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

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.

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.