The developmentally regulated fetal enterocyte gene, ZP4, mediates anti-inflammation by the symbiotic bacterial surface factor polysaccharide A on Bacteroides fragilis

Abstract

Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis ( B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1β-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1β, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 ( ZP4), is uniquely elevated after IL-1β stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1β. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC. NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1β.

Gut microbiome changes in anti-N-methyl-D-aspartate receptor encephalitis patients

“…Evidence of many beneficial functions of Bacteroides strains suggests their intervention capabilities in lipopolysaccharide-induced immune response and gut microbiome shift, even having potential as therapeutic probiotics to prevent inflammatory disorders [ 18 , 19 ]. The polysaccharide A surface component of Bacteroides fragilis is mainly responsible for this protective effect [ 20 ]. The expression of polysaccharide A can also protect against central nervous system demyelination [ 21 ].…”

Enterotoxigenic Bacteroides fragilis induces the stemness in colorectal cancer via upregulating histone demethylase JMJD2B

“…5 Recent studies have shown that the biological activities of B. fragilis-derived Polysaccharide A (PSA) and LPS are mediated by TLR4 activation. 60,62 Similarly, Ahmadi et al reported that B. fragilis and B. fragilis-derived outer membrane vesicles (OMVs, which contain bacterial components including LPS, outer membrane proteins, phospholipids, periplasmic components, DNA, RNA, hydrolytic enzymes and signaling molecules) both increase the mRNA levels of TLR4. 57 BFT, key virulence factor of ETBF, binds to an uncharacterized cell surface receptor, 63,64 triggering an array of signal transduction and contributing to key aspects of ETBF carcinogenic potential.…”

The potential role of adherence factors in probiotic function in the gastrointestinal tract of adults and pediatrics: a narrative review of experimental and human studies

“… 44 , 45 EPSs were shown to protect from innate immune mechanism via AMPs the probiotic LGG after adhesion to IECs 46 (3b). PSA on B. fragilis or isolated PSA has been shown to inhibit IL-1β induced inflammation through interaction with TLR2 and 4 on IECs 47 , 48 (4a) and can also directly bind to antigen-presenting cells (dendritic cells) triggering downstream immune responses 49 , 50 (4b). Distinct adhesins in the bacteria cells, not belonging to any of the aforementioned class, could support the sustained effects of L. casei on IgA and calprotectin 51–54 (5).…”

“… 48 In addition, our novel study described the anti-inflammatory role of Zona pellucida protein 4 (ZP4). 47 ZP4 is a distinctive protein on immature fetal IECs that mediates PSA anti-inflammation effects by involving TLR2 and IL-8 47 ( Figure 1 ). IL-1β is a pro-inflammatory cytokine released mainly from intestinal macrophages during cell activation and acute inflammation.…”

“…PSA In vitro : Inhibits IL-1β induced inflammation on IECs. 47–49 Bacteroides fragilis (non-toxigenic) Component of type VI secretion system (T6SS) Deletion mutant Mutant confers colonization resistance to enterotoxigenic Bacteroides fragilis that is associated with IBD, childhood diarrhea and colon cancer. 150 , 151 Enterococcus Faecium WEFA23 SLP Removal of SLP by treatment with 5 mol/L LiCl, isolated SLP Removal of SLP reduced adhesion capacity on pathogen Listeria monocytogenes CMCC54007.…”