, and irritable bowel syndrome (IBS)-like presentations. Mechanistic studies demonstrate that long-COVID is associated with sustained dysbiosis, persistent alterations in gut microbial composition beyond the acute infection phase, impaired intestinal barrier integrity, and mucosal immune dysregulation[5]. Importantly, gastrointestinal dysbiosis and systemic long-COVID manifestations may be mechanistically linked, and intestinal barrier dysfunction, microbial dysbiosis, and bacterial translocation of lipopolysaccharide (LPS) can mediate systemic symptoms, including post-exertional malaise, autonomic dysfunction, and neurological dysfunction through endotoxemia and systemic inflammation[6].

Despite its clinical significance, no comprehensive review has synthesized a mechanistic understanding of gastrointestinal dysbiosis in post-acute COVID-19 or examined the integrated evidence on barrier dysfunction, dysbiosis-driven biomarkers, and microbiota-targeted therapeutic strategies. This review describes the current knowledge of gastrointestinal sequelae following acute COVID-19, defines the mechanisms linking dysbiosis and intestinal barrier dysfunction to long-COVID phenotypes, and reviews the diagnostic and therapeutic approaches that may benefit affected patients. By consolidating epidemiological, mechanistic, and clinical evidence, this review aims to improve awareness of the gastrointestinal component of long-COVID and address critical knowledge gaps for internists and gastroenterologists.

LITERATURE SEARCH STRATEGY AND STUDY SELECTION

This article is a narrative-based literature review with a structured, non-systematic search of the existing literature. The search engine results from PubMed, Web of Science, and EMBASE databases were obtained from January 2020 to April 2026 to identify evolving evidence of post-acute COVID-19 and long COVID. The search strategy included controlled vocabulary and free-text words with the following Boolean operators: (long-COVID OR long COVID OR post-acute COVID-19 OR PASC OR “post-COVID syndrome”) AND (gastrointestinal OR gut OR diarrhea OR dysbiosis OR microbiome OR microbiota OR “intestinal barrier” OR “barrier dysfunction” OR permeability OR “tight junction” OR IBS OR “irritable bowel syndrome”). There was no structured PRISMA screening, dual independent study selection, or quantitative risk of bias scoring, and the synthesis was interpretive rather than systematic. Although there were no language restrictions on the search, we included only English-language full-text articles.

STUDY SELECTION CONSIDERATIONS

We screened studies of adult human participants (≥ 18 years) with confirmed or probable COVID-19 that reported gastrointestinal symptoms, microbiota composition, intestinal barrier markers, or mechanistic effects in the post-acute phase (≥ 4 weeks after acute illness), including observational cohorts, case-control studies, and mechanistic investigations of biological specimens (stool, serum, or intestinal tissue). Research conducted only in the acute phase in pediatric populations and a small number of case reports lacking mechanistic explanation were de-emphasized. Foundational mechanistic and experimental publications were also cited as relevant to the biological contextualization of these findings.

SYNTHESIS

Key findings were reported narratively and organized according to mechanistic themes (epidemiology and clinical phenotype, acute gut pathology, dysbiosis, intestinal barrier dysfunction and biomarkers, and microbiota-targeted therapy). Because of the heterogeneity of the study designs, no quantitative pooling was performed. Findings from longitudinal cohorts or studies employing standardized microbiological methods (16S rRNA sequencing or shotgun metagenomics) and validated biomarker assays were assigned a greater interpretive weight. As noted in the narrative review, we did not apply formal study-level risk-of-bias scoring, which is a recognized limitation.

EPIDEMIOLOGY AND CLINICAL PHENOTYPES OF POST-ACUTE COVID-19 GASTROINTESTINAL MANIFESTATIONS

Prevalence and heterogeneity of persistent gastrointestinal symptoms

Gastrointestinal symptoms in patients with post-acute COVID-19 represent a heterogeneous clinical problem affecting a significant proportion of long-COVID survivors. Prospective observational cohorts have demonstrated that 15%-25% of patients with long-COVID experience persistent gastrointestinal symptoms, with diarrhea being the most commonly reported symptom, followed by abdominal pain, bloating, and nausea[7-9]. Evidence on the prevalence of persistent gastrointestinal manifestations is also heterogeneous: A systematic review examining 45 studies found a weighted pooled prevalence of 10.8% for any persistent gastrointestinal symptom compared with 4.9% in healthy controls, but with individual study prevalence ranging from 0.2% to 24.1%, reflecting differences in population characteristics and follow-up methodologies[7].

Notably, some cohorts have documented gastrointestinal symptoms that develop or worsen weeks to months after acute symptom resolution, indicating that post-acute gastrointestinal dysfunction should not be viewed merely as a residual effect of acute infection but rather as a distinct pathophysiological process[8,9]. Persistent gastrointestinal symptoms have significant clinical implications owing to their association with reduced quality of life, occupational disability, and functional impairment, with gastrointestinal symptoms being reported as the most bothersome long-COVID manifestation in 11% of affected patients[8,10].

Phenotypic characterization: From diarrhea to IBS-like syndrome

In the post-acute phase of acute COVID-19 with gastrointestinal involvement, patients present with diverse overlapping gastrointestinal manifestations encompassing a spectrum of phenotypes. The most common phenotype is chronic diarrhea, reported in 10%-15% of patients with long-COVID, with symptoms persisting beyond 12 months in some cases[7,11]. Simultaneously, a substantial subset of patients exhibits an IBS-like presentation, defined as abdominal pain and bloating with altered bowel habits, without inflammatory markers or endoscopic abnormalities, in up to 60% of patients with long-COVID meeting the Rome IV criteria for functional gastrointestinal disorders[11,12].

Other phenotypes, including constipation, dysmotility syndrome, and functional dyspepsia, have received less attention than diarrhea. The overlap between phenotypes is clinically relevant as individual patients frequently present with multiple concurrent symptoms, suggesting a common underlying mechanism mediating mucosal and systemic dysfunction rather than distinct disease categories[8,9].

Temporal dynamics and recovery patterns

The temporal course of post-acute COVID-19 gastrointestinal symptoms has revealed variable patterns of onset, progression, and recovery. Some patients experience persistent gastrointestinal symptoms during the acute infection phase, whereas others develop or experience worsening symptoms weeks after acute illness, suggesting that late-phase mechanisms are distinct from acute viral cytopathic injury[9,11].

Symptom duration is prolonged; prospective cohorts with longitudinal follow-up demonstrate that approximately half of the patients with persistent diarrhea continue experiencing symptoms six months after infection, with resolution extending over 12 months or longer[8,11]. This lengthy symptom duration distinguishes post-acute COVID-19 gastrointestinal dysfunction from typical post-infectious diarrheal syndromes, which typically resolve within weeks. Notably, symptom burden does not correlate with acute COVID-19 severity, suggesting that gastrointestinal phenotypes in long-COVID may be influenced by host factors independent of acute infection severity, including genetic predisposition, preexisting comorbidities, psychological trauma, and preexisting microbiota composition[10,11].

Demographic and clinical variation

Post-acute COVID-19 gastrointestinal symptoms exhibit variable associations with demographic and clinical features across cohorts. Although age does not consistently predict gastrointestinal symptoms, some studies have reported an increased prevalence among middle-aged and older individuals[9,10]. Sex-related differences are emerging, with evidence suggesting a slight female predominance of gastrointestinal symptoms in patients with long-COVID, a pattern also observed in other long-COVID manifestations and warranting further investigation[8,10].

The relationship between acute COVID-19 severity and subsequent gastrointestinal dysfunction is inconsistent, and hospitalized individuals experience a greater frequency of gastrointestinal symptoms during acute infection. The frequency of persistent gastrointestinal symptoms at follow-up does not consistently correlate with initial disease severity, suggesting that post-acute gastrointestinal dysfunction involves mechanisms distinct from acute infection severity[9,11]. Other factors related to the acute illness experience, including anxiety and post-traumatic stress disorder, significantly predicted gastrointestinal symptom severity at follow-up, highlighting the importance of the gut-brain axis in post-acute gastrointestinal dysfunction[10,11].

Overlap with post-infectious disorders of gut-brain interaction

Many post-acute COVID-19 gastrointestinal phenotypes, including IBS, such as diarrhea, bloating, abdominal pain, and functional dyspepsia, overlap substantially with post-infectious disorders of the gut-brain interaction (DGBI), particularly post-infectious IBS (PI-IBS), a recognized sequel of bacterial, viral, and protozoal enteritis. The shared mechanisms include transient mucosal inflammation, altered serotonergic signaling, increased intestinal permeability, and microbial perturbation. Interpreting post-acute COVID-19 gastrointestinal symptoms within the established DGBI/PI-IBS construct provides a validated diagnostic and therapeutic framework (Rome IV criteria, neuromodulators, and dietary therapy) and suggests that some cases may represent SARS-CoV-2-triggered PI-IBS rather than a wholly novel entity[13].

ACUTE COVID-19 PATHOPHYSIOLOGY AND GASTROINTESTINAL TROPISM

Clinical gastrointestinal manifestations in acute COVID-19

The gastrointestinal tract is an important target organ in acute SARS-CoV-2 infection, and gastrointestinal symptoms are present in a substantial proportion of hospitalized patients. In prospective cohort studies of hospitalized patients with COVID-19, diarrhea is the most common gastrointestinal symptom, occurring in approximately 10%-34% of patients, followed by nausea, vomiting, and abdominal pain[4,10].

Gastrointestinal manifestations are often accompanied by systemic respiratory and inflammatory signs, and their presence during acute hospitalization is correlated with greater disease severity and a prolonged clinical course[10]. The extensive gastrointestinal involvement in acute COVID-19 indicates direct viral tropism of the gastrointestinal epithelium, warranting investigation of the mechanisms underlying SARS-CoV-2 gastrointestinal infection.

SARS-CoV-2 receptor expression and intestinal epithelial tropism

The molecular basis of SARS-CoV-2 gastrointestinal tropism is related to the high expression of ACE2, the primary cellular receptor for SARS-CoV-2, in the gut epithelium[14-16]. Notably, ACE2 expression in small intestinal enterocytes and colonic epithelial cells exceeds that in the pulmonary airways by approximately 100-fold, establishing the intestinal tract as a highly permissive target for SARS-CoV-2 infection[15].

Following ACE2 receptor binding, the viral spike protein is cleaved by TMPRSS2, facilitating viral entry[14,17]. In vitro studies using human intestinal organoid models and ex vivo intestinal tissue have demonstrated robust SARS-CoV-2 replication in mature enterocytes, with viral RNA and infectious particles recovered throughout the small and large intestines[14,17]. This enterocyte tropism explains the onset of acute gastrointestinal symptoms, and represents a potential site for prolonged viral persistence.

Viral presence and fecal shedding in the gastrointestinal tract

A cardinal feature of acute COVID-19 is the presence of SARS-CoV-2 in stool, indicating active replication in the gastrointestinal tract. Approximately 50% of patients with COVID-19 shed detectable viral RNA in their fecal specimens, with fecal viral shedding persisting for weeks beyond respiratory viral clearance from the nasopharynx[4,17-19].

The high frequency and prolonged duration of fecal shedding suggests that the intestinal epithelium provides a permissive environment for SARS-CoV-2 replication[4,19]. Notably, the fecal viral shedding burden did not correlate uniformly with disease severity, suggesting that the inflammatory mediators in gastrointestinal viral replication may differ from those driving systemic COVID-19 severity[4]. The strong correlation between the duration of fecal viral shedding and gastrointestinal symptom persistence suggests that direct viral involvement in the gut epithelium is critical for acute gastrointestinal manifestations.

Alterations in gut microbiota composition during acute infection

Acute SARS-CoV-2 infection elicits profound dysbiosis, extending beyond direct viral cytopathic effects, with considerable alterations in fecal microbiota composition during acute hospitalization[6]. Metagenomic studies have documented the loss of microbial diversity and selective depletion of beneficial commensals in acutely infected patients, which correlate with markers of systemic inflammation and disease severity[5,6].

The dysbiotic microbiota signature in acute COVID-19 may result from direct viral perturbation of the intestinal ecosystem, as well as from the immune-mediated effects of antimicrobial therapy, systemic immune activation, and acute illness stress[6]. Notably, the severity of acute microbiota dysbiosis correlated with the intensity of the systemic inflammatory response, suggesting that dysbiosis may contribute to the inflammatory cascade characteristic of severe COVID-19[5].

Integration of acute pathophysiology and post-acute sequelae

Changes in viral shedding, microbiota composition, and mucosal inflammation during the acute phase establish the biological milieu in which post-acute COVID-19 gastrointestinal sequelae develop. Patients experiencing acute gastrointestinal symptoms during hospitalization are at increased risk of subsequently developing persistent gastrointestinal dysfunction and functional gastrointestinal disorders during long-term follow-up[10,11].

This temporal association indicates that acute SARS-CoV-2 gastrointestinal infection initiates pathophysiological processes involving dysbiosis, mucosal injury, and immune dysregulation that persist and evolve beyond the acute infection phase. Therefore, understanding the acute pathophysiological mechanisms of gastrointestinal COVID-19 is essential to clarify the mechanistic basis of post-acute gastrointestinal manifestations (Figure 1).

Figure 1 Integrated pathophysiological mechanisms in post-acute coronavirus disease-19 gastrointestinal dysbiosis. Arrow style denotes the strength of evidence: Solid arrows indicate direct human (long-coronavirus disease) evidence; dashed arrows indicate experimental or preclinical evidence; and dotted arrows indicate hypothesized relationships. COVID: Coronavirus disease; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; LPS: Lipopolysaccharide; SCFA: Short-chain fatty acid; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin.

DYSBIOSIS MECHANISMS

Persistent gut dysbiosis in long-COVID reflects a substantial disruption of microbial homeostasis, including markedly decreased microbial alpha diversity and selective depletion of beneficial SCFA-producing commensals[20]. Specifically, beneficial bacteria, such as Faecalibacterium prausnitzii and Bifidobacterium species are significantly reduced in patients with long-COVID, while opportunistic taxa, including Ruminococcus gnavus, Bacteroides vulgatus, and Veillonella species are enriched, a pattern consistent across geographic cohorts and resembling what is observed in acute infection[21].

These dysbiotic changes represent more than compositional alterations and result in profound metabolic dysfunction. The depletion of butyrate- and propionate-producing bacteria reduces SCFA production, with critical metabolic consequences, as SCFAs serve as primary energy substrates for colonocytes and ligands for G protein-coupled receptors that regulate epithelial barrier integrity and immune homeostasis[22].

Beyond SCFA deficiency, dysbiosis in long-COVID phenotypes is associated with impaired tryptophan metabolism and reduced production of indole derivatives, which are essential for maintaining regulatory T cell (Treg) function and mucosal immune tolerance[21]. Dysbiotic microbiota generate increased levels of LPS and other pathogen-associated molecular patterns (PAMPs) through the enrichment of Gram-negative bacteria, perpetuating systemic endotoxemia and low-grade inflammation for weeks to months after viral clearance[20].

In a prospective study of recovered healthcare workers, specific microbial signatures stratified symptom burden: Elevated Escherichia species correlated with persistent fatigue and myalgia; enrichment of Intestinibacter bartlettii correlated with anorexia and fatigue; conversely, increased counts of the butyrate-producing Intestinimonas butyriciproducens and Faecalibacterium prausnitzii were inversely associated with chest tightness and cough[20]. These associations suggest that dysbiosis-driven reductions in anti-inflammatory metabolite production enable the expansion of opportunistic pathogens and perpetuate chronic gastrointestinal and systemic symptoms.

The mechanisms that maintain dysbiosis in the post-acute phase remain incompletely understood but likely involve both persistent viral factors and immune-mediated disturbances. Preliminary evidence suggests that SARS-CoV-2 viral RNA and antigens persist within the gastrointestinal epithelium and associated lymphoid tissue for weeks to months after acute infection, potentially driving sustained dysbiotic selection pressure[23].

Additionally, intestinal barrier dysfunction resulting from dysbiosis establishes a feed-forward loop: Impaired tight junctions (TJ) permit bacterial translocation, amplify systemic immune activation, and further perpetuate dysbiotic microbiota composition by altering intestinal selectivity[23]. The microbial dysbiosis observed in long-COVID thus functions as more than a passive consequence of infection; rather, it operates as an active, self-perpetuating pathophysiological driver of symptom persistence, making microbiota restoration a rational therapeutic target.

Mechanistic refinements

Several mechanistic relationships must be adjusted. Short-chain fatty acids, specifically butyrate, act through the G protein-coupled receptors GPR43 (FFAR2) and GPR41 (FFAR3) and are histone deacetylase inhibitors that promote enterocyte energy metabolism, mitochondrial function, and autophagy, and elicit antimicrobial peptide and TJ synthesis; therefore, depletion of these short-chain fatty acids during dysbiosis can impair barrier maintenance and epithelial restitution[24,25]. Butyrate also induces the differentiation of colonic Tregs via Foxp3 acetylation. Thus, short-chain fatty acid loss may drive a Th17/Th1-skewed antigen-driven mucosal response with reduced tolerance[24]. Host factors may affect these pathways; estrogen modulates the renin-angiotensin system and reduces ACE2/TMPRSS2 availability, whereas androgens enhance it. A long with sex differences in immunity and microbiome composition, these influences may be reflected in the preponderance of some long-COVID phenotypes[26]. Lastly, it remains to be determined whether SARS-CoV-2 drives sustained dysbiosis directly or acts more indirectly. Viral antigen persistence and prolonged fecal shedding have been documented in the post-acute phase and may correlate with bowel symptoms, but persistent interferon and cytokine signaling may equally maintain dysbiosis and barrier dysfunction. However, current human data cannot separate these possibilities, and the relationship is best described as bidirectional and associative[13,21,27,28].

BARRIER DYSFUNCTION, IMMUNE DYSREGULATION, AND BIOMARKERS

Intestinal barrier integrity, maintained by TJ proteins, including occludin, claudins, and zonula occludens, is compromised in patients with long-COVID through SCFA depletion and chronic immune dysregulation[29]. Zonulin, the master physiological regulator of intercellular TJ, has been reported to be elevated in long-COVID serum, suggesting barrier dysfunction and increased intestinal permeability, thus serving as a biomarker of a compromised mucosal barrier[29].

I-FABP, an intestinal epithelium-specific protein released during acute epithelial injury, is particularly elevated in patients with long-COVID and serves as a direct marker of ongoing enterocyte damage[30] while dysregulation of other TJ proteins, such as occludin and claudin-2, parallels systemic inflammation markers[30]. Barrier disruption results from SCFA depletion and impaired tryptophan metabolism, which normally sustains mTOR signaling and de novo synthesis of antimicrobial peptides and TJ proteins, resulting in weakened epithelial barrier function and increased paracellular permeability to bacterial LPS and other PAMPs[23].

Concurrent with barrier dysfunction, patients with long-COVID exhibit mucosal immune dysregulation characterized by T helper cell dysbalance (Th17 and Th1 skewing), reduced Treg differentiation, and sustained upregulation of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6[21]. The dysbiosis-driven loss of metabolites that support Treg differentiation, specifically reduced butyrate and decreased tryptophan metabolites, including aryl hydrocarbon receptor ligands, contributes to immune imbalance and loss of oral tolerance, thereby enabling dysbiotic bacterial antigens to perpetuate mucosal inflammation[21].

Furthermore, increased intestinal permeability permits bacterial translocation across the epithelium, allowing viable bacteria and their metabolites (particularly LPS) to access the lamina propria and systemic circulation, where they activate pattern recognition receptors (TLRs and NOD-like receptors) on innate immune cells and perpetuate endotoxemia-driven inflammation through the gut-brain and gut-lung axes[31].

The integration of these mechanistic insights enables clinical assessments using accessible biomarkers. In addition to serum zonulin and I-FABP levels, fecal calprotectin (a neutrophil-derived marker of intestinal inflammation), elevated plasma LPS levels, and decreased fecal SCFA concentrations provide complementary diagnostic information[29,31].

Additionally, dysbiotic microbial signatures, particularly reductions in Faecalibacterium prausnitzii, enrichment of Ruminococcus gnavus, and depletion of SCFA-producing taxa, serve as biomarkers of disease state and predictors of therapeutic response to microbiota-targeted interventions. However, the lack of standardization in microbiome profiling methods across clinical centers remains a barrier to biomarker adoption[21]. Serial measurement of these biomarkers may enable the stratification of patients with long-COVID into mechanistically distinct endotypes and facilitate precision medicine approaches to therapy. These biomarkers are still under investigation in long-term COVID: Zonulin assays are analytically controversial with debated specificity; I-FABP, fecal calprotectin, and LPS are non-specific and altered in other enteropathies; and none are standardized or validated for routine clinical use. Several corroborating findings were derived from barrier biology or other disease settings rather than from long-COVID cohorts and are presented here as a mechanistic background (Table 1).

Table 1 Pathophysiological mechanisms, clinical phenotypes, biomarkers, and therapeutic targets in post-acute coronavirus disease 2019 dysbiosis.

Domain	Key mechanism/finding	Candidate biomarker	Level of evidence
Viral GI tropism	ACE2-mediated enterocyte infection; prolonged fecal shedding	Fecal SARS-CoV-2 RNA	Direct human (long COVID)
Dysbiosis	Reduced Faecalibacterium prausnitzii; enriched Ruminococcus gnavus; reduced alpha-diversity	Microbial signature; fecal SCFA	Direct human (observational)
SCFA/metabolic	Reduced butyrate impairs mTOR, antimicrobial peptide and tight junction synthesis	Fecal SCFA	Experimental + human associative
Barrier dysfunction	Reduced occludin/claudin; increased permeability	Serum zonulin; I-FABP	Human associative (assays unvalidated)
Immune dysregulation	Th17/Th1 skew; reduced Treg; raised TNF-α and IL-6	Cytokines; fecal calprotectin	Human + experimental
Endotoxemia	LPS translocation activates TLRs; gut-brain and gut-lung axes	Plasma LPS	Experimental + human associative
Therapeutics	Probiotics/synbiotics vs FMT/postbiotics		RCT (probiotics/synbiotics); investigational (FMT/postbiotics)

COVID: Coronavirus disease; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; LPS: Lipopolysaccharide; SCFA: Short-chain fatty acid; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; FMT: Fecal microbiota transplantation; RCT: Randomised controlled trial; GI: Gastrointestinal.

A proposed self-reinforcing cycle

A self-reinforcing cycle links acute injury to post-acute persistence. Infection of ACE2-expressing enterocytes by SARS-CoV-2 can compromise the physical barrier through apoptosis, pyroptosis, and downregulation of TJ proteins (e.g., occludin and claudin-5)[28]. The resulting barrier injury permits the translocation of microbial products (LPS and flagellin), amplifying local inflammation and creating selective pressure that favors the expansion of pathogenic taxa[25]. Dysbiosis-associated depletion of short-chain fatty acids and tryptophan metabolites impairs mTOR-dependent epithelial repair and antimicrobial peptide synthesis, further weakening the barrier and yielding the proposed loop of viral injury, barrier disruption, microbial translocation, inflammation, dysbiosis, and impaired repair[13,21]. This cascade is mechanistically coherent but is currently mostly inferred from experimental and cross-sectional human data rather than longitudinal causal studies.

THERAPEUTIC STRATEGIES AND FUTURE DIRECTIONS

Interventions targeting the microbiota are of growing interest, although the supporting evidence remains early stage and heterogeneous, because dysbiosis and barrier dysfunction have been implicated in the pathogenesis of long COVID. Probiotics (live microorganisms that replenish dysbiotic microbiota composition) have shown benefit in reducing symptom duration and severity in a single randomized, blinded trial; a randomized, blinded trial of a four-strain probiotic formulation demonstrated significant benefits for symptom remission, which included shorter duration of fever, nausea, abdominal pain, and headache, possibly by restoring SCFA-producing bacteria and regulating the immune response via the gut-lung axis[32].

Another approach, synbiotics [i.e., probiotics and prebiotics (non-digestible substances that preferentially enhance the growth of beneficial bacteria)], has been reported in recent clinical trials for post-acute COVID-19 syndrome, with positive effects on fatigue, memory loss, cognitive impairment, gastrointestinal upset, and mood disturbances[33]. Fecal microbiota transplantation (FMT), which transfers the donor microbiota to dysbiotic recipients, has shown promise in restoring microbial diversity, reinforcing intestinal barrier function, and ameliorating gastrointestinal and systemic long-COVID manifestations. However, evidence in long-term COVID is currently limited to small, uncontrolled series without randomized data, and FMT should be regarded as investigational, with optimal donor selection, preparation protocols, and patient selection still to be defined[33,34].

Emerging evidence suggests that postbiotics, bioactive metabolites, or components of the bacterial composition derived from probiotic bacteria[22], may be therapeutically beneficial without necessarily incurring the regulatory and practical challenges associated with administering living organisms[22]. However, postbiotic preparations enriched with butyrate and propionate to restore the metabolic status due to dysbiosis also positively affect epithelial barrier functional regulation, Treg differentiation, and Th17 proinflammatory responses. Clinical trials currently underway examining postbiotic effectiveness in long-COVID are promising as a more focused and scalable route compared with whole-organism probiotics and FMT[22]. Apart from microbiota-mediated interventions, dietary strategies that provide high levels of prebiotics (insoluble fibers, resistant starch, and polyphenol-rich foods) may preferentially favor SCFA-producing taxa and are suggested as a first-line adjunctive therapy alongside pharmaceutical and probiotic therapies[32].

Future management of long-COVID should also consider addressing pressing unmet needs. Multi-omic mechanistic studies (metagenomics, metabolomics, and immunophenotyping) are critical for identifying dysbiosis-specific biomarkers that can predict treatment response and, in turn, enable precision medicine to stratify patients with long-COVID into mechanistically distinct endotypes[21].

Longitudinal randomized controlled trials with standardized biomarkers are urgently needed to delineate the clinical efficacy, optimal dosing, and treatment duration of probiotics, synbiotics, and FMT, especially given the current variability in evidence[35]. Insights into whether dysbiosis is the main driver or a secondary cause of long-COVID symptoms are important for mechanistic understanding and resource allocation in the research and development of therapies. Finally, combination therapy, in which barrier-restoring approaches are combined with dysbiosis-correcting approaches (i.e., TJ-stabilizing compounds), may be synergistic and warrants further study in clinical trials[36] (Table 2).

Table 2 Proposed biomarker-based stratification of post-acute coronavirus disease-19 gastrointestinal phenotypes (investigational).

Phenotype	Dominant biomarkers	Candidate targeted approach	Assay availability/caveats
Barrier-dominant	Raised zonulin; raised I-FABP	Barrier-restoring (butyrate/postbiotics)	Zonulin assay controversial; not standardized
Dysbiosis-dominant	Reduced alpha-diversity; reduced SCFA	Probiotics/synbiotics; FMT (investigational)	Metagenomics costly; not point-of-care
Immune-dominant	Raised fecal calprotectin; raised cytokines	Anti-inflammatory/immunomodulatory	Calprotectin available but non-specific

This framework is hypothesis-generating and not validated; overlap between phenotypes is expected, and assays vary in cost, availability, and standardization. SCFA: Short-chain fatty acid; FMT: Fecal microbiota transplantation.

Evidence limitations

Across these modalities, the evidence base is limited owing to small sample sizes, varying formulations and endpoints, short follow-up periods, and insufficient control of placebo effects. Only probiotics and synbiotics have been assessed in randomized trials in this setting, whereas postbiotic and FMT data are largely preclinical or observational. Therefore, these methods should be considered investigational until properly powered, long-term, randomized controlled trials have been conducted[27].

LIMITATIONS

This study had several limitations. It is a narrative, not a systematic review. The study selection was performed by a single author without dual independent screening or formal risk-of-bias assessment, and only English-language full-text-retrievable articles were included, which introduces a risk of selection and language bias. The relevant literature is dominated by observational and cross-sectional cohort studies with diverse definitions of long COVID, variable post-acute time windows, and non-standardized microbiome and biomarker approaches that preclude comparison and causal inference. Several mechanistic associations have been inferred from experimental or non-long-COVID studies. These limitations must be considered when interpreting the conclusions of this study.

CONCLUSION

Gastrointestinal symptoms in patients with post-acute COVID-19 are indicative of enduring dysbiosis, gut barrier dysfunction, and immune dysregulation sustained by multiple mechanisms, including SCFA depletion, elevated barrier biomarkers (zonulin and I-FABP), and dysbiosis-driven endotoxemia. Consistent findings across international cohorts suggest that the gut microbiota is a central pathophysiological domain, establishing microbiota-targeted interventions (probiotics, synbiotics, and FMT) as rational therapeutic approaches with preliminary clinical efficacy.

However, prospective randomized controlled trials with standardized biomarker assessments and long-term follow-up are urgently required to establish the clinical efficacy, optimal dosing regimens, and patient-level predictors of treatment response. Until such evidence accumulates, clinicians should recognize dysbiosis as a plausible contributor to persistent gastrointestinal symptoms in long-COVID and consider microbiota assessment and microbiota-targeted interventions as rational components of comprehensive patient management.