Abstract: Journal of Clinical Medicine Article COVID-19 Pneumonia and Gut Inflammation: The Role of a Mix of Three Probiotic Strains in Reducing Inflammatory Markers and Need for Oxygen Support Angela Saviano 1 , Annalisa Potenza 2 , Valentina Siciliano 3 , Carmine Petruzziello 4 , Claudia Tarli 2 , Alessio Migneco 1 , Flavia Nasella 1 , Francesco Franceschi 1 and Veronica Ojetti 1, * 1 2 3 4 * Citation: Saviano, A.; Potenza, A.; Siciliano, V.; Petruzziello, C.; Tarli, C.; Migneco, A.; Nasella, F.; Franceschi, F.; Ojetti, V. COVID-19 Pneumonia and Gut Inflammation: The Role of a Mix of Three Probiotic Strains in Reducing Inflammatory Markers and Need for Oxygen Support. J. Clin. Med. 2022, 11, 3758. https://doi.org/ 10.3390/jcm11133758 Academic Editors: Uri Kopylov and Andrew Day Received: 14 May 2022 Accepted: 26 June 2022 Published: 28 June 2022 Publisher’s Note: MDPI stays neutral Emergency Medicine Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00165 Rome, Italy; angela.saviano@policlinicogemelli.it (A.S.); alessio.migneco@policlinicogemelli.it (A.M.); flavia.nasella@gmail.com (F.N.); francesco.franceschi@policlinicogemelli.it (F.F.) Internal Medicine Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00165 Rome, Italy; annalisa.potenza@policlinicogemelli.it (A.P.); claudia.tarli@policlinicogemelli.it (C.T.) Department of Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00165 Rome, Italy; valentina.siciliano@policlinicogemelli.it Emergency Medicine Department, Ospedale San Carlo di Nancy, 00165 Rome, Italy; carminepetruzziello@live.it Correspondence: veronica.ojetti@policlinicogemelli.it Abstract: Background: COVID-19 disease, which typically presents with respiratory symptoms, can trigger intestinal inflammation through SARS-CoV-2 replication in the gastrointestinal tract. Supplementation with probiotics may have beneficial effects on gut inflammation due to their analgesic and anti-inflammatory properties. The primary objective of our study was to evaluate the efficacy of a mix of three probiotic strains (Bifidobacterium lactis LA 304, Lactobacillus salivarius LA 302, and Lactobacillus acidophilus LA 201; Lactibiane Iki® ) in the reduction in fecal calprotectin in patients with COVID-19 pneumonia, compared to a control group. The secondary aim was to evaluate the reduction in oxygen support and length of hospital stay in patients taking the probiotic mix. Patients and Methods: We conducted a prospective randomized controlled trial at Fondazione Policlinico Gemelli, Rome. We enrolled patients with COVID-19 interstitial pneumonia. One group received the probiotic mix twice a day for 10 days in addition to the standard COVID-19 therapy, and a second group received standard COVID-19 therapy without probiotics. We administered oxygen support (through Ventimask or Optiflow® ) on days (D) 1, 3, 5, 7 and 10, and the level of fecal calprotectin between D3–D5 and D7–D10. Results: A total of 80 patients (44 M/36 F; mean age: 59.8 ± 17.3) were enrolled with a mean value of calprotectin at enrollment of 140 mg/dL. At D7–10, the probiotic group showed a 35% decrease in fecal calprotectin compared to 16% in the control group, a decrease in C-reactive protein (CRP) of 72.7% compared to 62%, and a slight but not significant decrease in oxygen support compared to the control group. Conclusion: Supplementation with a mix of probiotics for 10 days in patients with COVID-19 interstitial..