Ulcerative colitis-associated neoplasms often harbor poor prognostic histologic components with low detection by biopsy.

Background/Aims: Poorly differentiated adenocarcinoma, signet-ring cell carcinoma, and mucinous adenocarcinoma (por/sig/muc), which are considered to be histologic subtypes with a poor prognosis, occur more frequently with colitis-associated cancer than with sporadic tumors. However, their invasiveness and manifestations are unclear. This study aimed to determine the prevalence of the por/sig/muc component in ulcerative colitis-associated neoplasms (UCANs) and its association with invasiveness and to clarify its clinicohistologic and endoscopic features. Methods: This retrospective observational study included patients diagnosed with ulcerative colitis-associated high-grade dysplasia or adenocarcinoma from 1997 to 2022 who were divided according to the presence or absence of a por/sig/muc component. Results: Thirty-five patients had UCAN with a por/sig/muc component and 66 had UCAN without this component. The 5-year survival rate was significantly lower in the por/sig/muc group than in the tub group (67% vs. 96%, P= 0.001), which was attributed to disease above stage III and depth to below the subserosa. Biopsy-based diagnosis before resection detected a por/sig/muc component in only 40% of lesions (14/35). Lesions with a por/sig/muc component were prevalent even in the early stages: stage 0 (4/36, 11%), I (8/20, 40%), II (7/12, 58%), III (10/14, 71%), and IV (6/8, 75%). Conclusions: This is the first investigation that shows UCANs with a por/sig/muc component tended to be deeply invasive and were often not recognized preoperatively. Endoscopists should be aware that UCAN often has a por/sig/muc component that is not always recognized on biopsy, and the optimal treatment strategy needs to be carefully considered.

Efficacy and safety of the water pressure method for endoscopic submucosal dissection in superficial pharyngeal cancer.

Background and study aims Superficial pharyngeal cancers can be cured with transoral surgery (TOS), which preserves organ function and quality of life. Pharyngeal endoscopic submucosal dissection (ESD) is challenging to perform because of limited maneuverability and complex anatomical features. The water pressure method (WPM) is useful for natural traction techniques during ESD and is potentially useful for pharyngeal ESD. This study aimed to investigate the short-term outcomes of WPM-ESD for pharyngeal lesions. Patients and methods Therapeutic outcomes of patients who underwent WPM-ESD for pharyngeal lesions at Keio University between May 2019 and February 2022 were retrospectively analyzed. Results Twenty-one pharyngeal lesions treated with WPM-ESD were analyzed. Three lesions were located in the oropharynx and 18 in the hypopharynx. All ESD procedures were performed under general anesthesia. The endoscopic en bloc resection rate was 100%. The median procedure time was 15 minutes (range 4-45 minutes). All patients were successfully extubated on the day of ESD. No serious adverse events (AEs) related to WPM-ESDs were observed. None of the patients required nasogastric intubation, percutaneous endoscopic gastrostomy, or tracheotomy. The median fasting time and hospital stay were 2 days (range 2-5 days) and 6 days (range 6-10 days), respectively. All the histological results indicated squamous cell carcinoma. The complete histologic resection rate was 76.2%. Conclusions WPM-ESD achieved a high en bloc resection rate and short procedure time without serious AEs. Thus, it may be a useful treatment for pharyngeal lesions.

Efficacy of Dose Escalation of Oral 5-Aminosalicylic Acid for Ulcerative Colitis With a Mayo Endoscopic Subscore of 1: An Open Label Randomized Controlled Trial.

BACKGROUND: Endoscopic healing is generally defined as Mayo endoscopic subscore (MES) ≤1 in ulcerative colitis (UC). However, patients with an MES of 1 are at higher relapse risk than those with an MES of 0. This study evaluated the therapeutic efficacy of proactive dose escalation of oral 5-aminosalicylic acid (5-ASA) in UC patients with an MES of 1. METHODS: An open-label, randomized controlled trial was conducted in 5 hospitals between 2018 and 2022. Ulcerative colitis patients in clinical remission under oral 5-ASA therapy and diagnosed as having an MES of 1 were enrolled. Patients receiving maintenance therapy other than 5-ASA and immunomodulator were excluded. Patients were randomly assigned in a 1:1 ratio to receive either a dose-escalated (intervention) or constant dose (control) of 5-ASA. Concomitant immunomodulator was used as the stratification factor in the randomization. The primary end point was relapse within 1 year. The subgroup analysis was stratified for the use of immunomodulators. RESULTS: The full analysis set included 79 patients (39 intervention and 40 control). Immunomodulators were used in 20 (25.3%) patients. Relapse was less in the intervention group (15.4%) than the control group (37.5%; P = .026). In the subgroup with concomitant immunomodulators, relapse was also less in the intervention group (10.0%) than the control group (70.0%; P = .020). In patients without immunomodulators, the difference was not significant between 2 groups (intervention, 17.2%; control, 26.7%; P = .53). CONCLUSIONS: Dose escalation of 5-ASA reduced relapse within 1 year in UC patients in clinical remission with an MES of 1.

Dose escalation of 5-aminosalicylic acid for ulcerative colitis reduced relapse rate in patients in clinical remission with a Mayo endoscopic subscore of 1. The therapeutic efficacy was more evident in those whom immunomodulators were used.

Video capsule endoscopy in overt and occult obscure gastrointestinal bleeding: Insights from a single-center, observational study in Japan.

Objective: This study aimed to evaluate the use of video capsule endoscopy (VCE) in patients with obscure gastrointestinal bleeding (OGIB), compare cases of overt and occult OGIB, assess the rates of balloon-assisted enteroscopy (BAE) interventions and rebleeding, and identify predictive markers of positive VCE findings. Methods: Medical records of 430 patients who underwent VCE for OGIB between 2004 and 2022 were analyzed. Occult OGIB was defined as IDA or positive fecal occult blood, whereas overt OGIB was defined as clinically imperceptible bleeding. We retrospectively analyzed demographics, VCE findings based on Saurin classification (P0, P1, and P2), outcome of BAE interventions, and rebleeding rates. Results: A total of 253 patients with overt OGIB and 177 with occult OGIB were included. P1 findings were predominant in both groups, with a similar distribution. The percentage of patients receiving conservative therapy was higher in P1 than in P2 for both overt and occult OGIB. BAE was more frequently performed in P2 than in P1 VCE (83.0% vs. 35.3% in overt OGIB, 84.4% vs. 24.4% in occult OGIB). The percentage of positive findings and intervention in total BAE performed patients were comparable in P1 and P2 of overt OGIB, whereas these percentages in P2 were more than P1 of occult OGIB. Conclusion: VCE effectively identified OGIB lesions requiring intervention, particularly occult OGIB lesions, potentially reducing unnecessary BAE. Rebleeding rates varied according to the VCE findings, emphasizing the importance of follow-up in high-risk patients.

Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis.

Indigo naturalis is an effective treatment for ulcerative colitis. However, long-term use of indigo naturalis causes adverse events, such as pulmonary hypertension. The natural history of patients with ulcerative colitis who discontinued indigo naturalis after induction therapy is unknown. Moreover, the clinical features of patients who relapsed within 52 weeks after the discontinuation of indigo naturalis are unclear. This study aimed to assess the clinical outcomes of patients with ulcerative colitis after discontinuation of indigo naturalis and to identify potential markers responsible for relapse. This single-center retrospective study investigated the follow-up of 72 patients who achieved a clinical response 8 weeks after indigo naturalis treatment. We observed relapse in patients with ulcerative colitis after the discontinuation of indigo naturalis. We analyzed the factors predicting long-term outcomes after discontinuation of indigo naturalis. Relapse was observed in 24%, 57%, and 71% of patients at 8, 26, and 52 weeks, respectively. There were no predictive markers in patients who relapsed within 52 weeks after the discontinuation of indigo naturalis. The ulcerative colitis relapse rate after indigo naturalis discontinuation was high. Follow-up treatment is required after the discontinuation of indigo naturalis in patients with ulcerative colitis.

Gastrointestinal symptoms in COVID-19 and disease severity: a Japanese registry-based retrospective cohort study.

BACKGROUND: Research on whether gastrointestinal symptoms correlate with the severity of Coronavirus Disease 2019 (COVID-19) has been inconclusive. This study aimed to clarify any associations between gastrointestinal symptoms and the prognosis of COVID-19. METHODS: We collected data from the Japanese nationwide registry for COVID-19 to conduct a retrospective cohort study. Data from 3498 Japanese COVID-19 patients, diagnosed at 74 facilities between February 2020 and August 2022, were analyzed in this study. Hospitalized patients were followed up until discharge or transfer to another hospital. Outpatients were observed until the end of treatment. Associations between gastrointestinal symptoms and clinical outcomes were investigated using multivariable-adjusted logistic regression models. RESULTS: The prevalence of diarrhea, nausea/vomiting, abdominal pain, and melena were 16.6% (581/3498), 8.9% (311/3498), 3.5% (121/3498), and 0.7% (23/3498), respectively. In the univariable analysis, admission to intensive care unit (ICU) and requirement for mechanical ventilation were less common in patients with diarrhea than those without (ICU, 15.7% vs. 20.6% (p = 0.006); mechanical ventilation, 7.9% vs. 11.4% (p = 0.013)). In the multivariable-adjusted analysis, diarrhea was associated with lower likelihood of ICU admission (adjusted odds ratio (aOR), 0.70; 95% confidence interval (CI), 0.53-0.92) and mechanical ventilation (aOR, 0.61; 95% CI, 0.42-0.89). Similar results were obtained in a sensitivity analysis with another logistic regression model that adjusted for 14 possible covariates with diarrhea (ICU; aOR, 0.70; 95% CI, 0.53-0.93; mechanical ventilation; aOR 0.62; 95% CI, 0.42-0.92). CONCLUSIONS: Diarrhea was associated with better clinical outcomes in COVID-19 patients.

Characteristics of flat-type ulcerative colitis-associated neoplasia on chromoendoscopic imaging with indigo carmine dye spraying.

OBJECTIVES: Despite recent advances in endoscopic equipment and diagnostic techniques, early detection of ulcerative colitis-associated neoplasia (UCAN) remains difficult because of the complex background of the inflamed mucosa of ulcerative colitis and the morphologic diversity of the lesions. We aimed to describe the main diagnostic patterns for UCAN in our cohort, including lateral extension surrounding flat lesions. METHODS: Sixty-three lesions in 61 patients with flat-type dysplasia that were imaged with dye chromoendoscopy (DCE) were included in this analysis. These DCE images were analyzed to clarify the dye-chromoendoscopic imaging characteristics of flat dysplasia, and the lesions were broadly classified into dysplastic and nondysplastic mucosal patterns. RESULTS: Dysplastic mucosal patterns were classified into two types: small round patterns with round to roundish structures, and mesh patterns with intricate mesh-like structures. Lesions with a nondysplastic mucosal pattern were divided into two major types: a ripple-like type and a gyrus-like type. Of note, 35 lesions (55.6%) had a small round pattern, and 51 lesions (80.9%) had some type of mesh pattern. About 70% of lesions with small round patterns and 49% of lesions with mesh patterns were diagnosed as high-grade dysplasia or carcinoma, while about 30% of lesions with small round patterns and 51% of lesions with mesh patterns were diagnosed as low-grade dysplasia. CONCLUSION: When a characteristic mucosal pattern, such as a small round or mesh pattern, is found by DCE, the possibility of UCAN should be considered.

Resectability of Small Duodenal Tumors: A Randomized Controlled Trial Comparing Underwater Endoscopic Mucosal Resection and Cold Snare Polypectomy.

INTRODUCTION: Underwater endoscopic mucosal resection (UEMR) and cold snare polypectomy (CSP) are novel endoscopic procedures for superficial nonampullary duodenal epithelial tumors (SNADET). However, consensus on how to use both procedures appropriately has not been established. In this study, we evaluated treatment outcomes of both procedures, including resectability. METHODS: In this single-center randomized controlled study conducted between January 2020 and June 2022, patients with SNADET ≤12 mm were randomly allocated to UEMR and CSP groups. The primary end point was sufficient vertical R0 resection (SVR0), which was defined as R0 resection including a sufficient submucosal layer. We compared treatment outcomes including SVR0 rate between groups. RESULTS: The SVR0 rate was significantly higher in the UEMR group than in the CSP group (65.6% vs 41.5%, P = 0.01). By contrast, the R0 resection rate was not significantly different between study groups (70.3% vs 61.5%, P = 0.29). The submucosal layer thickness was significantly greater in the UEMR group than in the CSP group (median 546 [range, 309-833] µm vs 69 [0-295] µm, P < 0.01). CSP had a shorter total procedure time (median 12 [range, 8-16] min vs 1 [1-3] min, P < 0.01) and fewer total bleeding events (9.4% vs 1.5%, P = 0.06). DISCUSSION: UEMR has superior vertical resectability compared with CSP, but CSP has a shorter procedure time and fewer bleeding events. Although CSP is preferable for most small SNADET, UEMR should be selected for lesions that cannot be definitively diagnosed as mucosal low-grade neoplasias.

Prospective cross-organ analysis for the causes of fever and increased inflammatory response after endoscopic resection.

OBJECTIVES: Fever and increased inflammatory responses sometimes occur following endoscopic resection (ER). However, the differences in causes according to the organ are scarcely understood, and several modified ER techniques have been proposed. Therefore, we conducted a comprehensive prospective study to investigate the cause of fever and increased inflammatory response across multiple organs after ER. METHODS: We included patients who underwent gastrointestinal endoscopic submucosal dissection (ESD) and duodenal endoscopic mucosal resection at our hospital between January 2020 and April 2022. Primary endpoints were fever and increased C-reactive protein (CRP) levels following ER. The secondary endpoints were risk factors for aspiration pneumonia. Blood tests and radiography were performed on the day after ER, and computed tomography was performed if the cause was unknown. RESULTS: Among the 822 patients included, aspiration pneumonia was the most common cause of fever and increased CRP levels after ER of the upper gastrointestinal tract (esophagus, 53%; stomach, 48%; and duodenum, 71%). Post-ER coagulation syndrome was most common after colorectal ESD (38%). On multivariate logistic regression analysis, lesions located in the esophagus (odds ratio [OR] 3.57; P < 0.001) and an amount of irrigation liquid of ≥1 L (OR 3.71; P = 0.003) were independent risk factors for aspiration pneumonia. CONCLUSIONS: Aspiration pneumonia was the most common cause of fever after upper gastrointestinal ER and post-ER coagulation syndrome following colorectal ESD. Lesions in the esophagus and an amount of irrigation liquid of ≥1 L were independent risk factors for aspiration pneumonia.

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis.

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

D-amino Acids Ameliorate Experimental Colitis and Cholangitis by Inhibiting Growth of Proteobacteria: Potential Therapeutic Role in Inflammatory Bowel Disease.

BACKGROUND & AIMS: D-amino acids, the chiral counterparts of protein L-amino acids, were primarily produced and utilized by microbes, including those in the human gut. However, little was known about how orally administered or microbe-derived D-amino acids affected the gut microbial community or gut disease progression. METHODS: The ratio of D- to L-amino acids was analyzed in feces and blood from patients with ulcerative colitis (UC) and healthy controls. Also, composition of microbe was analyzed from patients with UC. Mice were treated with D-amino acid in dextran sulfate sodium colitis model and liver cholangitis model. RESULTS: The ratio of D- to L-amino acids was lower in the feces of patients with UC than that of healthy controls. Supplementation of D-amino acids ameliorated UC-related experimental colitis and liver cholangitis by inhibiting growth of Proteobacteria. Addition of D-alanine, a major building block for bacterial cell wall formation, to culture medium inhibited expression of the ftsZ gene required for cell fission in the Proteobacteria Escherichia coli and Klebsiella pneumoniae, thereby inhibiting growth. Overexpression of ftsZ restored growth of E. coli even when D-alanine was present. We found that D-alanine not only inhibited invasion of pathological K. pneumoniae into the host via pore formation in intestinal epithelial cells but also inhibited growth of E. coli and generation of antibiotic-resistant strains. CONCLUSIONS: D-amino acids might have potential for use in novel therapeutic approaches targeting Proteobacteria-associated dysbiosis and antibiotic-resistant bacterial diseases by means of their effects on the intestinal microbiota community.

Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development.

Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differentiation of T cells is well established, the mechanisms preventing it from occurring in the LP remain unclear. Here, we show that chemokine receptor 9 (CCR9) expression is low in epithelial CD4+CD8αα+ IELs, but CCR9 deficiency results in CD4+CD8αα+ over-differentiation in both the epithelium and the LP. Single-cell RNA sequencing shows an enriched precursor cell cluster for CD4+CD8αα+ IELs in Ccr9-/- mice. CD4+ T cells isolated from the epithelium of Ccr9-/- mice also display increased expression of Cbfß2, and the genomic occupancy modification of Cbfß2 expression reveals its important function in CD4+CD8αα+ differentiation. These results implicate a link between CCR9 downregulation and Cbfb2 splicing upregulation to enhance CD4+CD8αα+ IEL differentiation.

A Roadmap for the Human Gut Cell Atlas.

The number of studies investigating the human gastrointestinal tract using various single-cell profiling methods has increased substantially in the past few years. Although this increase provides a unique opportunity for the generation of the first comprehensive Human Gut Cell Atlas (HGCA), there remains a range of major challenges ahead. Above all, the ultimate success will largely depend on a structured and coordinated approach that aligns global efforts undertaken by a large number of research groups. In this Roadmap, we discuss a comprehensive forward-thinking direction for the generation of the HGCA on behalf of the Gut Biological Network of the Human Cell Atlas. Based on the consensus opinion of experts from across the globe, we outline the main requirements for the first complete HGCA by summarizing existing data sets and highlighting anatomical regions and/or tissues with limited coverage. We provide recommendations for future studies and discuss key methodologies and the importance of integrating the healthy gut atlas with related diseases and gut organoids. Importantly, we critically overview the computational tools available and provide recommendations to overcome key challenges.

Risk of venous thromboembolism with a central venous catheter in hospitalized Japanese patients with inflammatory bowel disease: a propensity score-matched cohort study.

BACKGROUND/AIMS: Thromboprophylaxis is recommended for hospitalized patients with inflammatory bowel disease (IBD) in Western countries, although it is selectively administered to high-risk patients in East Asia. A central venous catheter (CVC) is commonly placed in patients with IBD. Although CVC placement is considered a risk factor for venous thromboembolism (VTE), the degree of increased risk in patients with IBD is uncertain. This study aimed to identify the risk of VTE with CVC placement in hospitalized Japanese patients with IBD without thromboprophylaxis. METHODS: This retrospective cohort study included patients with ulcerative colitis or Crohn's disease who were admitted for disease flares at Keio University Hospital between January 2016 and December 2020. Patients who already had thrombosis or were administered any antithrombotic treatment on admission were excluded. VTE development during the hospitalization was surveyed, and VTE risk associated with CVC indwelling was estimated using propensity score matching and inverse probability of treatment weighting analyses. RESULTS: Altogether, 497 hospitalized patients with IBD (ulcerative colitis, 327; Crohn's disease, 170) were enrolled. VTE developed in 9.30% (12/129) of catheterized patients and in 0.82% (3/368) of non-catheterized patients. The propensity score matching yielded 127 matched pairs of patients. The catheterized group demonstrated higher odds for VTE than the non-catheterized group (odds ratio, 13.15; 95% confidence interval, 1.68-102.70). A similar result was obtained in the inverse probability of treatment weighting analysis (odds ratio, 11.02; 95% confidence interval, 2.64-46.10). CONCLUSIONS: CVC placement is a major risk factor for VTE among hospitalized Japanese patients with IBD without thromboprophylaxis.

Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis.

BACKGROUND AND AIMS: Endoscopic remission is known to be defined as a Mayo endoscopic subscore (MES) of ≤1 in patients with ulcerative colitis (UC). However, some individuals experience relapse even after showing endoscopic remission under white-light imaging (WLI), and no tool exists that can detect these individuals. The aim of this study was to clarify the usefulness of texture and color enhancement imaging (TXI) in the assessment of inflammation in patients with UC. METHODS: This was a prospective, single-arm, observational study conducted at a university hospital. From January 2021 to December 2021, 146 UC patients with endoscopic remission were enrolled. Images were evaluated by WLI, TXI, and pathologic evaluation, followed by prognostic studies. The primary endpoint of the study was the cumulative relapse of UC in each TXI score. The secondary endpoints were the association between TXI and pathologic scores, predictors of relapse, and interobserver agreement between the MES and TXI scores. RESULTS: Patients with TXI score 2 had significantly lower UC relapse-free rates than did those with TXI scores 0-1 (log-rank test, P < .01). When pathologic remission was defined as Matts grade ≤2, the rate of pathologic remission decreased significantly with higher TXI scores (P = .01). In multivariate analysis, TXI score 2 was the only risk factor for UC relapse (P < .01; hazard ratio, 4.16; 95% confidence interval, 1.72-10.04). Interobserver agreement on the TXI score was good (κ = 0.597-0.823). CONCLUSION: TXI can be used to identify populations with poor prognosis in MES 1, for whom treatment intensification has been controversial.

Feasibility and Safety of Endoscopic Ischemic Polypectomy and Clinical Outcomes in Patients with Peutz-Jeghers Syndrome (with Video).

OBJECTIVES: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant hereditary disease with a clinical features related to gastrointestinal (GI) hamartomatous polyposis, frequently observed in the small bowel. Balloon-assisted enteroscopy (BAE) has made non-surgical treatment of GI polyps possible. Endoscopic mucosal resection (EMR) has been performed but was associated with complications and difficulties. Recently, endoscopic ischemic polypectomy (EIP) has been developed and its usefulness reported. The study evaluated the feasibility and safety of EIP and the clinical outcomes of patients with PJS. METHODS: We retrospectively collected data of consecutive patients with PJS between September 2009 and March 2021. Data regarding clinical characteristics, follow-up methods, endoscopic management, and complications were collected. EIP feasibility and safety were assessed. RESULTS: Twenty-two patients were included. The observation period was 70 months (range, 5-153). Of the 124 therapeutic endoscopy procedures performed, 68 used BAE. Of the 607 polyps treated, 329 polyps were located in the small bowel. EIP was able to treat a greater number of polyps per patient than EMR (P < 0.003), without any complications, carcinoma, or intussusception in the small bowel (P < 0.001). During the follow-up period, 3 patients developed GI cancer. CONCLUSION: Long-term follow-up in patients with PJS showed that EIP was a feasible and safe technique.

Localization and movement of Tregs in gastrointestinal tract: a systematic review.

BACKGROUND: The intestine is rich in food-derived and microbe-derived antigens. Regulatory T cells (Tregs) are an essential T-cell population that prevents systemic autoimmune diseases and inhibits inflammation by encountering antigens. Previously, it was reported that the functional loss of Tregs induces systemic inflammation, including inflammatory bowel disease and graft-versus-host disease in human and murine models. However, there is a dearth of information about how Tregs localize in different tissues and suppress effector cells. MAIN BODY: The development of Tregs and their molecular mechanism in the digestive tract have been elucidated earlier using murine genetic models, infectious models, and human samples. Tregs suppress immune and other nonimmune cells through direct effect and cytokine production. The recent development of in vivo imaging technology allows us to visualize how Tregs localize and move in the settings of inflammation and homeostasis. This is important because, according to a recent report, Treg characterization and function are regulated by their location. Tregs located in the proximal intestine and its draining lymph nodes induce tolerance against food antigens, and those located in the distal intestine suppress the inflammation induced by microbial antigens. Taken together, various Tregs are induced in a location-specific manner in the gastrointestinal tract and influence the homeostasis of the gut. CONCLUSION: In this review, we summarize how Tregs are induced in the digestive tract and the application of in vivo Treg imaging to elucidate immune homeostasis in the digestive tract.

Single-cell transcriptomics of human gut T cells identifies cytotoxic CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells.

Cytotoxic CD4+ T cells (CD4-CTLs) show the presence of cytolytic granules, which include the enzymes granzyme and perforin. The cells have a pathogenic and protective role in various diseases, including cancer, viral infection, and autoimmune disease. In mice, cytotoxic CD4+ T cells express CD8αα+ and reside in the intestine (mouse CD4+CTLs; mCD4-CTLs). The population of cytotoxic CD4+ T cells in the human intestine is currently unknown. Moreover, it is unclear how cytotoxic CD4 T cells change in patients with inflammatory bowel disease (IBD). Here, we aimed to identify cytotoxic CD4+ T cells in the human intestine and analyze the characteristics of the population in patients with IBD using single-cell RNA-seq (scRNA-seq). In CD4+ T cells, granzyme and perforin expression was high in humanMAIT (hMAIT) cells and hCD4+CD8A+ T cell cluster. Both CD4 and CD8A were expressed in hTreg, hMAIT, and hCD4+CD8A+ T cell clusters. Next we performed fast gene set enrichment analysis to identify cell populations that showed homology to mCD4CTLs. The analysis identified the hCD4+CD8A+ T cell cluster (hCTL-like population; hCD4-CTL) similar to mouse CTLs. The percentage of CD4+CD8A+ T cells among the total CD4+ T cells in the inflamed intestine of the patients with Crohn's disease was significantly reduced compared with that in the noninflamed intestine of the patients. In summary, we identified cytotoxic CD4+CD8+ T cells in the small intestine of humans. The integration of the mouse and human sc-RNA-seq data analysis highlight an approach to identify human cell populations related to mouse cell populations, which may help determine the functional properties of several human cell populations in mice.