The present disclosure concerns a Reg3α polypeptide (also known as Hepatocarcinoma-Intestine-Pancreas/Pancreatitis Associated Protein (HIP/PAP)) for protecting oxygen sensitive gram-positive bacteria, compositions including the polypeptide, and their use. The disclosure shows that increasing concentration of the hReg3α lectin into the gastrointestinal tract (GIT) lumen of hReg3α-transgenic mice induced significant changes in composition of gut microbiota, and dramatically improved host resistance to intestinal inflammation. The Reg3α polypeptide may be used for preventing or treating microbiota-related diseases and/or disorders, including inflammatory bowel disease (IBD), colitis, gastrointestinal infections, irritable bowel syndrome and other gastrointestinal functional diseases, gastrointestinal tract cancer, metabolic syndrome and obesity, diabetes, liver diseases, allergic diseases, neurodegenerative diseases and psychological disorders, and the prevention and treatment methods may also include transferring to said patient fecal microbiota from a human or animal expressing the Reg3α polypeptide.