Gerald Wayne Dryden

The aryl hydrocarbon receptor (AHR) plays a central role in orchestrating gut barrier and mucosal immune functions in the pathogenesis of inflammatory bowel disease (IBD). Nevertheless, activation of the AHR by diverse ligands yields varied outcomes, and the downstream pathways responsible for these effects remain unknown. Here, we report that selective activation of AHR in mouse intestinal epithelial cells (IEC) by the microbial metabolite, urolithin A (UroA), triggers the Nod-like receptor pyrin domain-containing protein 6 (NLRP6) inflammasome, resulting in the release of interleukin (IL)−18 but not IL-1β. Further, we show that UroA-induced IL-18 in IECs is critical for IL-22, mucin 2 and REG3γ production, as well as protection against colitis. Moreover, UroA significantly upregulates IL-18 and IL-22 levels in IECs and type-3 innate lymphoid cells, respectively, in intestinal biopsies from patients with IBD patients. These results demonstrate that activation of AHR by UroA modulates intestinal barrier function through an NLRP6-IL-18-IL-22 pathway in both healthy and IBD conditions.

Purpose of Review: Enteral nutrition plays a pivotal role in maintaining nutritional status and supporting recovery in hospitalized patients who are unable to meet their caloric requirements. The benefits of enteral nutrition include preserving gut integrity, reducing infection risks, and supporting immune function, which are vital in critically ill and post-operative patients. Nasoenteric feeding tubes often serve as important tools to deliver enteral nutrition efficiently, yet their optimal placement remains a subject of significant clinical consideration. Recent findings: Nasoenteric feeding tubes can be compromised by placement-related complications such as displacement, malpositioning, and tube-related discomfort. Our review of the relevant literature is complemented by review of our recent data. Our own clinical experience suggests that endoscopic placement of naso-enteric feeding tubes fails during the wire exchange process. Summary: This report reviews the importance of enteral nutrition for enhancing patient outcomes, documents findings from our retrospective study on endoscopically placed nasoenteric feeding tubes and focuses on the challenges and future advancements in nasoenteric feeding tube placement techniques.

Purpose of Review Inflammatory bowel disease (IBD) patients commonly inquire about the role of diet in the onset and management of their disease process. This review sought to assess the impact of the inflammatory bowel diseases on the nutritional state of patients and evaluate the evidence supporting nutritional interventions as therapy. Recent Findings The role of nutrition has evolved from one of deficient nutrient and calorie replacement alone into a proactive therapeutic for treating active inflammatory disease symptoms. The realization that initiating total parenteral nutrition (TPN) in place of oral take could improve disease symptoms provided the first indication that food intake played a causative role in the IBD. The evolution of TPN to enteral nutrition improved tolerance and reduced side effects but clouded the role of oral intake in the pathophysiology of IBD. Advanced understanding of the role of the microbiota in IBD combined with recognition of the influence of nutrients on microbial composition have ushered in a new era of food as therapy. Summary The role of nutrition in IBD has evolved significantly over the past 30-40 years. From complete elimination of oral intake to the carefully curated menu intended to mold the intestinal microbiota to a non-inflammatory milieu has revolutionized the approach to dietary intervention. Additional studies are warranted to optimize dietary intervention strategies.

Inflammatory bowel disease is associated with several genetic risk loci. Loss-of-function mutation in the α1,2-fucosyltransferase (fut2) gene, which alters fucosylation on the surface of intestinal epithelial cells, is one example. However, whether bacterial fucosylation can contribute to gut inflammation is unclear. Here we show that host fucosylation status influences fucosylation biosynthesis by gut commensal bacteria. Mice colonized with faecal microbiota of Fut2 knockout mice or Bacteroides fragilis with lower surface fucosylation are predisposed to colitis. This was supported by human cohort data showing that bacterial fucosylation levels decrease in patients with inflammatory bowel disease and correlate with intestinal inflammation. Using a mouse model for Bacteroides fragilis to explore the role of fucosylation in gut immunity, we show that the fucosylation status of epithelial cells and bacteria is critical for maintaining B cell responses in the gut. Host-derived and dietary fucose mediate immunoglobulin A (IgA) recognition of gut microbiota, and this interaction facilitates the translocation of commensals to Peyer’s patches and alters the immune landscape of Peyer’s patches with increased germinal centre B cells and IgA-secreting antigen-specific B cells. Finally, dietary fucose enhances the IgA response against Salmonella and protects against systemic bacterial dissemination. This highlights the role of host and bacterial fucosylation in maintaining IgA homeostasis and immune escape mechanisms.

Inflammatory bowel disease (IBD) treatment often involves systemic administration of anti-inflammatory drugs or biologics such as anti-TNF-α antibodies. However, current drug therapies suffer from limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we developed inflammation-targeting nanoparticles (ITNPs) using biopolymers derived from the gum kondagogu (Cochlospermum gossypium) plant. These ITNPs enable selective drug delivery to inflamed regions, offering improved therapeutic outcomes. We designed ITNPs that specifically bind to inflamed regions in both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the inflamed tissues. Furthermore, we demonstrated that oral administration of ITNPs loaded with urolithin A (UroA), a microbial metabolite or its synthetic analogue UAS03 significantly attenuated chemical- and immune checkpoint inhibitor- induced colitis in pre-clinical models. In conclusion, ITNPs show great promise for delivering UroA or its analogues while enhancing therapeutic efficacy at lower doses and reduced frequency compared to free drug administration. This targeted approach offers a potential solution to enhance IBD treatment while minimizing systemic side effects. Inflammatory Bowel Disease (IBD) is a complex medical condition characterized by alternating phases of inflammation and remission in the gastrointestinal tract. Despite the success of immune checkpoint inhibitors (ICI) in cancer therapy, ICI-mediated colitis remains a challenge for cancer patients. Current treatments targeting systemic inflammation have limitations and adverse effects. To overcome these challenges, we have developed inflammation-targeted nanoparticles from natural compounds to deliver the microbial metabolite urolithin A or its synthetic analog UAS03 to inflammatory sites to ameliorate colitis. Our data showed that oral treatment with these nanoparticles attenuated chemically induced and ICI-triggered colitis in preclinical models. These studies highlight the utilization of these inflammation-targeted nanoparticles to deliver urolithin A will have significant implications for the treatment of IBD.

Fibroblast growth factor 21 (FGF21) is a glucose and lipid metabolic regulator. Recent research revealed that FGF21 was also induced by inflammatory stimuli. Its role in inflammatory bowel disease (IBD) has not been investigated. In this study, an experimental IBD model was established in FGF21 knockout (KO) and wild-type (WT) mice by adding 2.5% (wt/vol) dextran sodium sulfate (DSS) to their drinking water for 7 days. The severity of the colitis and the inflammation of the mouse colon tissues were analyzed. In WT mice, acute DSS treatment induced an elevation in plasma FGF21 and a significant loss of body weight in a time-dependent manner. Surprisingly, the loss of body weight and the severity of the colitis induced by DSS treatment in WT mice were significantly attenuated in FGF21 KO mice. Colon and circulating pro-inflammatory factors were significantly lower in the FGF21 KO mice compared to the WT mice. As shown by BrdU staining, the FGF21 KO mice demonstrated increased colonic epithelial cell proliferation. DSS treatment reduced intestinal Paneth cell and goblet cell numbers in the WT mice, and this effect was attenuated in the FGF21 KO mice. Mechanistically, FGF21 deficiency significantly increased the signal transducer and activator of transcription (STAT)-3 activation in intestinal epithelial cells and increased the expression of IL-22. Further study showed that the expression of suppressor of cytokine signaling-2/3 (SOCS 2/3), a known feedback inhibitor of STAT3, was significantly inhibited in the DSS-treated FGF2 KO mice compared to the WT mice. We conclude that FGF21 deficiency attenuated the severity of DSS-induced acute colitis, which is likely mediated by enhancing the activation of the IL-22-STAT3 signaling pathway in intestinal epithelial cells.

Ulcerative colitis (UC) is a common, chronic, inflammatory process limited to the colon. UC affects up to 1 million individuals in the USA alone and requires resection in up to 30% of patients. Resection is often followed by creation of a pouch. Pouchitis is the most common complication of ileal pouch-anal anastomosis (IPAA) following total proctocolectomy, affecting up to 50% of patients. Symptoms include increased stool frequency, urgency, cramping, and bleeding. Management of pouchitis is complex in antibiotic refractory cases. Plant-based polyphenolic compounds have shown protective effects against UC. We conducted a retrospective review of pouchitis patients treated with EGCG 200–400 mg twice daily.

Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic or relapsing immune activation and corresponding inflammation within the gastrointestinal (GI) tract. Diverse genetic mutations, encoding important aspects of innate immunity and mucosal homeostasis, combine with environmental triggers to create inappropriate, sustained inflammatory responses. Recently, significant advances have been made in understanding the interplay of the intestinal epithelium, mucosal immune system, and commensal bacteria as a foundation of the pathogenesis of inflammatory bowel disease. Complex interactions between specialized intestinal epithelial cells and mucosal immune cells determine different outcomes based on the environmental input: the development of tolerance in the presence of commensal bacterial or the promotion of inflammation upon recognition of pathogenic organisms. This article reviews key genetic abnormalities involved in inflammatory and homeostatic pathways that enhance susceptibility to immune dysregulation and combine with environmental triggers to trigger the development of chronic intestinal inflammation and IBD.