Background: The gut–lung axis could be a potential therapeutic target for improving post-acute COVID-19 symptoms, and probiotics have been proposed as possible modulators. Aim: We conducted a pilot study to understand alterations in the gut–lung axis and to explore the effects of a probiotic in post-acute COVID-19 disease. Methods: We included patients after severe COVID-19 disease (sCOV, n = 21) in a randomized, placebo-controlled trial to test the effect of a probiotic (Pro-Vi 5, Institute Allergosan, Graz, Austria) in a six-month intervention and used patients after mild disease (mCOV, n = 10) as controls, to compare the intestinal microbiome, metabolome, and patient-reported outcomes and biomarkers along the gut–lung axis at baseline and throughout probiotic intervention. Results: Compared to mCOV patients, sCOV patients showed lower microbial richness, which was significantly improved by probiotic intervention. A reorganization of Ruminococcaceae and Lachnospiraceae taxa was observed in sCOV patients but remained unaffected by the intervention. Serum metabolome showed a dysregulation of lipoproteins in accordance with higher BMI and comorbidities in sCOV patients. HDL and LDL fractions/components were temporarily decreased in the probiotic group. Stool metabolome was altered at baseline in sCOV patients and an increase in L-DOPA after 3 months and butyrate after 6 months of intervention could be observed. Probiotics partially improved reduced quality of life and modulated altered immune responses in sCOV patients. Increased intestinal permeability at baseline remained unaffected. Conclusion: The study provides evidence of long-term alterations of the gut–lung axis after severe COVID-19 infection and suggests that probiotics can modulate the biomarkers of the gut–lung axis.
