The gut microbiota and diabetes: research, translation, and clinical applications - 2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum.

This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

Review article: Management of the child with refractory constipation.

BACKGROUND: Caring for children with constipation refractory to conventional treatment can be challenging and management practices vary widely. AIMS: To review recent advances in the evaluation and treatment of children with refractory constipation and to propose an algorithm that incorporates the latest evidence and our institutional experience. METHODS: We performed a literature review on diagnostic tests and treatment options for children with refractory constipation. RESULTS: Evaluation of a child with refractory constipation seeks to better understand factors contributing to an individual child's presentation. Anorectal manometry evaluating for a rectal evacuation disorder and colonic manometry evaluating for colonic dysmotility can guide subsequent treatment. For the child who has not responded to conventional treatment, a trial of newer medications like linaclotide can be helpful. Transanal irrigation offers a safe and effective alternative for families able to administer daily rectal treatment. Despite mixed evidence in children, pelvic floor biofeedback therapy can help some children with pelvic floor dyssynergia. For younger children unable to cooperate with pelvic floor therapy, or older children with refractory symptoms, internal anal sphincter botulinum toxin injection can be beneficial. Antegrade continence enema treatment can be effective for children with either normal colonic motility or segmental dysmotility. Sacral nerve stimulation is generally reserved for symptoms that persist despite antegrade continence enemas, particularly if faecal incontinence is prominent. In more severe cases, temporary or permanent colonic diversion and segmental colonic resection may be needed. CONCLUSIONS: Recent advances offer hope for children with refractory constipation.

The colon targeting efficacies of mesalazine medications and their impacts on the gut microbiome.

Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.

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.

Organoid Culture of Different Intestinal Segments from Human and Mouse.

The intestine comprises distinct segments, each characterized by unique cell populations and functions. Intestinal organoids faithfully replicate the cellular composition and functions of the intestine. Over the past decade, the organoid model has garnered considerable attention for its application in investigation of organ development, renewal and functional performance. While the organoid culture systems for mouse small intestine and human large intestine have widely adopted, a comparison summary for different segments of the human or mouse intestine is lacking. In this study, we present a systematically detailed culture methodology for intestinal organoids, encompassing both the small intestine and the large intestine from humans or mice. This method provides a robust in vitro tool for intestinal research, and expands the possible clinical application of organoids.

Perineuronal net in the extrinsic innervation of the distal colon of mice and its remodeling in ulcerative colitis.

The perineuronal net (PNN) is a well-described highly specialized extracellular matrix structure found in the central nervous system. Thus far, no reports of its presence or connection to pathological processes have been described in the peripheral nervous system. Our study demonstrates the presence of a PNN in the spinal afferent innervation of the distal colon of mice and characterizes structural and morphological alterations induced in an ulcerative colitis (UC) model. C57Bl/6 mice were given 3% dextran sulfate sodium (DSS) to induce acute or chronic UC. L6/S1 dorsal root ganglia (DRG) were collected. PNNs were labeled using fluorescein-conjugated Wisteria Floribunda (WFA) l lectin, and calcitonin gene-related peptide (CGRP) immunofluorescence was used to detect DRG neurons. Most DRG cell bodies and their extensions toward peripheral nerves were found surrounded by the PNN-like structure (WFA+), labeling neurons' cytoplasm and the pericellular surfaces. The amount of WFA+ neuronal cell bodies was increased in both acute and chronic UC, and the PNN-like structure around cell bodies was thicker in UC groups. In conclusion, a PNN-like structure around DRG neuronal cell bodies was described and found modulated by UC, as changes in quantity, morphology, and expression profile of the PNN were detected, suggesting a potential role in sensory neuron peripheral sensitization, possibly modulating the pain profile of ulcerative colitis.

Systematic scoping review: Use of the faecal immunochemical test residual buffer to enhance colorectal cancer screening.

BACKGROUND: The faecal immunochemical test (FIT) is an inexpensive and convenient modality to screen for colorectal cancer. However, its one-time sensitivity for detecting colorectal cancer and cancer precursors is limited. There is growing interest in using the non-haemoglobin contents of FIT residual buffer to enhance colonic neoplasia detection. AIM: To establish from the literature a framework to catalogue candidate biomarkers within FIT residual buffer for non-invasive colorectal cancer screening. METHODS: The search strategy evaluated PubMed, Scopus, Web of Science, Embase, and Google Scholar for publications through 25 October 2023, with search terms including FIT, buffer, OC-sensor, biomarkers, microbiome, microRNA (miR), colon, rectum, screening, neoplasm, and early detection. Studies employing home-based collection samples using quantitative FIT first processed for haemoglobin were included. One author reviewed all articles; a second author completed a 20% full-text audit to ensure adherence to eligibility criteria. RESULTS: A broad search yielded 1669 studies and application of eligibility criteria identified 18 relevant studies. Multiple protein, DNA/RNA, and microbiome biomarkers (notably haptoglobin, miR-16, miR-27a-3p, miR-92a, miR-148a-3p, miR-223, miR-421, let-7b-5p, and Tyzzerella 4) were associated with colorectal neoplasia. Furthermore, studies highlighted the short-term stability of biomarkers for clinical use and long-term stability for research purposes. CONCLUSIONS: This scoping review summarises the framework and progress of research on stability of biomarkers in FIT residual buffer and their associations with colorectal neoplasia to guide opportunities for further confirmatory studies to enhance colorectal cancer screening.

Regional differences in the ultrastructure of mucosal macrophages in the rat large intestine.

We previously clarified the histological characteristics of macrophages in the rat small intestine using serial block-face scanning electron microscopy (SBF-SEM). However, the regional differences in the characteristics of macrophages throughout the large intestine remain unknown. Here, we performed a pilot study to explore the regional differences in the ultrastructure of mucosal macrophages in the large intestine by using SBF-SEM analysis. SBF-SEM analysis conducted on the luminal side of the cecum and descending colon revealed macrophages as amorphous cells possessing abundant lysosomes and vacuoles. Macrophages in the cecum exhibited a higher abundance of lysosomes and a lower abundance of vacuoles than those in the descending colon. Macrophages with many intraepithelial cellular processes were observed beneath the intestinal superficial epithelium in the descending colon. Moreover, macrophages in contact with nerve fibers were more prevalent in the cecum than in the descending colon, and a subset of them surrounded a nerve bundle only in the cecum. In conclusion, the present pilot study suggested that the quantity of some organelles (lysosomes and vacuoles) in macrophages differed between the cecum and the descending colon and that there were some region-specific subsets of macrophages like nerve-associated macrophages in the cecum.

Effects of Resistant Starch Infusion, Solely and Mixed with Xylan or Cellulose, on Gut Microbiota Composition in Ileum-Cannulated Pigs.

Fermentation of dietary fiber (DF) is beneficial for gut health, but its prebiotic effects are often impeded in the distal large intestine because of the fast degradation of fermentable substrates. One way to enhance the prebiotic effect of DF is to deliver fibers to the lower parts of the gut, which can be achieved by mixing different kinds of fiber. Therefore, in the present study, an ileum-cannulated pig model was employed to investigate the fermentation influence in the large intestine by infusing resistant starch solely (RS, fast fermentable fiber) and mixing with other fibers (xylan or cellulose). Twenty-four ileum-cannulated growing pigs were divided into four groups: one control group receiving saline ileal infusions and three experimental groups infused with RS, RS with xylan, or RS with cellulose. Fecal and plasma samples were analyzed for gut microbiota composition, short-chain fatty acids (SCFAs), and blood biochemistry. Results indicated no significant differences between the RS and control group for the microbiome and SCFA concentration (p > 0.05). However, RS combined with fibers, particularly xylan, resulted in enhanced and prolonged fermentation, marked by an increase in Blautia and higher lactate and acetate production (p < 0.05). In contrast, RS with cellulose infusion enriched bacterial diversity in feces (p < 0.05). Blood biochemistry parameters showed no significant differences across groups (p > 0.05), though a trend of increased glucose levels was noted in the treatment groups (p < 0.1). Overall, RS alone had a limited impact on the distal hindgut microbiota due to rapid fermentation in the proximal gut, whereas combining RS with other fibers notably improved gut microecology by extending the fermentation process.

Exploring the relationship between intestinal microbiota and immune checkpoint inhibitors in the treatment of non-small cell lung cancer: insights from the "lung and large intestine stand in exterior-interior relationship" theory.

Objective: This study is aim to discern the Traditional Chinese Medicine (TCM) syndrome classifications relevant to immunotherapy sensitive in non-small cell lung cancer (NSCLC) patients, and to delineate intestinal microbiota biomarkers and impact that wield influence over the efficacy of NSCLC immunotherapy, grounded in the TCM theory of "lung and large intestine stand in exterior-interior relationship." Methods: The study cohort consisted of patients with advanced NSCLC who received treatment at the Oncology Department of Chengdu Fifth People's Hospital. These patients were categorized into distinct TCM syndrome types and subsequently administered immune checkpoint inhibitors (ICIs), specifically PD-1 inhibitors. Stool specimens were collected from patients both prior to and following treatment. To scrutinize the differences in microbial gene sequences and species of the intestinal microbiota, 16S rRNA amplicon sequencing technology was employed. Additionally, peripheral blood samples were collected, and the analysis encompassed the assessment of T lymphocyte subsets and myeloid suppressor cell subsets via flow cytometry. Subsequently, alterations in the immune microenvironment pre- and post-treatment were thoroughly analyzed. Results: The predominant clinical manifestations of advanced NSCLC patients encompassed spleen-lung Qi deficiency syndrome and Qi-Yin deficiency syndrome. Notably, the latter exhibited enhanced responsiveness to ICIs with a discernible amelioration of the immune microenvironment. Following ICIs treatment, significant variations in microbial abundance were identified among the three strains: Clostridia, Lachnospiraceae, and Lachnospirales, with a mutual dependency relationship. In the subset of patients manifesting positive PD-L1 expression and enduring therapeutic benefits, the study recorded marked increases in the ratios of CD3+%, CD4+%, and CD4+/CD8+ within the T lymphocyte subsets. Conversely, reductions were observed in the ratios of CD8%, Treg/CD4+, M-MDSC/MDSC, and G-MDSC/MDSC. Conclusion: The strains Clostridia, Lachnospiraceae, and Lachnospirales emerge as potential biomarkers denoting the composition of the intestinal microbiota in the NSCLC therapy. The immunotherapy efficacy of ICIs markedly accentuates in patients displaying durable treatment benefits and those expressing positive PD-L1.

Recent Updates on the Therapeutics Benefits, Clinical Trials, and Novel Delivery Systems of Chlorogenic Acid for the Management of Diseases with a Special Emphasis on Ulcerative Colitis.

Ulcerative colitis (UC) is a multifactorial disorder of the large intestine, especially the colon, and has become a challenge globally. Allopathic medicines are primarily available for the treatment and prevention of UC. However, their uses are limited due to several side effects. Hence, an alternative therapy is of utmost importance in this regard. Herbal medicines are considered safe and effective for managing human health problems. Chlorogenic acid (CGA), the herbal-derived bioactive, has been reported for pharmacological effects like antiinflammatory, immunomodulatory, antimicrobial, hepatoprotective, antioxidant, anticancer, etc. This review aims to understand the antiinflammatory and chemopreventive potential of CGA against UC. Apart from its excellent therapeutic potential, it has been associated with low absorption and poor oral bioavailability. In this context, colon-specific novel drug delivery systems (NDDS)are pioneering to overcome these problems. The pertinent literature was compiled from a thorough search on various databases such as ScienceDirect, PubMed, Google Scholar, etc., utilizing numerous keywords, including ulcerative colitis, herbal drugs, CGA, pharmacological activities, mechanism of actions, nanoformulations, clinical updates, and many others. Relevant publications accessed till now were chosen, whereas non-relevant papers, unpublished data, and non-original articles were excluded. The present review comprises recent studies on pharmacological activities and novel drug delivery systems of CGA for managing UC. In addition, the clinical trials of CGA against UC have been discussed.

An exploration of the effect of Chinese herbal compound on the occurrence and development of large intestine cancer and intestinal flora.

This study was conducted to observe the effect of Chinese herbal compound on the treatment of colon cancer using AOM/DSS-induced C57BL/6J colon cancer mice and to validate potential influence on intestinal flora of mice. A colorectal cancer (CRC) mouse model was built with a total of 50 C57BL/6J mice that were induced by administrating AOM/DSS. These experimental animals were split up into 5 groups, a control group, a model group, and low-, medium- and high-dose Chinese herbal compound groups. All mice were given Chinese herbal compound treatment, and the colon tissues of each group were harvested with the length measured and the number of colon polyps accounted. The Ki-67 expression in the colon tissues was detected via immuno-histochemistry. Relative quantification of the expression of genes and proteins was determined through qPCR and WB assays. Contents of IL-6, TNF-α, IFN-γ, and IL-10 in serum and colon tissues of mice were determined by ELISA. An additional 16S rRNA sequencing analysis was implemented for the identification of mouse intestinal flora. The results suggested that all low-, medium- or high-dose Chinese herbal compound could markedly inhibit the shortening of colon length and significant number reduction of colon polyps in the model group. The relative expression of genes and proteins (PCNA, Muc16, and MMP-9) associated with proliferation in mouse colon tissues were inhibited. In addition, compared with the model group, the contents of IL-6, TNF-α, and IFN-γ in serum and colon tissues were substantially decreased in the high-dose Chinese herbal compound group, thereby reducing the structure damage in colon tissues and the infiltration degree of inflammatory cells. Besides, the expression of TLR4/MyD88/NF-κB protein was markedly decreased. The 16S rRNA sequencing analysis demonstrated that mice in the model group had decreased intestinal flora diversity, and there were significant changes in flora abundance and amino acid metabolism between the control group and the model group. Taken together, the treatment of Chinese herbal compound against CRC in this study might be regulated by the TLR4/MyD88/NF-κB signaling pathway, and the imbalance in intestinal flora was also closely related to CRC occurrence.

Canine Mucosal Artificial Colon: development of a new colonic in vitro model adapted to dog sizes.

Differences in dog breed sizes are an important determinant of variations in digestive physiology, mainly related to the large intestine. In vitro gut models are increasingly used as alternatives to animal experiments for technical, cost, societal, and regulatory reasons. Up to now, only one in vitro model of the canine colon incorporates the dynamics of different canine gut regions, yet no adaptations exist to reproduce size-related digestive parameters. To address this limitation, we developed a new model of the canine colon, the CANIne Mucosal ARtificial COLon (CANIM-ARCOL), simulating main physiochemical (pH, transit time, anaerobiosis), nutritional (ileal effluent composition), and microbial (lumen and mucus-associated microbiota) parameters of this ecosystem and adapted to three dog sizes (i.e., small under 10 kg, medium 10-30 kg, and large over 30 kg). To validate the new model regarding microbiota composition and activities, in vitro fermentations were performed in bioreactors inoculated with stools from 13 dogs (4 small, 5 medium, and 4 large). After a stabilization period, microbiota profiles clearly clustered depending on dog size. Bacteroidota and Firmicutes abundances were positively correlated with dog size both in vitro and in vivo, while opposite trends were observed for Actinobacteria and Proteobacteria. As observed in vivo, microbial activity also increased with dog size in vitro, as evidenced from gas production, short-chain fatty acids, ammonia, and bile acid dehydroxylation. In line with the 3R regulation, CANIM-ARCOL could be a relevant platform to assess bilateral interactions between food and pharma compounds and gut microbiota, capturing inter-individual or breed variabilities. KEY POINTS: • CANIM-ARCOL integrates main canine physicochemical and microbial colonic parameters • Gut microbiota associated to different dog sizes is accurately maintained in vitro • The model can help to move toward personalized approach considering dog body weight.

Efficacy and safety of lubiprostone for the treatment of chronic idiopathic constipation: A phase 3, randomized, placebo-controlled study.

INTRODUCTION: Chronic idiopathic constipation (CIC) negatively impacts quality of life and increases healthcare costs. Lubiprostone stimulates the secretion of intestinal fluid, in turn facilitating the passage of stools and alleviating associated symptoms. Lubiprostone has been available in Mexico since 2018, but its clinical efficacy has not been studied in a Mexican population. AIM: To evaluate the efficacy of lubiprostone, assessed by changes in spontaneous bowel movement (SBM) frequency after one week of treatment with 24 µg oral lubiprostone (b.i.d.), as well as its safety, over four weeks of treatment. STUDY: Randomized, double-blind, placebo-controlled study on 211 adults with CIC in Mexico. RESULTS: The increase in SBM frequency, after one week of treatment, was significantly higher in the lubiprostone group than in the placebo group (mean: 4.9 [SD: 4.45] vs. 3.0 [3.14], p = 0.020). Secondary efficacy endpoints revealed a significantly higher proportion of SBM frequency/week in the lubiprostone group at weeks 2, 3, and 4. There was a better response within 24 h after the first dose with lubiprostone vs. placebo (60.0% vs. 41.5%; OR: 2.08, CI95%: [1.19, 3.62], p = 0.009) and the lubiprostone group also had significant improvement, with respect to straining, stool consistency, abdominal bloating, and Satisfaction Index. The main adverse events were gastrointestinal disorders in 13 (12.4%) lubiprostone-treated subjects and 4 (3.8%) control subjects. CONCLUSIONS: Our data confirm the efficacy and safety of lubiprostone for the treatment of CIC in a Mexican population. Lubiprostone treatment induces relief from the most bothersome symptoms associated with constipation.

Regulation of chlamydial spreading from the small intestine to the large intestine by IL-22-producing CD4+ T cells.

Following an oral inoculation, Chlamydia muridarum descends to the mouse large intestine for long-lasting colonization. However, a mutant C. muridarum that lacks the plasmid-encoded protein pGP3 due to an engineered premature stop codon (designated as CMpGP3S) failed to do so even following an intrajejunal inoculation. This was because a CD4+ T cell-dependent immunity prevented the spread of CMpGP3S from the small intestine to the large intestine. In the current study, we found that mice deficient in IL-22 (IL-22-/-) allowed CMpGP3S to spread from the small intestine to the large intestine on day 3 after intrajejunal inoculation, indicating a critical role of IL-22 in regulating the chlamydial spread. The responsible IL-22 is produced by CD4+ T cells since IL-22-/- mice were rescued to block the CMpGP3S spread by donor CD4+ T cells from C57BL/6J mice. Consistently, CD4+ T cells lacking IL-22 failed to block the spread of CMpGP3S in Rag2-/- mice, while IL-22-competent CD4+ T cells did block. Furthermore, mice deficient in cathelicidin-related antimicrobial peptide (CRAMP) permitted the CMpGP3S spread, but donor CD4+ T cells from CRAMP-/- mice were still sufficient for preventing the CMpGP3S spread in Rag2-/- mice, indicating a critical role of CRAMP in regulating chlamydial spreading, and the responsible CRAMP is not produced by CD4+ T cells. Thus, the IL-22-producing CD4+ T cell-dependent regulation of chlamydial spreading correlated with CRAMP produced by non-CD4+ T cells. These findings provide a platform for further characterizing the subset(s) of CD4+ T cells responsible for regulating bacterial spreading in the intestine.

Morphology of the small and large intestines of the six-banded armadillo (Euphractus sexcinctus) Linnaeus, 1758.

Euphractus sexcinctus has a diverse diet, so it needs anatomical and habitual features to help it get its meals. Therefore, the objective is to study the morphology of the small and large intestines of the six-banded armadillo (E. sexcinctus). The research was authorized and approved under number 136/16. Six animals, obtained from victims of predatory hunting, were dissected for the research. For the anatomical analysis, the specimens were dissected and photographed. The fragments of each organ were submitted to histological routine to obtain slides stained with hematoxylin-eosin, toluidine blue and Masson's trichrome for further analysis. The small intestine has three parts: duodenum, jejunum, and ileum. Histologically, it has the typical four layers of tubular organs. The mucosa is covered by simple cylindrical epithelium with the presence of specializations in the form of microvilli and variation in the number of goblet cells, depending on the portion observed. In the duodenal portion, the presence of the serous layer was not observed. In the jejunal portion, it is possible to observe lymphoid tissue aggregates in the submucosa, which become more evident in the ileum. The large intestine is divided into cecum, colon, and rectum and has the same histological subdivisions as the small intestine, but with some specializations. The presence of simple cylindrical intestinal crypts is clearly observed and the presence of a large number of goblet cells, which increase as it approaches the rectum. In the submucosa of the large intestine, the presence of organized lymphoid plaques is detected. RESEARCH HIGHLIGHTS: The presence of large numbers of goblet cells, which increase as one approaches the rectum. The presence of organized lymphoid plaques is detected. The duodenal portion was not observed presence of the serous layer.

Metastatic pancreatic cancer with multiple metastases confined to the large intestine: a case report and literature review.

The incidence and mortality rate of pancreatic cancer are increasing worldwide. Regional lymph nodes, liver, lung, and peritoneum are common sites of metastasis from pancreatic cancer, but the gastrointestinal tract is rare as a metastatic organ from pancreatic cancer. An 80-year-old man was referred to our department for a hypovascular pancreatic mass on contrast-enhanced computed tomography (CECT). Endoscopic ultrasound-guided fine needle aspiration revealed adenocarcinoma, and he was diagnosed with pancreatic cancer. No lymph nodes or distant metastases were detected by either CECT or gadolinium-enhanced magnetic resonance imaging, and we evaluated this case as borderline resectable. However, total colonoscopy for positive fecal occult blood tests revealed a reddish and hemorrhagic mucosal thickening in the ascending and sigmoid colon and rectum, which was inconsistent with primary colorectal cancer. Biopsy specimens from these sites revealed cytokeratin (CK)7-positive and CK20- and CDX2-negative adenocarcinoma, consistent with cancer of pancreatic origin. The patient underwent palliative chemotherapy with gemcitabine but died from COVID-19 infection eight months after diagnosis. Performing total colonoscopy as a preoperative screening is important for accurate cancer staging of patients with possible resectable pancreatic cancer.

Review article: Emerging insights into the epidemiology, pathophysiology, diagnostic and therapeutic aspects of eosinophilic oesophagitis and other eosinophilic gastrointestinal diseases.

BACKGROUND: Eosinophilic gastrointestinal diseases (EGIDs) are chronic, immune-mediated disorders characterised clinically by gastrointestinal symptoms and histologically by a pathologic increase in eosinophil-predominant inflammation in the gastrointestinal tract, in the absence of secondary causes of eosinophilia. AIMS: To highlight emerging insights and research efforts into the epidemiology, pathophysiology, diagnostic and therapeutic aspects of eosinophilic oesophagitis (EoE) and non-EoE EGIDs, and discuss key remaining knowledge gaps. METHODS: We selected and reviewed original research, retrospective studies, case series, randomised controlled trials, and meta-analyses. RESULTS: Standardised nomenclature classifies EGIDs as EoE, eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). Incidence and prevalence of EoE are rising, emphasising the need to better understand how environmental risk factors and genetic features interact. Advances in understanding EoE pathophysiology have led to clinical trials of targeted therapy and the approval (in the United States) of dupilumab for EoE. Several therapies that are under investigation hope to satisfy both histologic and clinical targets. For non-EoE EGIDs, efforts are focused on better defining clinical and histopathologic disease determinants and natural history, as well as establishing new therapies. CONCLUSIONS: Unmet needs for research are dramatically different for EoE and non-EoE EGIDs. In EoE, non-invasive diagnostic tests, clinicopathologic models that determine the risk of disease progression and therapeutic failure, and novel biologic therapies are emerging. In contrast, in non-EoE EGIDs, epidemiologic trends, diagnostic histopathologic thresholds, and natural history models are still developing for these more rare disorders.

Chinese Medicine Regulates Intestinal Flora to Treat Ulcerative Colitis in Patients with Syndrome of Large Intestine Dampness-heat： A Review / 中国实验方剂学杂志

The clinical changes of ulcerative colitis （UC） with the main syndrome of large intestine dampness-heat and the alterations of intestinal flora in UC were summarized to reveal the underlying mechanism. After review of the treatment methods for UC with the syndrome of large intestine dampness-heat， we identified the representative traditional Chinese medicines and compound prescriptions and explored the treatment mechanisms. Furthermore， we probed into the associations of UC and the treatment methods with the intestinal flora. The related articles were retrieved from China National Knowledge Infrastructure （CNKI）. The available studies have shown that Akkermansia muciniphila， Escherichia coli， Enterococcus， and probiotics such as Bifidobacterium and Lactobacillus are closely associated with Chinese medicines in UC patients with the syndrome of large intestine dampness-heat. However， due to the shortcomings in clinical research and the susceptibility of intestinal flora to diverse factors， it is still challenging to accurately characterize the intestinal flora changes associated with diseases. Additionally， the research on the mechanisms of Chinese medicines in regulating intestinal flora in UC patients with the syndrome of large intestine dampness-heat remains to be improved. The feasibility of using Chinese medicines and compound prescriptions for precise regulation of intestinal flora in these patients is still debatable. In this regard， scientific issues such as the biological connotation of UC with the syndrome of large intestine dampness-heat and the correlation between syndrome and intestinal flora have become primary research tasks. Additionally， attention should also be paid to the interactions between the intestinal lumen exposure profile of Chinese medicines and intestinal flora. Finally， the thinking of traditional Chinese medicine （TCM） and the concepts of modern medicine should be combined for the research on the formulation of TCM regimens for regulating intestinal flora in treating UC.

Connotation of Traditional Chinese Medicine in Treatment of Chronic Obstructive Pulmonary Disease by Regulating Gut Microbiota Based on "Lung and Large Intestine Being Interior-exterior Related" / 中国实验方剂学杂志

Chronic obstructive pulmonary disease （COPD） is a heterogeneous lung condition characterized by persistent and often progressive airflow obstruction， including airway abnormalities （e.g.， bronchitis and bronchiolitis） and chronic respiratory symptoms （e.g.， dyspnea， cough， and expectoration）. It is one of the leading causes of death worldwide. According to the theory of traditional Chinese medicine （TCM）， the lung and large intestine are interior-exterior related. Therefore， COPD can be treated from both the lung and intestine by the methods of tonifying and invigorating lung， spleen， and kidney， dispelling phlegm， and expelling stasis. Gut microbiota plays a key role in human immunity， nerve， and metabolism and may act on COPD by affecting the structures and functions of lung and intestine tissue and regulating lung inflammation and immunity. TCM can restore the balance of gut microbiota， which is conducive to the recovery from COPD. For example， the treatment method of tonifying lung and invigorating kidney can regulate gut microbiota， alleviate pulmonary and intestinal injuries， and improve lung immunity. The treatment methods of dispelling phlegm and expelling stasis can regulate gut microbiota and reduce pulmonary inflammation. According to the TCM theory of lung and large intestine being interior-exterior related， this review elaborates on the connotation of TCM in the treatment of COPD by regulating gut microbiota， aiming to provide new ideas for the clinical treatment of COPD via gut microbiota.