Gut microbiota dysbiosis in Post-COVID condition symptoms: relation with chronic fatigue and functional limitation

Post-COVID Condition (PCC) is a heterogeneous clinical syndrome in which chronic fatigue and functional limitation are among the most disabling manifestations. Alterations in the gut microbiota have been proposed as contributors to PCC pathophysiology; however, it remains unclear whether distinct clinical PCC phenotypes are associated with specific microbiota signatures. This cross-sectional pilot study analysed gut microbiota composition and predicted functional capacity in 50 participants from Aragón (Spain), including 30 patients with PCC and 20 healthy controls. PCC patients were stratified according to the presence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-like symptoms and functional limitation assessed using the 6-Minute Walking Test. Alpha and beta diversity did not differ significantly between groups (Figs. 2 and 3). Differential abundance analysis identified taxon-level differences between groups. Escherichia/Shigella was enriched in PCC-CFS relative to controls, both overall and in the subgroup without functional limitation, representing the most consistent signal. Additional differences included higher Streptococcus and Veillonella in controls, and higher Flavonifractor and Hungatella in PCC-NCFS. After adjustment for digestive symptoms and vaccine dose, these associations attenuated and none remained significant, indicating that they may be partly driven by confounding.PICRUSt2 functional predictions suggested differences in pathways related to nucleotide and amino acid metabolism; however, none remained significant after correction for multiple testing and should therefore be considered exploratory. These findings suggest the presence of phenotype-associated taxonomic differences within PCC despite the absence of global diversity alterations. The results should be considered exploratory and hypothesis-generating due to the limited subgroup sample sizes. Larger studies incorporating metagenomic and metabolomic approaches are needed to validate these observations and clarify their potential clinical relevance.