Effect of prenatal antibiotics on breast milk and neonatal IgA and microbiome: a case-control translational study protocol Carlo Pietrasanta, Andrea Ronchi, Carolina Carlosama, Michela Lizier, Alessandra Silvestri, Giulia Fornasa, Alessia Melacarne, Martin Mihula, Francesco D’Ambrosi, Martina Lutterotti, Elisa Carbone, Irene Cetin, Monica Fumagalli, Enrico Ferrazzi, Giuseppe Penna, Fabio Mosca, Lorenza Pugni, Maria Rescigno Pediatric Research, 2025 Background Up to 25–35% of women receive antibiotics (ABX) during pregnancy, but little is known about the consequences on a key mucosal interface such as the mammary gland, and on the development of the neonatal gut’s microbiota and IgA. We hypothesize that prenatal ABX negatively affect the immune functionality of mammary gland, the composition of breast milk microbiota, the development of neonatal fecal microbiota and the abundance of neonatal fecal IgA. Methods Case-control translational cohort study on women and neonates in the presence or absence (N = 41 + 41 pairs) of exposure to prenatal ABX for at least 7 consecutive days after 32 weeks of gestation. Results We will evaluate IgA concentration in breast milk and in neonatal feces up to one year after delivery. We will also evaluate clinical parameters, neurodevelopment and the composition of the IgA-coated and uncoated fractions of breast milk and fecal microbiota by means of magnetic-activated cell sorting (MACS) coupled with shotgun metagenomics. Finally, we will measure the concentration of the chemokine CCL28 on maternal serum and breast milk, as a marker of activity of the entero-mammary pathway. Conclusions Our results might support a data-driven evaluation of breast milk immune function in women exposed to prenatal ABX. Impact Breast milk IgA and microbiota are critical to determine the positive effects of breastfeeding in infants. This research protocol will investigate breast milk IgA, microbiota, and the IgA+ / IgA− fractions of neonatal fecal microbiota upon exposure to prenatal antibiotics. Fecal IgA and microbiota in infants exposed or not exposed to prenatal antibiotics will be analyzed up to 1 year after birth. This research will clarify the impact of prenatal antibiotics on the immune function of breast milk. This, in turn, might support the selective evaluation of breast milk IgA/microbiota in mothers exposed to prenatal antibiotics, or in donor human milk.
A multi-strain probiotic formulation preserves intestinal epithelial and vascular barriers during enteropathogenic infection Anna Maria Naso, Michela Lizier, Carmen Correale, Alessandra Silvestri, Giuseppe Penna, Paola Brescia, Maria Rescigno Frontiers in Microbiology, 2025 BackgroundThe integrity of the intestinal barrier, composed progressively of a mucus, epithelial and vascular layer is critical for maintaining gut homeostasis and preventing systemic translocation of pathogens. Disruptions in any of these protective layers can lead to various health issues, highlighting the need for strategies to preserve barrier function. This study investigated the effects of a multi-strain probiotic formulation (MPF), on intestinal barrier integrity in a murine model infected with Salmonella typhimurium.MethodsC57BL/6 mice were pre-treated with MPF for 10 days before oral infection with Salmonella. Intestinal barrier integrity was assessed through histological analysis, immunofluorescence for key barrier proteins, quantification of bacterial translocation and morphological changes in the ileum and colon.ResultsMice pre-treated with the probiotic formulation exhibited a preserved mucus layer, maintained intestinal epithelial barrier (IEB) integrity, evidenced by sustained expression of mucins and the tight junction protein Zonula occludens-1 (ZO-1), and reduced Salmonella translocation in the colon. Furthermore, the MPF maintained the gut vascular barrier (GVB) integrity by preventing the upregulation of plasmalemma vesicle-associated protein-1 (PV1), typically induced by Salmonella infection. The treatment also mitigated morphological damage, including villus and crypt shortening, caused by the pathogen.ConclusionThese findings suggest that this new formulation of multi-strain probiotics protects against Salmonella-induced damage to both the IEB and GVB, supporting its potential as a therapeutic intervention for managing conditions associated with intestinal barrier dysfunction. Further research is warranted to elucidate the specific mechanisms of action and validate these results in human populations.
Prenatal antibiotics reduce breast milk IgA and induce dysbiosis in mouse offspring, increasing neonatal susceptibility to bacterial sepsis Carlo Pietrasanta, Carolina Carlosama, Michela Lizier, Giulia Fornasa, Tanja Rezzonico Jost, Sara Carloni, Silvia Giugliano, Alessandra Silvestri, Paola Brescia, Benedetta De Ponte Conti, Daniele Braga, Martin Mihula, Lavinia Morosi, Alessandro Bernardinello, Andrea Ronchi, Giuseppe Martano, Fabio Mosca, Giuseppe Penna, Fabio Grassi, Lorenza Pugni, Maria Rescigno Cell Host and Microbe, 2024 Antibiotics (Abx) are administered to 20%–30% of pregnant women, but their effects on neonatal immune development are poorly understood. We show that newborn mice born to Abx-treated dams are more susceptible to late-onset sepsis. This susceptibility is linked to lower maternal breast milk immunoglobulin A (IgA), neonatal fecal IgA, and IgA coating of intestinal bacteria, thus causing the translocation of intestinal pathobionts. Weaned young adults born to Abx-treated mothers had reduced IgA+ plasma cells in the ileum and colon, fecal secretory IgA (SIgA), colonic CD4 + T regulatory lymphocytes and T helper 17-like lymphocytes, and a less diverse fecal microbiome. However, treatment with apyrase, which restores SIgA secretion, prompted IgA production in breast milk and protected pups from sepsis. Additionally, breast milk from untreated mothers rescued the phenotypes of pups born to Abx-treated mothers. Our data highlight the impact of prenatal Abx on breast milk IgA and their long-term influence on intestinal mucosal immune function mediated by breastfeeding.
Optimizing abemaciclib-induced diarrhea management in patients with breast cancer: A pragmatic 2-group study using a postbiotic microbiota stabilizer Rita De Sanctis, Paola Tiberio, Flavia Jacobs, Mariangela Gaudio, Chiara Benvenuti, Laura Giordano, Rosalba Torrisi, Alberto Zambelli, Chiara Pozzi, Giuseppe Penna, Armando Santoro, Maria Rescigno Oncologist, 2024 Background Abemaciclib-induced diarrhea is a relevant concern in clinical practice. Postbiotics have emerged as a promising option for managing it. Materials and Methods We conducted a retrospective-prospective, 2-group, observational study to assess the impact of the postbiotic PostbiotiX-Restore, derived by Lactobacillus paracasei CNCM I-5220, on abemaciclib-induced diarrhea in patients with hormone receptor-positive HER2-negative breast cancer. The prospective population (Postbio group) received postbiotic during the first cycle of abemaciclib, while the retrospective one received standard care (Standard group). Diarrhea grading was defined according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Results During the first cycle, diarrhea occurred in 78.9% of patients in the Standard cohort and 97.1% in the Postbio one, with most cases being G1-G2. Severe (G3) diarrhea was significantly less frequent in the Postbio group (0%) compared to the Standard one (7.9%; P = .029). Over the entire study period, while the grading difference was not statistically significant, G3 events were less frequent in the Postbio population (5.9%) than the Standard one (15.4%). Moreover, Postbio patients required fewer dose reductions due to diarrhea compared to the Standard group (P = .002). Notably, in the Postbio population, G1 and G2 events had short median durations (3 and 1 days, respectively) and, for the 2 patients experiencing G3 events during the second abemaciclib cycle (off postbiotic), diarrhea lasted only 1 day. Conclusions Our study demonstrates the effect of PostbiotiX-Restore in mitigating abemaciclib-induced diarrhea, resulting in reduced severity, fewer dose reductions, and shorter duration. Further exploration and validation in larger cohorts are needed.
Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion Angélica Díaz-Basabe, Georgia Lattanzi, Federica Perillo, Chiara Amoroso, Alberto Baeri, Andrea Farini, Yvan Torrente, Giuseppe Penna, Maria Rescigno, Michele Ghidini, Elisa Cassinotti, Ludovica Baldari, Luigi Boni, Maurizio Vecchi, Flavio Caprioli, Federica Facciotti, Francesco Strati Gut Microbes, 2024 The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). Porphyromonas gingivalis is a keystone oral pathogen associated with CRC. The oral pathobiont Fusobacterium nucleatum influences the anti-tumour functions of CRC-infiltrating iNKT cells. However, the impact of other oral bacteria, like P. gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumour microenvironment in CRC. Mechanistically, in vivo and in vitro experiments show that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery though increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing iNKT cells to upregulate CHI3L1, thus impairing iNKT cell cytotoxicity and promoting host tumour immune evasion.
Biomimetic superabsorbent hydrogel acts as a gut protective dynamic exoskeleton improving metabolic parameters and expanding A. muciniphila Alessandra Silvestri, Antonio Gil-Gomez, Milena Vitale, Daniele Braga, Christian Demitri, Paola Brescia, Marta Madaghiele, Ilaria Spadoni, Bryan Jones, Giulia Fornasa, Juliette Mouries, Sara Carloni, Michela Lizier, Manuel Romero-Gomez, Giuseppe Penna, Alessandro Sannino, Maria Rescigno Cell Reports Medicine, 2023 The rising prevalence of obesity and metabolic disorders worldwide highlights the urgent need to find new long-term and clinically meaningful weight-loss therapies. Here, we evaluate the therapeutic potential and the mechanism of action of a biomimetic cellulose-based oral superabsorbent hydrogel (OSH). Treatment with OSH exerts effects on intestinal tissue and gut microbiota composition, functioning like a protective dynamic exoskeleton. It protects from gut barrier permeability disruption and induces rapid and consistent changes in the gut microbiota composition, specifically fostering Akkermansia muciniphila expansion. The mechanobiological, physical, and chemical structures of the gel are required for A. muciniphila growth. OSH treatment induces weight loss and reduces fat accumulation, in both preventative and therapeutic settings. OSH usage also prevents liver steatosis, immune infiltration, and fibrosis, limiting the progression of non-alcoholic fatty liver disease. Our work shows the potential of using OSH as a non-systemic mechanobiological approach to treat metabolic syndrome and its comorbidities.
Lactobacillus paracasei CNCM I-5220-derived postbiotic protects from the leaky-gut Francesca Algieri, Nina Tanaskovic, Cindy Cardenas Rincon, Elisabetta Notario, Daniele Braga, Graziano Pesole, Roberto Rusconi, Giuseppe Penna, Maria Rescigno Frontiers in Microbiology, 2023 The maintenance of intestinal barrier function is essential for preventing different pathologies, such as the leaky gut syndrome (LGS), which is characterized by the passage of harmful agents, like bacteria, toxins, and viruses, into the bloodstream. Intestinal barrier integrity is controlled by several players, including the gut microbiota. Various molecules, called postbiotics, are released during the natural metabolic activity of the microbiota. Postbiotics can regulate host–microbe interactions, epithelial homeostasis, and have overall benefits for our health. In this work, we used in vitro and in vivo systems to demonstrate the role of Lactobacillus paracasei CNCM I-5220-derived postbiotic (LP-PBF) in preserving intestinal barrier integrity. We demonstrated in vitro that LP-PBF restored the morphology of tight junctions (TJs) that were altered upon Salmonella typhimurium exposure. In vivo, LP-PBF protected the gut vascular barrier and blocked S. typhimurium dissemination into the bloodstream. Interestingly, we found that LP-PBF interacts not only with the host cells, but also directly with S. typhimurium blocking its biofilm formation, partially due to the presence of biosurfactants. This study highlights that LP-PBF is beneficial in maintaining gut homeostasis due to the synergistic effect of its different components. These results suggest that LP-PBF could be utilized in managing several pathologies displaying an impaired intestinal barrier function.
A ‘Multiomic’ Approach of Saliva Metabolomics, Microbiota, and Serum Biomarkers to Assess the Need of Hospitalization in Coronavirus Disease 2019 Chiara Pozzi, Riccardo Levi, Daniele Braga, Francesco Carli, Abbass Darwich, Ilaria Spadoni, Bianca Oresta, Carola Conca Dioguardi, Clelia Peano, Leonardo Ubaldi, Giovanni Angelotti, Barbara Bottazzi, Cecilia Garlanda, Antonio Desai, Antonio Voza, Elena Azzolini, Maurizio Cecconi, Alberto Mantovani, Giuseppe Penna, Riccardo Barbieri, Letterio S. Politi, Maria Rescigno, Aghemo Alessio, Anfray Clement, Badalamenti Salvatore, Belgiovine Cristina, Bertocchi Alice, Bombace Sara, Brescia Paola, Calcaterra Francesca, Calvi Michela, Cancellara Assunta, Capucetti Arianna, Carenza Claudia, Carloni Sara, Carnevale Silvia, Cazzetta Valentina, Cecconi Maurizio, Ciccarelli Michele, Coianiz Nicolò, Darwich Abbass, Lleo de Nalda Ana, De Paoli Federica, Di Donato Rachele, Digifico Elisabeth, Durante Barbara, FARINA Floriana Maria, Ferrari Valentina, Fornasa Giulia, Franzese Sara, Gil Gomez Antonio, Giugliano Silvia, Gomes Ana Rita, Lizier Michela, Lo Cascio Antonino, Melacarne Alessia, Mozzarelli Alessandro, My Ilaria, Oresta Bianca, Pasqualini Fabio, Pastò Anna, Pelamatti Erica, Perucchini Chiara, Pozzi Chiara, Rimoldi Valeria, Rimoldi Monica, Scarpa Alice, Selmi Carlo, Silvestri Alessandra, Sironi Marina, Spadoni Ilaria, Spano' Salvatore, Spata Gianmarco, Supino Domenico, Tentorio Paolo, Ummarino Aldo, Valentino Sonia, Voza Antonio, Zaghi Elisa, Zanon Veronica Gastro Hep Advances, 2022 BACKGROUND AND AIMS: The SARS-CoV-2 pandemic has overwhelmed the treatment capacity of the health care systems during the highest viral diffusion rate. Patients reaching the emergency department had to be either hospitalized (inpatients) or discharged (outpatients). Still, the decision was taken based on the individual assessment of the actual clinical condition, without specific biomarkers to predict future improvement or deterioration, and discharged patients often returned to the hospital for aggravation of their condition. Here, we have developed a new combined approach of omics to identify factors that could distinguish coronavirus disease 19 (COVID-19) inpatients from outpatients. METHODS: Saliva and blood samples were collected over the course of two observational cohort studies. By using machine learning approaches, we compared salivary metabolome of 50 COVID-19 patients with that of 270 healthy individuals having previously been exposed or not to SARS-CoV-2. We then correlated the salivary metabolites that allowed separating COVID-19 inpatients from outpatients with serum biomarkers and salivary microbiota taxa differentially represented in the two groups of patients. RESULTS: were all underrepresented in the hospitalized population. CONCLUSION: This is a proof of concept that a combined omic analysis can be used to stratify patients independently from COVID-19.
Identification of a choroid plexus vascular barrier closing during intestinal inflammation Sara Carloni, Alice Bertocchi, Sara Mancinelli, Martina Bellini, Marco Erreni, Antonella Borreca, Daniele Braga, Silvia Giugliano, Alessandro M. Mozzarelli, Daria Manganaro, Daniel Fernandez Perez, Federico Colombo, Antonio Di Sabatino, Diego Pasini, Giuseppe Penna, Michela Matteoli, Simona Lodato, Maria Rescigno Science, 2021
Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver Alice Bertocchi, Sara Carloni, Paola Simona Ravenda, Giovanni Bertalot, Ilaria Spadoni, Antonino Lo Cascio, Sara Gandini, Michela Lizier, Daniele Braga, Francesco Asnicar, Nicola Segata, Chris Klaver, Paola Brescia, Elio Rossi, Achille Anselmo, Silvia Guglietta, Annalisa Maroli, Paola Spaggiari, Noelia Tarazona, Andres Cervantes, Silvia Marsoni, Luca Lazzari, Maria Giovanna Jodice, Chiara Luise, Marco Erreni, Salvatore Pece, Pier Paolo Di Fiore, Giuseppe Viale, Antonino Spinelli, Chiara Pozzi, Giuseppe Penna, Maria Rescigno Cancer Cell, 2021
Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth Elena Zagato, Chiara Pozzi, Alice Bertocchi, Tiziana Schioppa, Fabiana Saccheri, Silvia Guglietta, Bruno Fosso, Laura Melocchi, Giulia Nizzoli, Jacopo Troisi, Marinella Marzano, Bianca Oresta, Ilaria Spadoni, Koji Atarashi, Sara Carloni, Stefania Arioli, Giulia Fornasa, Francesco Asnicar, Nicola Segata, Simone Guglielmetti, Kenya Honda, Graziano Pesole, William Vermi, Giuseppe Penna, Maria Rescigno Nature Microbiology, 2020
A gut-vascular barrier controls the systemic dissemination of bacteria Ilaria Spadoni, Elena Zagato, Alice Bertocchi, Roberta Paolinelli, Edina Hot, Antonio Di Sabatino, Flavio Caprioli, Luca Bottiglieri, Amanda Oldani, Giuseppe Viale, Giuseppe Penna, Elisabetta Dejana, Maria Rescigno Science, 2015
