Bacteroides fragilis strain ZY-312 facilitates colonic mucosa regeneration in colitis via motivating STAT3 signaling pathway induced by IL-22 from ILC3 secretion

Abstract

IntroductionProbiotics play critical roles in relieving inflammatory bowel disease (IBD). However, the underlying mechanism of Bacteroides fragilis strain ZY-312 (B. fragilis) for colonic mucosa regeneration in IBD remains unclear.MethodsThe weight loss, disease activity index (DAI), colon length, and histopathology-associated index (HAI) were evaluated the therapeutic effects of B. fragilis in a DSS-induced colitis mouse model. Colonic mucosa proliferation and apoptosis level, and mucus density were detected by histological stain. Gut microbiota was sequenced by 16srRNA analysis. The expression of signal transducer and activator of transcription 3 (STAT3) phosphorylation in colonic mucosa was detected in B. fragilis-treated mice in colitis. B. fragilis-regulated immunity factors of motivating downstream STAT3 phosphorylation were screened by ELISA and flow cytometry. Lastly, B. fragilis-mediated colonic mucosa regeneration effects were verified though the knockout of STAT3 (Stat3△IEC) and IL-22 (IL-22-/-) in mice, and inhibitor of STAT3 and IL-22 in co-culture model.ResultsB. fragilis alleviated DSS-induced colitis in mice with less weight loss, DAI, colon length shortening, and HAI. Further the results showed that B. fragilis motivated STAT3 phosphorylation in colonic mucosa with the upregulation of proliferation index Ki-67 and mucus density, the downregulation of apoptosis level, and the modulation of gut microbiota through a Stat3△IEC mice model and STAT3 inhibitor-added model in vitro. Meanhwhile we found that B. fragilis promoted IL-22 production, and increased the percentage of IL-22-secreting type 3 innate lymphocytes (ILC3) in colitis. Consequently, We identified that B. fragilis did not increase the expression of pSTAT3, either proliferation level, mucus density, or alter gut microbiota in IL-22-/- mice.DiscussionB. fragilis may indirectly motivate ILC3 to secrete IL-22, followed by IL-22-induced STAT3 phosphorylation, hence promoting colonic mucosa regeneration in colitis. It indicates that B. fragilis has the potential to be a biological agent for IBD therapy.

Therapeutic Potential of Bacteroides fragilis SNBF-1 as a Next-Generation Probiotic: In Vitro Efficacy in Lipid and Carbohydrate Metabolism and Antioxidant Activity

“…B. fragilis , a pivotal inhabitant of the human gastrointestinal tract, plays a dual role in health, acting both as a beneficial probiotic and a potential opportunistic pathogen [ 11 ]. Early research has revealed that B. fragilis plays a role in modulating the gut microbiome by interfering with the growth or translocation of other microbes.…”

“…For immune regulation, studies note that B. fragilis ’s Polysaccharide A (PSA) is crucial and may protect against diseases like bowel disease [ 11 , 31 ]. B. fragilis administration in animal models leads to the binding of PSA with B cells, crucial for inducing regulatory CD4+ and CD8+ T cells that secrete IL-10, thereby controlling innate inflammatory responses.…”

“…The move toward NGPs represents a response to the shortcomings of traditional probiotics, aiming for more precise and effective treatments [ 8 , 9 ]. Notably, non-toxigenic B. fragilis stands out for its role in modulating immunity and reducing inflammation [ 10 , 11 ]. For instance, Strain NCTC 9343 is instrumental in the prevention of chronic colitis and tumor development, operating without reliance on the polysaccharide A molecule.…”

“…As crucial gut microbiota members, they are vital in maintaining gut health and influencing disease [ 13 , 14 ]. These strains provide numerous health benefits, including modulating the immune system [ 11 , 15 ], protecting against gastrointestinal diseases, and showing potential to manage metabolic disorders [ 10 , 16 ]. The specific attributes of B. fragilis , particularly those enhancing their resilience and adaptability in the gut environment, are of significant scientific interest.…”

ILC3: a case of conflicted identity

“…Intermediate stages of NK development are also thought to differentiate from this progenitor, at least in secondary lymphoid tissues, such as tonsils and lymph nodes (20). ILC differentiation further leads to the early tonsil progenitor cells (EToP), with two distinct phenotypes, EToP1 (Lin − CD34 + CD10 + KIT − ) or EToP2 (Lin − CD34 + CD10 + KIT + ) (21,22). EToP2 can be divided into two groups based on ST2 (IL-33R, IL1r1) expression and on their ability to form ILC (21).…”