Abstract: microorganisms Article Clinical Effects of Streptococcus salivarius K12 in Hospitalized COVID-19 Patients: Results of a Preliminary Study Francesco Di Pierro 1,2, * , Somia Iqtadar 3 , Sami Ullah Mumtaz 3 , Alexander Bertuccioli 4 , Martino Recchia 5 , Nicola Zerbinati 6 and Amjad Khan 7 1 2 3 4 5 6 7 * Scientific & Research Department, Velleja Research, 20100 Milan, Italy Digestive Endoscopy, Fondazione Poliambulanza, 25133 Brescia, Italy Department of Medicine, King Edward Medical University, Lahore 54000, Pakistan Department of Biomolecular Sciences (DISB), University of Urbino, 61029 Urbino, Italy Medistat, Unità di Epidemiologia Clinica e Biostatistica, 20100 Milan, Italy Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy Nuffield Division of Clinical and Laboratory Sciences (NDCLS), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK Correspondence: f.dipierro@vellejaresearch.com; Tel.: +39-0523-510848; Fax: +39-0523-511894 Academic Editor: Despoina Koulenti Abstract: Anatomical and physiological considerations indicate that the oral cavity is a primary source of the lung microbiota community, and recent studies have shown that the microbiota in the lungs contributes to immunological homeostasis, potentially altering the organ’s susceptibility to viral infection, including SARS-CoV-2. It has been proposed that, in the case of viral infection, lung Gram-negative bacteria could promote the cytokine cascade with a better performance than a microbiota mainly constituted by Gram-positive bacteria. Recent observations also suggest that Prevotella-rich oral microbiotas would dominate the oral cavity of SARS-CoV-2-infected patients. In comparison, Streptococcus-rich microbiotas would dominate the oral cavity of healthy people. To verify if the modulation of the oral microbiota could have an impact on the current coronavirus disease, we administered for 14 days a well-recognized and oral-colonizing probiotic (S. salivarius K12) to hospitalized COVID-19 patients. The preliminary results of our randomized and controlled trial seem to prove the potential role of this oral strain in improving the course of the main markers of pathology, as well as its ability to apparently reduce the death rate from COVID-19. Although in a preliminary and only circumstantial way, our results seem to confirm the hypothesis of a direct involvement of the oral microbiota in the construction of a lung microbiota whose taxonomic structure could modulate the inflammatory processes generated at the pulmonary and systemic level by a viral infection. Received: 27 August 2022 Keywords: oral microbiota; lantibiotics; salivaricins; Streptococcus salivarius; COVID-19; SARS-CoV-2 Citation: Di Pierro, F.; Iqtadar, S.; Mumtaz, S.U.; Bertuccioli, A.; Recchia, M.; Zerbinati, N.; Khan, A. Clinical Effects of Streptococcus salivarius K12 in Hospitalized COVID-19 Patients: Results of a Preliminary Study. Microorganisms 2022, 10, 1926. https://doi.org/ 10.3390/microorganisms10101926 Accepted: 24 September 2022 Published: 28 September 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in