Microbe–host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.

Background and aims: Mice orally infected with T. gondii develop Crohn's disease (CD)-like enteritis associated with severe mucosal damage and a systemic inflammatory response, resulting in high morbidity and mortality. Previously, helminthic infections have shown therapeutic potential in experimental colitis. However, the role of S. mansoni in T. gondii-induced CD-like enteritis has not been elucidated. Our study investigated the mechanisms underlying T. gondii-induced ileitis and the potential therapeutic effect of S. mansoni coinfection.Methods: C57BL/6 mice were infected by subcutaneous injection of cercariae of the BH strain of S. mansoni, and 7–9 weeks later, they were orally infected with cysts of the ME49 strain of T. gondii. After euthanasia, the ileum was removed for histopathological analysis; staining for goblet cells; immunohistochemistry characterizing mononuclear cells, lysozyme expression, apoptotic cells, and intracellular pathway activation; and measuring gene expression levels by real-time PCR. Cytokine concentrations were measured in the serial serum samples and culture supernatants of the ileal explants, in addition to myeloperoxidase (MPO) activity.Results: T. gondii-monoinfected mice presented dense inflammatory cell infiltrates and ulcerations in the terminal ileum, with abundant cell extrusion, apoptotic bodies, and necrosis; these effects were absent in S. mansoni-infected or coinfected animals. Coinfection preserved goblet cells and Paneth cells, remarkably depleted in T. gondii-infected mice. Densities of CD4- and CD11b-positive cells were increased in T. gondii- compared to S. mansoni-infected mice and controls. MPO was significantly increased among T. gondii-mice, while attenuated in coinfected animals. In T. gondii-infected mice, the culture supernatants of the explants showed increased concentrations of TNF-alpha, IFN-gamma, and IL-17, and the ileal tissue revealed increased expression of the mRNA transcripts for IL-1 beta, NOS2, HMOX1, MMP3, and MMP9 and activation of NF-kappa B and p38 MAPK signaling, all of which were counterregulated by S. mansoni coinfection.Conclusion: S. mansoni coinfection attenuates T. gondii-induced ileitis by preserving mucosal integrity and downregulating the local inflammatory response based on the activation of NF-kappa B and MAPK. The protective function of prior S. mansoni infection suggests the involvement of innate immune mechanisms and supports a conceptually new approach to the treatment of chronic inflammatory diseases, including CD.

Background: Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). Methods: CA-CRC was induced in P2X7R+/+ and P2X7R−/− mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R+/+ mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. Results: The P2X7R+/+ mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R−/− and the P2X7R+/+ mice treated with A740003. The P2X7R+/+ mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of NLRP3 and NLRP12 genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R−/− and P2X7R+/+-induced mice, partially reversed by the A740003 treatment. Conclusions: Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development.

No abstract

Phenolic compounds (PCs) present in foods are associated with a decreased risk of developing inflammatory diseases. The aim of this study was to extract and characterize PCs from craft beer powder and evaluate their potential benefits in an experimental model of inflammatory bowel disease (IBD). PCs were extracted and quantified from pure beer samples. BALB/c mice received either the beer phenolic extract (BPE) or beer powder fortified with phenolic extract (BPFPE) of PCs daily for 20 days by gavage. Colon samples were collected for histopathological and immunohistochemical analyses. Dextran sodium sulfate (DSS)-induced mice lost more weight, had reduced colon length, and developed more inflammatory changes compared with DSS-induced mice treated with either BPE or BPFPE. In addition, in DSS-induced mice, the densities of CD4- and CD11b-positive cells, apoptotic rates, and activation of NF-κB and p-ERK1/2 MAPK intracellular signaling pathways were higher in those treated with BPE and BPFPE than in those not treated. Pretreatment with the phenolic extract and BPFPE remarkably attenuated DSS-induced colitis. The protective effect of PCs supports further investigation and development of therapies for human IBD.