2’-Fucosyllactose alleviate immune checkpoint blockade-associated colitis by reshaping gut microbiota and activating AHR pathway

Immune checkpoint blockade(ICB)therapeutics are highly effective in cancer immunotherapy,but gastrointestinal toxicity limited the application.Intestinal microbiota plays a crucial role in ICB-associated colitis.2’-Fucosyllactose(2’FL)is most abundance prebiotic in human milk that can reshape gut microbiota and exert immune regulatory effect.The study aimed to determine the effects of 2’FL on ICB-associated colitis and to uncover the mediating mechanism.ICB-associated colitis was induced by the ipilimumab and dextran sulfate sodium.Oral administration of 2’FL(0.6 g/(kg∙day))ameliorated ICB-induced colitis by enhancing regulatory T cells(Treg)and the M2/M1 ratio of macrophages in colon.2’FL treatment also increased the expression of tight junction proteins(zonula occludens-1(ZO-1)and mucin 2(MUC2))and antioxidant stress indicators(superoxide dismutase(SOD)and catalase(CAT)).In addition,administration of 2’FL increased the abundance of Bifidobacterium and Lactobacillus,and elevated the levels of microbial metabolites,such as indole-3-lactic acid(ILA),which activated the aryl hydrocarbon receptor ligands(AHR)pathway.The protective effect of 2’FL was abolished upon depletion of gut microbiota,and ILA treatment partially simulated the protective effect of 2’FL.Notably,2’FL did not exhibit inhibition of antitumor immunity.These findings suggest that 2’FL could serve as a potential protective strategy for ICB-associated colitis by modulating the intestinal microbiota and bacterial metabolites.

Multidisciplinary management of ulcerative colitis complicated by immune checkpoint inhibitor-associated colitis with life-threatening gastrointestinal hemorrhage:A case report

BACKGROUND Programmed cell death 1(PD-1)inhibitors are immune checkpoint inhibitors(ICI)that have demonstrated significant efficacy in treating various advanced malignant tumors.While most patients tolerate treatment well,several adverse drug reactions,such as fatigue,myelosuppression,and ICI-associated colitis,have been reported.CASE SUMMARY This case involved a 57-year-old male patient with ulcerative colitis complicated by hepatocarcinoma who underwent treatment with tirelizumab(a PD-1 inhibitor)for six months.The treatment led to repeated life-threatening lower gastrointestinal hemorrhage.The patient received infliximab,vedolizumab,and other salvage procedures but ultimately required subtotal colectomy due to uncontrollable massive lower gastrointestinal bleeding.Currently,postoperative gastrointestinal bleeding has stopped,the patient’s stool has turned yellow,and his full blood cell count has returned to normal.CONCLUSION This case highlights the necessity of early identification,timely and adequate treatment of ICI-related colitis,and rapid escalation to achieve the goal of improving prognosis.

Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival

BACKGROUND Immune checkpoint inhibitor-mediated colitis(IMC)is a common adverse event following immune checkpoint inhibitor(ICI)therapy for cancer.IMC has been associated with improved overall survival(OS)and progression-free survival(PFS),but data are limited to a single site and predominantly for melanoma patients.AIM To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.METHODS We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age,sex,ICI class,and malignancy to a cohort of ICI users without IMC,from May 2011 to May 2020.Using univariate and multivariate logistic regression,we determined association of presence of IMC on OS,PFS,and clinical predictors of IMC.Kaplan-Meier curves were gen-erated to compare OS and PFS between ICI users with and without IMC.RESULTS IMC was significantly associated with a higher OS(mean 24.3 mo vs 17.7 mo,P=0.05)but not PFS(mean 13.7 mo vs 11.9 mo,P=0.524).IMC was significantly associated with OS greater than 12 mo[Odds ratio(OR)2.81,95%confidence interval(CI)1.17-6.77].Vitamin D supplementation was significantly associated with increased risk of IMC(OR 2.48,95%CI 1.01-6.07).CONCLUSION IMC was significantly associated with OS greater than 12 mo.In contrast to prior work,we found that vitamin D use may be a risk factor for IMC.

Differential diagnosis and management of immune checkpoint inhibitor-induced colitis: A comprehensive review

Immune checkpoint inhibitors(ICIs)are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4,programmed cell death 1 and programmed death-ligand 1.Checkpoint blockade by ICIs reactivates a tumor-specific T cell response.Immune-related adverse events can occur in various organs including skin,liver,and gastrointestinal tract.Mild to severe colitis is the most common side effect with some experiencing rapid progression to more serious complications including bowel perforation and even death.Prompt diagnosis and management of ICI-induced colitis is crucial for optimal outcome.Unfortunately,its clinical,endoscopic and histopathologic presentations are non-specific and overlap with those of colitis caused by other etiologies,such as infection,medication,graftversus-host disease and inflammatory bowel disease.Thus,a definitive diagnosis can only be rendered after these other possible etiologies are excluded.Sometimes an extensive clinical,laboratory and radiologic workup is required,making it challenging to arrive at a prompt diagnosis.Most patients experience full resolution of symptoms with corticosteroids and/or infliximab.For ICI-induced colitis that is treatment-refractory,small scale studies offer alternative strategies,such as vedolizumab and fecal microbiota transplantation.In this review,we focus on the clinical features,differential diagnosis,and management of ICIinduced colitis with special attention to emerging treatment options for treatmentrefractory ICI-induced colitis.

Moxibustion inhibits interleukin-12 and tumor necrosis factor alpha and modulates intestinal flora in rat with ulcerative colitis

AIM: To investigate the effect of moxibustion on intestinal flora and release of interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) from the colon in rat with ulcerative colitis (UC). METHODS: A rat model of UC was established by local stimulation of the intestine with supernatant from colonic contents harvested from human UC patients. A total of 40 male Sprague-Dawley rats were randomly divided into the following groups: normal (sham), model (UC), herb-partition moxibustion (HPM-treated), and positive control sulfasalazine (SA-treated). Rats treated with HPM received HPM at acupuncture points ST25 and RN6, once a day for 15 min, for a total of 8 d. Rats in the SA group were perfused with SA twice a day for 8 d. The colonic histopathology was observed by hematoxylin-eosin. The levels of intestinal flora, including Bifidobacterium, Lactobacillus, Escherichia coli (E. coli), and Bacteroides fragilis (B. fragilis), were tested by real-time quantitative polymerase chain reaction to detect bacterial 16S rRNA/DNA in order to determine DNA copy numbers of each specific species. Immunohistochemical assays were used to observe the expression of TNF-α and IL-12 in the rat colons. RESULTS: HPM treatment inhibited immunopathology in colonic tissues of UC rats; the general morphological score and the immunopathological score were significantly decreased in the HPM and SA groups compared with the model group [3.5 (2.0-4.0), 3.0 (1.5-3.5) vs 6.0 (5.5-7.0), P < 0.05 for the general morphological score, and 3.00 (2.00-3.50), 3.00 (2.50-3.50) vs 5.00 (4.50-5.50), P < 0.01 for the immunopathological score]. As measured by DNA copy number, we found that Bifidobacterium and Lactobacillus, which are associated with a healthy colon, were significantly higher in the HPM and SA groups than in the model group (1.395 ± 1.339, 1.461 ± 1.152 vs 0.045 ± 0.036, P < 0.01 for Bifidobacterium, and 0.395 ± 0.325, 0.851 ± 0.651 vs 0.0015 ± 0.0014, P < 0.01 for Lactobacillus). On the other hand, E. coli and B. fragilis, which are associated with an inflamed colon, were significantly lower in the HPM and SA groups than in the model group (0.244 ± 0.107, 0.628 ± 0.257 vs 1.691 ± 0.683, P < 0.01 for E. coli, and 0.351 ± 0.181, 0.416 ± 0.329 vs 1.285 ± 1.039, P < 0.01 for B. fragilis). The expression of TNF-α and IL-12 was decreased after HPM and SA treatment as compared to UC model alone (4970.81 ± 959.78, 6635.45 ± 1135.16 vs 12333.81 ± 680.79, P < 0.01 for TNF-α, and 5528.75 ± 1245.72, 7477.38 ± 1259.16 vs 12550.29 ± 1973.30, P < 0.01 for IL-12). CONCLUSION: HPM treatment can regulate intestinal flora and inhibit the expression of TNF-α and IL-12 in the colon tissues of UC rats, indicating that HPM can improve colonic immune response.

Role of the gut microbiota in inflammatory bowel disease pathogenesis: What have we learnt in the past 10 years?

Our understanding of the microbial involvement in inflammatory bowel disease (IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn&#x02019;s disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or &#x0201c;dysbiosis&#x0201d; is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity (including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.