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ObjectiveArtificial intelligence (AI) tools for histological diagnosis offer great potential to healthcare, yet failure to understand their clinical context is delaying adoption. IGUANA (Interpretable Gland-Graphs using a Neural Aggregator) is an AI algorithm that can effectively classify colonic biopsies into normal versus abnormal categories, designed to automatically report normal cases. We performed a retrospective pathological and clinical review of the errors made by IGUANA.MethodsFalse negative (FN) errors were the primary focus due to the greatest propensity for harm. Pathological evaluation involved assessment of whole slide image (WSI) quality, precise diagnoses for each missed entity and identification of factors impeding diagnosis. Clinical evaluation scored the impact of each error on the patient and detailed the type of impact in terms of missed diagnosis, investigations or treatment.ResultsAcross 5054 WSIs from 2080 UK National Health Service patients there were 220 FN errors across 164 cases (4.4% of WSI, 7.9% of cases). Diagnostic errors varied from cases of adenocarcinoma to mild inflammation. 88.4% of FN errors would have no impact on patient care, with only one error causing major patient harm. Factors that protected against harm included biopsies being low-risk polyps or diagnostic features were detected in other biopsies.ConclusionMost FN errors would not result in patient harm, suggesting that even with a 7.9% case-level error rate, this AI tool might be more suitable for adoption than statistics portray. Consideration of the clinical context of AI tool errors is essential to facilitate safe implementation.

Colorectal cancer (CRC) is a heterogeneous disease, including at least three major forms: hereditary, sporadic and colitis-associated CRC. A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC. As elevated cyclooxygenase-2 (COX-2) expression was found in most CRC tissue and is associated with worse survival among CRC patients, investigators have sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXIBs) on CRC. The epidemiological studies, clinical trials and animal experiments indicate that NSAIDs are among the most promising chemopreventive agents for this disease. NSAIDs exert their anti-inflammatory and antitumor effects primarily by reducing prostaglandin production by inhibition of COX-2 activity. In this review, we highlight breakthroughs in our understanding of the roles of COX-2 in CRC and inflammatory bowel disease. These recent data provide a rationale for re-evaluating COX-2 as both the prognostic and the predictive marker in a wide variety of malignancies and for renewing the interest in evaluating relative benefits and risk of COXIBs in appropriately selected patients for cancer prevention and treatment.

Colorectal cancer (CRC) is the third most common cancer worldwide and its incidence is expected to increase by almost 80% by 2030. CRC apparition is related to poor diet, mainly due to low consumption of phytochemicals present in fruits and vegetables. Hence, this paper reviews the most promising phytochemicals in the literature, presenting scientific evidence regarding potential CRC chemopreventive effects. Moreover, this paper reveals the structure and action of CRC mechanisms that these phytochemicals are involved in. The review reveals that vegetables rich in phytochemicals such as carrots and green leafy vegetables, as well as some fruits such as pineapple, citrus fruits, papaya, mango, and Cape gooseberry, that have antioxidant, anti-inflammatory, and chemopreventive properties can promote a healthy colonic environment. Fruits and vegetables in the daily diet promote antitumor mechanisms by regulating cell signaling and/or proliferation pathways. Hence, daily consumption of these plant products is recommended to reduce the risk of CRC.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to more than 200 countries and regions globally. SARS-CoV-2 is thought to spread mainly through respiratory droplets and close contact. However, reports have shown that a notable proportion of patients with coronavirus disease 2019 (COVID-19) develop gastrointestinal symptoms and nearly half of patients confirmed to have COVID-19 have shown detectable SARS-CoV-2 RNA in their faecal samples. Moreover, SARS-CoV-2 infection reportedly alters intestinal microbiota, which correlated with the expression of inflammatory factors. Furthermore, multiple in vitro and in vivo animal studies have provided direct evidence of intestinal infection by SARS-CoV-2. These lines of evidence highlight the nature of SARS-CoV-2 gastrointestinal infection and its potential faecal–oral transmission. Here, we summarize the current findings on the gastrointestinal manifestations of COVID-19 and its possible mechanisms. We also discuss how SARS-CoV-2 gastrointestinal infection might occur and the current evidence and future studies needed to establish the occurrence of faecal–oral transmission. Although COVID-19 is a respiratory disease and its causative agent, SARS-CoV-2, principally infects the respiratory tract, extrapulmonary manifestations are observed. This Perspective explores the gastrointestinal symptoms associated with COVID-19 and the putative underlying mechanisms, discussing experimental evidence on SARS-COV-2 gastrointestinal infection and the potential for faecal–oral transmission.

Desulfovibrio (DSV) are sulfate-reducing bacteria (SRB) that are ubiquitously present in the environment and as resident commensal bacteria within the human gastrointestinal tract. Though they are minor residents of the healthy gut, DSV are opportunistic pathobionts that may overgrow in the setting of various intestinal and extra-intestinal diseases. An increasing number of studies have demonstrated a positive correlation between DSV overgrowth (bloom) and various human diseases. While the relationship between DSV bloom and disease pathology has not been clearly established, mounting evidence suggests a causal role for these bacteria in disease development. As DSV are the most predominant genera of SRB in the gut, this review summarizes current knowledge regarding the relationship between DSV and a variety of diseases. In this study, we also discuss the mechanisms by which these bacteria may contribute to disease pathology.

Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut- innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other's functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.

Background Micro- and nanoplastic pollution has become a global environmental problem. Nanoplastics in the environment are still hard to detect because of analysis technology limitations. It is believed that when microplastics are found in the environment, more undetected nanoplastics are around. The current “microplastic exposure” is in fact the mixture of micro- and nanoplastic exposures. Therefore, the biological interaction between organisms among different sizes of micro- and nanoplastics should not be neglected. Results We measured the biodistribution of three polystyrene (PS) particles (50 nm PS, PS50; 500 nm PS, PS500; 5000 nm PS, PS5000) under single and co-exposure conditions in mice. We explored the underlying mechanisms by investigating the effects on three major components of the intestinal barrier (the mucus layer, tight junctions and the epithelial cells) in four intestine segments (duodenum, jejunum, ileum and colon) of mice. We found that the amounts of both PS500 and PS5000 increased when they were co-exposed with PS50 for 24 h in the mice. These increased amounts were due primarily to the increased permeability in the mouse intestines. We also confirmed there was a combined toxicity of PS50 and PS500 in the mouse intestines. This manifested as the mixture of PS50 and PS500 causing more severe dysfunction of the intestinal barrier than that caused by PS50 or PS500 alone. We found that the combined toxicity of PS micro- and nanoplastics on intestinal barrier dysfunction was caused primarily by reactive oxygen species (ROS)-mediated epithelial cell apoptosis in the mice. These findings were further confirmed by an oxidants or antioxidants pretreatment study. In addition, the combined toxicity of PS micro- and nanoplastics was also found in the mice after a 28-day repeated dose exposure. Conclusions There is a combined toxicity of PS50 and PS500 in the mouse intestines, which was caused primarily by ROS-mediated epithelial cell apoptosis in the mice. Considering that most recent studies on PS micro- and nanoplastics have been conducted using a single particle size, the health risks of exposure to PS micro- and nanoplastics on organisms may be underestimated.

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn , and limited the upregulation of inflammation amplifiers, including S100A8 , Lcn2 , Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD. Lucas and colleagues describe loss-of-function variants in the X-linked ETS transcription factor ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD)-like features.

Intestinal diseases, such as Crohn's disease (CD), ulcerative colitis (UC) and pseudomembranous colitis (CDI), are among the most common diseases in humans and may lead to more serious pathologies, e.g. colorectal cancer (CRC). Next generation sequencing has in recent years allowed the identification of correlations between intestinal bacteria and diseases, although the formulation of universal gut microbial biomarkers for such diseases is only in its infancy. In the current study, we selected and reanalyzed a total of 3048 public datasets obtained from 16S rRNA profiling of individuals affected by CD, UC, CDI and CRC. This meta-analysis revealed possible biases in the reconstruction of the gut microbiota composition due to the use of different primer pairs employed for PCR of 16S rRNA gene fragments. Notably, this approach also identified common features of individuals affected by gut diseases (DS), including lower biodiversity compared to control subjects. Moreover, potential universal intestinal disease microbial biomarkers were identified through cross-disease comparisons. In detail, CTRL showed high abundance of the genera Barnesiella, Ruminococcaceae UCG-005, Alistipes, Christensenellaceae R-7 group and unclassified member of Lachnospiraceae family, while DS exhibited high abundance of Lactobacillus, unclassified member of Erysipelotrichaceae family and Streptococcus genera.

Vascular cell adhesion molecule (VCAM)-1 has garnered significant research attention due to its potential as a disease biomarker and drug target across several inflammatory pathologies—including atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease (IBD). The VCAM-1 protein has also been noted for its functional involvement in cancer metastasis and drug resistance to conventional chemotherapeutics. Although the anti-inflammatory and anti-cancer facets of VCAM-1 antagonisation have been examined separately, there is yet to be a review that explicitly addresses the functional interrelationship between these mechanisms. Furthermore, the pleiotropic mechanisms of anti-VCAM-1 therapies may present a useful paradigm for designing drug candidates with synergistic anti-inflammatory and anti-tumorigenic effects. The pathological overlap between inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC) serves as the quintessential disease model to observe this therapeutic duality. This review thereby details the adhesive mechanisms of VCAM-1 in colorectal disease—specifically, driving immune cell infiltration during IBD and tumour cell metastasis in CRC—and posits the potential of this receptor as a common drug target for both diseases. To explore this hypothesis, the current progress of novel VCAM-1-directed drug candidates in experimental models of IBD and CRC is also discussed. Graphical Abstract TOC Figure: Graphical abstract illustrating the multi-functional role of vascular cell adhesion molecule (VCAM)-1 in colorectal diseases. VCAM-1 facilitates adhesive cell-to-cell attachments via a receptor-ligand binding mechanism with its complementary integrin ligands, α 4 β 1 and α 4 β 7 . These VCAM-1-mediated interactions are involved in both inflammatory cell recruitment during inflammatory bowel disease (IBD) and cancer cell metastasis in colorectal cancer (CRC), highlighting the therapeutic potential of VCAM-1 as a drug target for both pathologies