Role of PD-L1 in Gut Mucosa Tolerance and Chronic Inflammation

The gastrointestinal (GI) mucosa is among the most complex systems in the body. It has a diverse commensal microbiome challenged continuously by food and microbial components while delivering essential nutrients and defending against pathogens. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut mucosal homeostasis. Recent lessons from cancer immunotherapy point out the critical role of the B7 negative co-stimulator PD-L1 in mucosal homeostasis. In this review, we summarize the current knowledge supporting the critical role of PD-L1 in gastrointestinal mucosal tolerance and how abnormalities in its expression and signaling contribute to gut inflammation and cancers. Abnormal expression of PD-L1 and/or the PD-1/PD-L1 signaling pathways have been observed in the pathology of the GI tract. We also discuss the current gap in our knowledge with regards to PD-L1 signaling in the GI tract under homeostasis and pathology. Finally, we summarize the current understanding of how this pathway is currently targeted to develop novel therapeutic approaches.

Familial adenomatous polyposis: a case study

Familial adenomatous polyposis (FAP) is an inherited syndrome characterized by several adenomatous polyps of the gastrointestinal (GI) mucosa. If treatment is not provided, an average individual with classic FAP will develop colorectal carcinoma around the age of 40 years. The incidence rate of FAP in developing countries like Ghana is unknown compared to advanced countries. We present the first FAP case of a 22-year-old Ghanaian female who presented with massive lower GI bleeding and underwent surgical management after a thorough investigation. The initial assumption that colonic polyps are scarce in native Africans may be more than what is perceived. This highlights the need for the availability of endoscopic services in Ghana.

Solid Nanocrystals of Rebamipide Promote Recovery from Indomethacin-Induced Gastrointestinal Bleeding

Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30–190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.

Role of Formyl Peptide Receptors in Gastrointestinal Healing

The wound healing and the barrier restoration of the gastrointestinal (GI) mucosa must be continuously ensured to allow homeostasis of the gastrointestinal tract and of all the surrounding tissues. Several lines of the evidence report a key role of innate immunity, and in particular of Pattern Recognition Receptors (PRRs), in controlling the homeostasis of GI tract by sensing commensal and pathogen bacteria, activating the immune response and regulating epithelial repair, thus guaranteeing the morphological and functional recovery of the injured tissue. We will discuss the role of a particular class of PRRs - the Formyl Peptide Receptors - in the homeostasis of GI mucosa. We here report the results of studies that strongly suggest the possibility that the activation of FPRs is crucial in the maintenance of homeostasis of the GI tract and provide indications of the potential clinical relevance of new treatment regimens involving FPR modulation for several GI disorders.

Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.

Clostridium subterminale Septicemia in a Patient with Metastatic Gastrointestinal Adenocarcinoma

Clostridium subterminale is a rare member of the Clostridiaceae family that is rarely cultured. This report examines a case of Clostridium subterminale cultured from the blood of a 72-year-old man who was ultimately diagnosed with metastatic gastrointestinal (GI) adenocarcinoma. The patient was receiving treatment for nosocomial pneumonia prior to culture of the C. subterminale, which led to suspicion for malignancy. Extensive GI and oncologic workup demonstrated multiple comorbidities and a primary GI cancer, which likely caused a breach in the GI mucosa and C. subterminale entrance into the bloodstream. After a prolonged intensive care unit (ICU) stay, the patient died on hospital day 23. Though rarely reported, C. subterminale septicemia has been demonstrated in patients with malignancy, specifically of the GI tract. Therefore, this case represents a typical C. subterminale septicemia patient. Given the prevalence of Clostridia and the contemporary emergence of multidrug resistant (MDR) microorganisms, both typical and atypical cases regarding rare members of the species have a significant role in the clinical management and public health planning.

RNAi-mediated beta-catenin knockdown in the gastrointestinal mucosa (GI) of patients with familial adenomatous polyposis (FAP): Results of START-FAP trial.

e15065 Background: FAP is an inherited GI disorder that predisposes patients to early-onset of colorectal cancer due to mutations in the APC gene resulting in accumulation of β-catenin contributing to the formation of polyps. CEQ508 is a novel agent using live-attenuated bacteria genetically engineered to produce and deliver β-catenin short-hairpin RNA into the GI mucosa. Methods: A dose-escalating Phase I study (START-FAP) evaluated the safety and tolerability of single daily oral doses of CEQ508 in FAP patients (3 each in Cohort 1 and 2 with 108 and 109 CFU for 28 days). The primary objective was to establish safety of oral CEQ508. The secondary objective was to test the effectiveness of CEQ508 in targeting β‐catenin gene in GI mucosa. GI tissues (duodenum, ileum, colon, antrum) obtained during endoscopy exam at baseline and end-of-treatment (EOT) were measured using qPCR and analyzed with ViiA™ 7 Real-Time system. Ct values were normalized to 2 of 3 housekeeping genes (EIF2B1, HPRT1, GUSβ). A mixed Nested-ANOVA model was used to evaluate β-catenin knockdown in normal mucosa and polyps. Results: Oral dosing of 108 and 109 CFU of CEQ508 for 28 days was well-tolerated. Histological evaluation of polyps and normal mucosa at baseline and EOT indicated minimal changes in tissue morphology or inflammation. β-catenin knockdown differed significantly between tissue types, with duodenum exhibiting the highest and antrum with the lowest (~2-fold difference). No significant effects from CEQ508 treatment were observed in normal mucosa. Significant reduction was observed in overall β-catenin expression in polyps at EOT (P = 0.0005). Patient to patient variation accounted for 8.2% of total variations. Reduction was observed primarily in the duodenum (39.3% decrease, P < 0.0001) and ileum (28.8% decrease, P = 0.012). Conclusions: Bacterial delivery of RNAi via CEQ508 in FAP patients demonstrated an acceptable safety profile at the two bacterial dose levels tested, with no MTD having been identified. START-FAP achieved both the primary endpoint of safety and secondary endpoint of β-catenin knockdown. Clinical development of CEQ508 with Celecoxib/Lisinopril (IT-102) for FAP is planned.

Expression of Reg family genes in the gastrointestinal tract of mice treated with indomethacin

Regenerating gene ( Reg) family proteins, which are classified into four types, commonly act as trophic and/or antiapoptotic factors in gastrointestinal (GI) diseases. However, it remains unclear how these proteins coordinate their similar roles under such pathophysiological conditions. Here, we investigated the interrelationships of Reg family gene expression with mucosal cell proliferation and apoptosis in nonsteroidal anti-inflammatory drug (NSAID)-induced GI injury. GI injury was induced by subcutaneous injection of indomethacin into Reg I knockout (KO) and wild-type (WT) mice, and its severity was scored histopathologically. Temporal changes in the expression of Reg family genes, mucosal proliferation, and apoptosis were evaluated throughout the GI tract by real-time RT-PCR, Ki-67 immunoreactivity, and TUNEL assay, respectively. Reg I, Reg III family, and Reg IV were predominantly expressed in the upper, middle, and lower GI mucosa, respectively. Expression of Reg I and Reg III family genes was upregulated in specific portions of the GI tract after indomethacin treatment. Ki-67-positive epithelial cells were significantly decreased in the gastric and small-intestinal mucosa of Reg I KO mice under normal conditions. After treatment with indomethacin, the number of TUNEL-positive cells was significantly greater throughout the GI mucosa in Reg I KO mice than in WT mice. Expression of Reg I was independent of that of other Reg family genes in, not only normal GI tissues, but also indomethacin-induced GI lesions. Members of the Reg gene family show distinct profiles of expression in the GI tract, and Reg I independently plays a role in protecting the GI mucosa against NSAID-induced injury.

Adult Dermatomyositis with Bleeding Ulcer in the Pharynx

Dermatomyositis (DM) is one of the idiopathic inflammatory myopathies caused by complement-mediated vasculopathy or vasculitis in the muscle. Although the gastrointestinal (GI) mucosa has been reported to be involved as a result of vasculitis or vasculopathy, ulceration in the pharynx is a rare manifestation of DM. A 54-year-old woman complaining of muscle weakness in the extremities, low-grade fever, and dysphagia was diagnosed as having DM. Despite medical treatment with corticosteroids and immunosuppressive agents, her DM progressed rapidly, leading to exacerbation of the dysphagia. About 3 weeks after undergoing tracheostomy as a preventive measure against aspiration, the patient developed intractable respiratory tract hemorrhage. Repeated laryngoendoscopy revealed a bleeding ulceration in the pharynx that required hemostasis with electric cautery under general anesthesia. No bleeding recurred thereafter. Histopathologically, the pharynx exhibited nonspecific inflammatory cell infiltration in the muscle tissue. This rare manifestation may be considered in cases of DM with unexplainable airway bleeding.