Dysbiosis and pathobionts contribute to inflammation and the risk of colitis-associated carcinoma (CAC) in animal models, but their roles in humans with this uncommon disease are unknown. We identified microbiome differences in human CAC compared with longstanding inflammatory bowel disease (IBD) and sporadic colorectal carcinoma (CRC). Twenty-four CAC resections were matched with CRC and IBD controls. Methods included histopathology, 16S rDNA metagenomics, and pathobiont-specific qPCR. Beta diversity differed by diagnosis (PERMANOVA p = 0.007). The distinguishing taxa included Akkermansia enriched in CRC, and Bacteroides spp. enriched in IBD. The non-neoplastic mucosae presented distinct beta diversity (p = 0.005), but the CAC/CRC tumor microbiomes were similar (p = 0.7). Within metastases and margins, Enterobacteriaceae were enriched in CAC, and Bacteroidales in CRC. Pathobiont-specific qPCR confirmed a greater frequency of pks+ E. coli and enterotoxigenic Bacteroides fragilis in CAC than IBD. High alpha diversity was associated with active inflammation, advanced cancer stage, and shorter overall survival (log-rank p = 0.008). Mucosal microbiomes distinguish CAC from longstanding IBD, implicating pathobionts as markers for disease progression. Integrating our findings with prior animal model research, pathobionts promote carcinogenesis in IBD patients through genotoxicity and host cell signaling.

As one of the three major malignant tumors in women, the morbidity of endometrial cancer is second only to that of cervical cancer and is increasing yearly. Its etiological mechanism is not clear, and the risk factors are numerous and common and are closely related to obesity, hypertension, diabetes, etc. The gut microbiota has many strains, which play a considerable part in normal digestion and absorption in the human body and the regulation of the immune response. In the last few years, research on the gut microbiota has been unprecedentedly popular, and it has been confirmed that the gut microbiota closely correlates with the occurrence and development of all kinds of benign and malignant diseases. In this article, the effects of the gut microbiota and its metabolites on the occurrence and development of endometrial cancer is reviewed, and its application in the prevention, diagnosis and treatment of endometrial cancer is explored.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, highlighting the urgent need for novel preventive and therapeutic strategies. Emerging research highlights the crucial role of the gut microbiota, including bacteria, fungi, viruses, and their metabolites, in the pathogenesis of CRC. Dysbiosis, characterized by an imbalance in microbial composition, contributes to tumorigenesis through immune modulation, metabolic reprogramming, and genotoxicity. Specific bacterial species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis , along with fungal agents like Candida species, have been implicated in CRC progression. Moreover, viral factors, including Epstein-Barr virus and human cytomegalovirus, are increasingly recognized for their roles in promoting inflammation and immune evasion. This review synthesizes the latest evidence on host-microbiome interactions in CRC, emphasizing microbial metabolites, such as short-chain fatty acids and bile acids, which may act as both risk factors and therapeutic agents. We further discuss the latest advances in microbiota-targeted clinical applications, including biomarker-assisted diagnosis, next-generation probiotics, and microbiome-based interventions. A deeper understanding of the role of gut microbiome in CRC pathogenesis could pave the way for diagnostic, preventive, and personalized therapeutic strategies.

The biology of cancer is characterized by an intricate interplay of cells originating not only from the tumor mass, but also its surrounding environment. Different microbial species have been suggested to be enriched in tumors and the impacts of these on tumor phenotypes is subject to intensive investigation. For these efforts, model systems that accurately reflect human-microbe interactions are rapidly gaining importance. Here we present a guide for selecting a suitable in vitro co-culture platform used to model different cancer-microbiome interactions. Our discussion spans a variety of in vitro models, including 2D cultures, tumor spheroids, organoids, and organ-on-a-chip platforms, where we delineate their respective advantages, limitations, and applicability in cancer microbiome research. Particular focus is placed on methodologies that facilitate the exposure of cancer cells to microbes, such as organoid microinjections and co-culture on microfluidic devices. We highlight studies offering critical insights into possible cancer-microbe interactions and underscore the importance of in vitro models in those discoveries. We anticipate the integration of more complex microbial communities and the inclusion of immune cells into co-culture systems to more accurately simulate the tumor microenvironment. The advent of ever more sophisticated co-culture models will aid in unraveling the mechanisms of cancer-microbiome interplay and contribute to exploiting their potential in novel diagnostic and therapeutic strategies.

The etiology of prostate cancer (PC) is multifactorial and poorly understood. It has been suggested that colibactin-producing Escherichia coli positive for the pathogenicity island pks (pks+) initiate cancers via induction of genomic instability. In PC, androgens promote oncogenic translocations. Our aim was to investigate the association of pks+E. coli with PC diagnosis and molecular architecture, and its relationship with androgens.

We quantified the association of pks+E. coli with PC diagnosis in a volunteer-sampled 235-person cohort from two institutional practices (UT San Antonio). We then used colibactin 742 and DNA/RNA sequencing to evaluate the effects of colibactin 742, dihydrotestosterone (DHT), and their combination in vitro.

Colibactin exposure was positively associated with PC diagnosis (p = 0.04) in our clinical cohort, and significantly increased replication fork stalling and fusions in vitro (p < 0.01). Combined in vitro exposure to colibactin 742 and DHT induced more somatic mutations of all types than exposure to either alone. The combination also elicited kataegis, with a higher density of somatic point mutations. Laboratory analyses were conducted using a single cell line, which limited our ability to fully recapitulate the complexity of PC etiology.

Our findings are consistent with synergistic induction of genome instability and kataegis by colibactin 742 and DHT in cell culture. Colibactin-producing pks+ E. coli may plausibly contribute to PC etiology.

We investigated whether a bacterial toxin that is linked to colon cancer can also cause prostate cancer. Our results support this idea by showing a link between the toxin and prostate cancer diagnosis in a large patient population. We also found that this toxin causes genetic dysfunction in prostate cancer cells when combined with testosterone.

Bacteria are associated with certain cancers and may induce genetic instability and cancer progression. The gut microbiome modulates the response to cancer therapy. Training machine learning models with response associated taxa or bacterial genes predict patients' response to immunotherapies with moderate accuracy. Clinical trials targeting the gut microbiome to improve immunotherapy efficacy have been conducted. While single bacterial strains or small consortia have not be reported yet to be successful, encouraging results have been reported in small single arm and randomized studies using transplant of fecal microbiome from cancer patients who successfully responded to therapy or from healthy volunteers.

The intratumoral microbe-host interaction plays crucial role in the development of cancer. The microbiome can influence cancer development by modulating inflammation, immune responses and metabolic pathways. Therefore, we aim to delineate the landscape and role of intratumoral microbiota in cervical cancer (CC).

The presence of bacterial community in CC tissues was confirmed by fluorescence in situ hybridization (FISH). Then 16s rRNA and RNA-Seq were used to characterize the composition of intratumoral microbiota. Combined with cervical squamous cell carcinoma (CESC) data from the Tumor Cancer Genome Atlas (TCGA), the clinical signatures of intratumoral microbiota and DEGs were further analyzed. Finally, the effect of the up-regulated Fibrinogen beta chain (FGB) expressed fragment peptide on the biological behavior of cancer was verified in vitro.

We found the composition heterogeneity of bacteria in CC tumors. Pseudomonas was most highly enriched in CC tissues and grouped according to the relative abundance level. The clinical characteristics of patients with relatively high abundance of Pseudomonas had the higher levels of fibrinogen and lower levels of white blood cell (WBC) and albumin (ALB) expression. Combining transcriptome data from the two our collective CC and TCGA-CESC cohorts, we found that Pseudomonas abundance was significantly associated with fibrinogen beta peptide expression and worse overall survival in CC patients. In vitro experiment revealed that Pseudomonas could promote the proliferation and migration of cervical cancer cells through overexpression of FGB.

We characterized the composition of the intratumoral microbiota in CC tissues and identified the most significantly differentially abundant bacteria between cancerous and non-cancerous tissues. Our findings provide novel insights into the relationship between intratumoral Pseudomonas and the tumorigenesis of CC. A deeper understanding of the tumor microenvironment and its associated microbiota may reveal new potential therapeutic targets and improve clinical outcomes.

Colibactin, a human microbiome-derived genotoxin, promotes colorectal cancer by damaging the host gut epithelial genomes. While colibactin is synthesized via a hybrid non-ribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) pathway, known as pks or clb, the structural details of its biosynthetic enzymes remain limited, hindering our understanding of its biosynthesis and clinical application. In this study, we report the cryo-EM structures of two colibactin-producing PKS enzymes, ClbC and ClbI, captured in different reaction states using a substrate-mimic crosslinker. Our structural analysis revealed the binding sites of carrier protein (CP) domains of the ClbC and ClbI on their ketosynthase (KS) domains. Further, we identified a novel NRPS-PKS docking interaction between ClbI and its upstream enzyme, ClbH, mediated by the C-terminal peptide ClbH and the dimeric interface of ClbI, establishing a 1:2 stoichiometry. These findings advance our understanding of colibactin assembly line and provide broader insights into NRPS-PKS natural product biosynthesis mechanisms.

Colorectal cancer (CRC) is a significant global health challenge, with rising incidence, particularly among individuals under 50. Increasing evidence highlights the gut microbiota as key contributors to CRC development, with certain oncogenic bacteria influencing cancer initiation, progression, and therapy response. Among these is pks+ Escherichia coli, which produces colibactin, a genotoxic compound that induces DNA damage and leaves a distinct mutational signature in healthy individuals and CRC patients. While research has focused on its genotoxic effects, this review examines the kinetics of colibactin-induced mutations and the epithelial and environmental changes that promote E. coli expansion and colibactin exposure. We also explore the broader role of pks+ E. coli in cancer initiation and progression beyond genotoxicity, and discuss potential therapeutic approaches.

The increasing interest in utilizing three-dimensional (3D) in vitro models with innovative biomaterials to engineer functional tissues arises from the limitations of conventional cell culture methods in accurately reproducing the complex physiological conditions of living organisms. This study presents a strategy for replicating the intricate microenvironment of the intestine by cultivating intestinal cells within bioinspired 3D interfaces that recapitulate the villus-crypt architecture and 3D tissue arrangement of the intestine. Intestinal cells cultured on these biomimetic substrates exhibited phenotypes and differentiation characteristics resembling intestinal-specific cell types, effectively replicating intestinal tissue. Notably, tissue proliferation and differentiation were achieved within 72-120 h-significantly faster than the several weeks required by conventional bioengineered materials, which often pose risks of tissue necrosis or cross-contamination. Additionally, the differentiated cells on these villi-crypts mimicking bio-interfaces exhibit higher production of natural antimicrobial peptides, resulting in reduced pathogenic infection compared to control samples. Furthermore, our method stands out for simplicity in fabrication, eliminating the need for cleanroom procedures and complex microfabrication techniques.

Tumor is one of the leading causes of death worldwide. The occurrence and development of tumors are related to multiple systems and factors such as the immune system, gut microbiota, and nervous system. The immune system plays a critical role in tumor development. Studies have also found that the gut microbiota can directly or indirectly affect tumorigenesis and tumor development. With increasing attention on the tumor microenvironment in recent years, the nervous system has emerged as a novel regulator of tumor development. Some tumor therapies based on the nervous system have also been tested in clinical trials. However, the nervous system can not only directly interact with tumor cells but also indirectly affect tumor development through the gut microbiota. The nervous system-mediated gut microbiota can regulate tumorigenesis, growth, invasion, and metastasis through the immune system. Here, we mainly explore the potential effects of the nervous system-gut microbiota-immune system axis on tumorigenesis and tumor development. The effects of the nervous system-gut microbiota-immune system axis on tumors involve the nervous system regulating immune cells through the gut microbiota, which can prevent tumor development. Meanwhile, the direct effects of the gut microbiota on tumors and the regulation of the immune system by the nervous system, which can affect tumor development, are also reviewed.

Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.

Colorectal cancer (CRC) is responsible for over 900,000 annual deaths worldwide. Emerging evidence supports pro-carcinogenic bacteria in the colonic microbiome are at least promotional in CRC development and may be causal. We previously showed toxigenic C. difficile from human CRC-associated bacterial biofilms accelerates tumorigenesis in ApcMin/+ mice, both in specific pathogen-free mice and in gnotobiotic mice colonized with a defined consortium of bacteria. To further understand host-microbe interactions during colonic tumorigenesis, we combined single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and immunofluorescence to define the molecular spatial organization of colonic dysplasia in our consortium model with or without C. difficile. Our data show a striking bipartite regulation of Deleted in Malignant Brain Tumors 1 (DMBT1) in the inflamed versus dysplastic colon. From scRNA-seq, differential gene expression analysis of normal absorptive colonocytes at 2 weeks postinoculation showed DMBT1 upregulated by C. difficile compared to colonocytes from mice without C. difficile exposure. In contrast, our spatial transcriptomic analysis showed DMBT1 dramatically downregulated in dysplastic foci compared with normal-adjacent tissue. We further integrated our datasets to generate custom colonic dysplasia scores and ligand-receptor mapping. Validation with immunofluorescence showed DMBT1 protein downregulated in dysplastic foci from three mouse models of colonic tumorigenesis and in adenomatous dysplasia from human samples. Finally, we used mouse and human organoids to implicate WNT signaling in the downregulation of DMBT1 mRNA and protein. Together, our data reveal cell type-specific regulation of DMBT1, a potential mechanistic link between bacteria and colonic tumorigenesis. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The gut microbiome has a crucial role in cancer development and therapy through its interactions with the immune system and tumour microenvironment. Although evidence links gut microbiota composition to cancer progression, its precise role in modulating treatment responses remains unclear. In this Review, we summarize current knowledge on the gut microbiome's involvement in cancer, covering its role in tumour initiation and progression, interactions with chemotherapy, radiotherapy and targeted therapies, and its influence on cancer immunotherapy. We discuss the impact of microbial metabolites on immune responses, the relationship between specific bacterial species and treatment outcomes, and potential microbiota-based therapeutic strategies, including dietary interventions, probiotics and faecal microbiota transplantation. Understanding these complex microbiota-immune interactions is critical for optimizing cancer therapies. Future research should focus on defining microbial signatures associated with treatment success and developing targeted microbiome modulation strategies to enhance patient outcomes.

Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.

Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect-a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.

Cancer metastasis is the leading cause of death in patients. In recent years, there has been a growing recognition of the role of tumor-associated microflora in tumor metastasis. The connection between oral and gut microflora and the tumor microenvironment has also been extensively studied. The migration of oral and gut microflora is closely associated with tumor development. Although there is awareness regarding the significant impact of microbial communities on human health, the focus on their relationship with host organisms, particularly those related to tumor-associated microflora, remains inadequate. As an integral part of the body, the host microflora is crucial for regulating the cancer risk and preventing tumor recurrence. The oral-gut axis plays an indispensable role in human immunity, and many types of cancers, such as colorectal, pancreatic, and breast, are significantly influenced by their internal microbial communities. However, further exploration into the mechanisms underlying the role of the intratumoral microflora in cancer is necessary to achieve a comprehensive understanding. We have summarized and analyzed related articles in PubMed. This article reviews the impact of the oral-gut axis on the human immune system, explores the relationship between the translocation of the oral and intestinal flora and the tumor microenvironment, analyzes the specific mechanisms involved in the translocation of the oral and intestinal microflora during the evolution and progression of tumors, and elaborates on the correlations between the occurrence and development of tumors and the changes in the microflora. Finally, a summary of these abovementioned points is provided.

Biomedical research has implicated the bacterial metabolite colibactin as a causal risk factor for several cancer types, in particular, colorectal cancer. Colibactin has been known to drive tumorigenesis by inducing double-strand breaks in the DNA of epithelial cells exposed to colibactin-producing bacteria. Some phylogroup B2 Escherichia coli secrete colibactin during interbacterial warfare, concomitantly exposing the host to an increasing risk of DNA damage. This Personal View reviews the current knowledge about the cancer-colibactin interface and summarises metagenomics-based and population-genomics-based surveys to show that the prevalence of dominant colibactin-producing lineages of E coli varies considerably across geographical regions. The prevalence is further strongly associated with the age-standardised incidences of colorectal cancer, bladder cancer, and prostate cancer, suggesting that the degree of colibactin exposure in a population might contribute to the geographical variation of these cancers. Our observations provide a strong impetus for further research and the development of novel interventions to reduce the risks for colibactin-related cancers.

The global incidence of colorectal cancer (CRC) is increasing. In the majority of CRC cases, colon cancer develops from alterations in the adenoma-carcinoma sequence pathway. Currently, there are few studies regarding the effects of enteric viruses on the adenoma-carcinoma sequence pathway, and subsequently, the progression and development of the CRC. Here, fecal and tissue samples from a normal control group, an adenomatous polyp group, and a colorectal adenocarcinoma group were collected to gain a deeper understanding of the variations in enteric viruses in CRC patients and to analyze their significance. With the progression of CRC from adenoma to adenocarcinoma, the number of DNA viruses in the virus-like particles (VLPs) of fecal and tissue samples gradually increased, and there were distinct differences in the composition of enteric viruses among the different groups. Multiple species correlation analysis revealed extensive interactions among viruses, bacteria, and fungi in fecal and tissue samples. Functional analysis also revealed that the functional pathways in fecal and tissue samples also underwent significant changes. In conclusion, the changes in the composition and function of enteric viruses in the progression of CRC via adenoma-carcinoma sequence pathway were analyzed in this study, and these changes hold certain importance for exploring the role of enteric viruses in the occurrence of this disease; however, their mode of action and specific mechanisms require further investigation.

We undertook this study to assess the efficacy of probiotics in managing adverse reactions during chemoradiotherapy in patients with colorectal cancer.

A comprehensive literature search was conducted on PubMed, ClinicalTrials.gov, Embase, Cochrane library,Web of Science, and Chinese databases until July 27, 2024. Data analysis was performed using RevMan5.3 statistical software. The risk of bias was assessed using the Cochrane collaboration tool. Relative risk (RR) was employed to incorporate statistical measures and calculate 95% confidence intervals (95%CI) for bipartite data. Standardized mean difference (SMD) was utilized to incorporate statistical measures and calculate 95% confidence intervals for continuous variables.

A meta-analysis of 633 patients with colorectal cancer was conducted across eight studies. In comparison to the control group, probiotics demonstrated a significant reduction in the incidence of chemoradiotherapy-induced diarrhea among colorectal cancer patients(RR = 0.51,95%Cl:0.38 ~ 0.68,P < 0.001). Additionally, probiotic usage exhibited improvements in pain index (SMD = -2.27,95%Cl: -4.49 ~ -0.05,P = 0.04), dyspnea (SMD = -0.92,95%Cl: -1.61 ~ 0.22, P = 0.01) and insomnia (SMD = -2.95, 95%Cl: -5.44 ~ -0.47, P = 0.02) compared to the control group. However, there were no significant differences between two groups in abdominal distension(RR = 0.79, 95%Cl:0.21 ~ 3.00, P = 0.72), stomatitis risk (RR = 1.23, 95%Cl: 0.48 ~ 3.21, P = 0.67), fatigue (SMD = -7.12, 95%Cl:-14.99 ~ 0.75, P = 0.08)and loss of appetite(SMD = -2.86, 95%Cl: -5.83 ~ 0.11, P = 0.06). Furthermore, the use of probiotics did not significantly improve the quality of life (QOL) (SMD = 8.82, 95%Cl: -1.11 ~ 18.75, P = 0.08)of colorectal cancer patients receiving chemoradiotherapy.

This meta-analysis suggested that probiotic consumption may ameliorate certain adverse reactions in patients with colorectal cancer receiving chemoradiotherapy.

Prospero registration number: PROSPERO (CRD42023465966).

Despite advances in metastatic colorectal cancer (mCRC) treatment, long-term survival remains poor, particularly in right-sided colorectal cancer (RCRC), which has a worse prognosis compared to left-sided CRC (LCRC). This disparity is driven by the complex biological diversity of these malignancies. RCRC and LCRC differ not only in clinical presentation and outcomes but also in their underlying molecular and genetic profiles. This article offers a detailed literature review focusing on the distinctions between RCRC and LCRC. We explore key differences across embryology, anatomy, pathology, omics, and the tumor microenvironment (TME), providing insights into how these factors contribute to prognosis and therapeutic responses. Furthermore, we examine the therapeutic implications of these differences, considering whether the conventional classification of CRC into right- and left-sided forms should be refined. Recent molecular findings suggest that this binary classification may overlook critical biological complexities. Therefore, we propose that future approaches should integrate molecular insights to better guide personalized treatments, especially anti-EGFR therapies, and improve patient outcomes.

Tumor-residing microbiota poses a new challenge in cancer progression and therapy; however, the functional behavior of patient tumor-derived microbes remains poorly understood. We previously reported the presence of tumor microbiota in intraductal papillary mucinous neoplasms (IPMNs), which are precursors of pancreatic cancer.

We examined the metabolic and pathogenic potential of clinical microbiota strains obtained from IPMN tumors using various pancreatic cell lines and 3D spheroid models.

Our findings revealed that several strains from IPMNs with invasive cancer or high-grade dysplasia, such as E. cloacae, E. faecalis, and K. pneumoniae, induced a cancer metabolite signature in human pancreatic cells when infected ex vivo. Bacterial invasiveness was significantly correlated with DNA damage in spheroids derived from normal and tumor-derived pancreatic cells, particularly in strains derived from advanced neoplasia IPMN and under hypoxic conditions. Additionally, microbial metabolites activate human mucosal-associated invariant T (MAIT) cells and restrict the infection, both extra- and intracellularly, in hypoxic tumor conditions and in synergy with antibiotics.

Immune sensing of tumor microbiota metabolites may have clinical implications in cancer management.

Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, MSH3 and probably MLH3, and in the base excision repair genes MUTYH, NTHL1 and MBD4. This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.

Among the emerging issues in probiotic safety, the possible presence of pks, a gene cluster synthetizing a genotoxin known as colibactin, is one of the most alarming. Indeed, indigenous E. coli strain pks-positive are found in 60% of patients with colorectal cancer, and the most widely used E. coli-based probiotic, known as E. coli Nissle 1917 (DSM 6601), is pks-positive. Starting from 25 potential candidates selected by screening 25 infant stool samples, we have selected an E. coli strain (named 5C, deposited as LMG S-33222) belonging to the phylotype A and having the serovar O173:H1. Having been previously completely sequenced by our group, we have further characterized this strain, demonstrating that it is (i) devoid of the most known potential pathogenic-related genes, (ii) devoid of possible plasmids, (iii) antibiotic-sensitive according to the EFSA panel, (iv) resistant in gastric and enteric juice, (v) significantly producing acetate, (vi) poorly producing histamine, (vii) endowed with a significant in vitro antipathogenic profile, (viii) promoting a significant in vitro immunological response based on IL-10 and IL-12, and (ix) devoid of the pks genes. A comparative genomics versus E. coli Nissle 1917 is also provided. Considering that the other two most commonly used E. coli-based probiotics (E. coli DSM 17252 and E. coli A0 34/86) are respectively pks-positive and alpha-hemolysin-(hly) and cytotoxic necrotizing factor-1-(cnf1) positive, this novel strain (E. coli 5C) is likely the probiotic E. coli strain with the best safety profile available to date for human use.

Structural variations (SVs) have significant effects on microbial phenotypes. The underlying mechanism of functional changes caused by gut microbial SVs in the development of ulcerative colitis (UC) need further investigation.

We performed long-read (Oxford Nanopore Technology-based) and short-read (Illumina-based) metagenomic sequencing on stool samples from 93 patients with UC and 100 healthy controls (HCs) and analyzed microbial SVs. A total of 648 Escherichia coli strains from fecal samples of patients with UC (UC-strains) and HCs (HC-strains) were isolated. SV-associated scrK gene deletion was verified via whole-genome sequencing or targeted polymerase chain reaction. Then, representative UC-strains, HC-strains, and scrK-knockout E coli were used for the in vitro and in vivo experiments to investigate the effects of specific SVs in E coli on fructose utilization ability and colitis.

E coli in UC with the highest fold change had SV-affected functional differences on fructose metabolism to that of HCs. The fructose utilization gene deletion was common in UC-strains, ostensibly reducing fructose utilization in vitro and leading to fructose-dependent aggravation of colitis in murine models. UC-strains and HC-strains induced comparable colitis under low fructose. However, high fructose exacerbated colitis severity exclusively in UC-strain-colonized mice, with elevated intestinal fructose residues, significant microbiome/metabolome changes, increased inflammation, and gut barrier disruption. These changes were mechanistically dependent on the deletion of the fructose utilization gene scrK.

SV-caused difference in fructose utilization and proinflammatory properties in E coli from patients with UC influence the development of UC, emphasizing the importance of fine-scale metagenomic studies in disease.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

Background: While intratumoral microbiota have been identified in various cancers, their presence and clinical significance in lacrimal gland tumors remain largely unexplored. This study investigates the existence, composition, and potential clinical significance of intratumoral bacteria in lacrimal gland tumors. Methods: High-throughput 16S rDNA sequencing was performed on tumor DNA extracted from 89 paraffin-embedded tissues from patients with lacrimal gland tumors. Diversity analysis and LEfSe differential analysis were conducted to identify tumor-type-specific bacterial taxa. LASSO regression and the Cox proportional hazards models were used to analyze the relationship between intratumoral microbiota and prognosis. Results: Significant differences in the β diversity of intratumoral microbiota were observed across adenoid cystic carcinoma (ACC), carcinoma ex pleomorphic adenoma (CXPA), pleomorphic adenoma (PA), and IgG4-related disease (IgG4-RD) patients. After FDR correction, Garicola, Prevotella, Polaribacter, and Helicobacter were notably enriched in the tumors of ACC, CXPA, PA, and IgG4-RD patients, respectively. Importantly, patients with malignant lacrimal gland tumors who experienced relapse, distant metastasis, or death had significantly higher α diversity within their tumors. Furthermore, specific genera, such as Roseburia and Alloprevotella, were particularly associated with poorer prognosis in patients with malignant lacrimal gland tumors. Conclusions: This study provides a comprehensive analysis of microbial profiles in lacrimal gland tumors, highlighting distinct microbial characteristics across tumor types. Our findings suggest that intratumoral bacterial diversity and specific genera may serve as potential prognostic markers for malignant lacrimal gland tumors.

Short-chain fatty acids (SCFAs), mainly produced by gut microbiota through the fermentation process of dietary fibers and proteins, are crucial to human health, with butyrate, a famous four-carbon SCFA, standing out for its inevitably regulatory impact on both gut and immune functions. Within this narrative review, the vital physiological functions of SCFAs were examined, with emphasis on butyrate's role as an energy source for colonocytes and its ability to enhance the gut barrier while exhibiting anti-inflammatory effects. Knowledge of butyrate synthesis, primarily generated by Firmicutes bacteria, can be influenced by diets with specifically high contents of resistant starches and fiber. Butyrate can inhibit histone deacetylase, modulate gene expression, influence immune functionality, and regulate tight junction integrity, supporting the idea of its role in gut barrier preservation. Butyrate possesses systemic anti-inflammatory properties, particularly, its capacity to reduce pro-inflammatory cytokines and maintain immune homeostasis, highlighting its therapeutic potential in managing dysbiosis and inflammatory diseases. Although butyrate absorption into circulation is typically minimal, its broader health implications are substantial, especially regarding obesity and type 2 diabetes through its influence on metabolic regulation and inflammation. Furthermore, this narrative review thoroughly examines butyrate's growing recognition as a modulator of neurological health via its interaction with the gut-brain axis. Additionally, butyrate's neuroprotective effects are mediated through activation of specific G-protein-coupled receptors, such as FFAR3 and GPR109a, and inhibition of histone deacetylases (HDACs). Research indicates that butyrate can alleviate neurological disorders, including Alzheimer's, Parkinson's, autism spectrum disorder, and Huntington's disease, by reducing neuroinflammation, enhancing neurotransmitter modulation, and improving histone acetylation. This focus will help unlock its full therapeutic potential for metabolic and neurological health, rather than exclusively on its well-known benefits for gut health, as these are often interconnected.

Colorectal cancer (CRC) represents a relevant public health problem, with high incidence and mortality in Western countries. CRC can occur as sporadic (65%-75%), common familial (25%), or as a consequence of an inherited predisposition (up to 10%). While unravelling its genetic basis has been a long trip leading to relevant clinical implementation over more than 30 years, other contributing factors remain to be clarified. Among these, micro-organisms have emerged as critical players in the development and progression of the disease, as well as for CRC treatment response. Fusobacterium nucleatum (Fn) has been associated with CRC development in both pre-clinical models and clinical settings. Fusobacteria are core members of the human oral microbiome, while being less prevalent in the healthy gut, prompting questions about their localization in CRC and its precursor lesions. This review aims to critically discuss the evidence connecting Fn with CRC pathogenesis, its molecular subtypes and clinical outcomes.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

Here, we discuss the seven new challenges set by Cancer Grand Challenges that are currently open for creative applications. We invite the research community to assemble global, interdisciplinary teams to tackle these challenges and ultimately change the way we think about, study, prevent, and treat cancer.

The adverse gut microbiome may underlie the variability in risks of colorectal cancer (CRC) and metachronous CRC in people with Lynch syndrome (LS). The role of pks+/-Escherichia coli (pks+/-E. coli), Enterotoxigenic Bacteroides fragilis (ETBF), and Fusobacterium nucleatum (Fn) in CRCs and adenomas in people with LS is unknown.

A total of 358 LS cases, including 386 CRCs, 90 adenomas, 195 normal colonic mucosa DNA from the Australasian Colon Cancer Family Registry were tested using multiplex TaqMan qPCR. Logistic regression was used to compare the intratumoural prevalence of each bacteria in Lynch CRCs with 1336 sporadic CRCs. Cox proportional-hazards regression estimated the associations of each bacteria with the risk of metachronous CRC and neoplasia.

Pks+ E. coli (odds ratio [95% confidence interval] = 1.60 [1.08-2.35], P = 0.017), pks-E. coli (3.87 [2.58-5.80], P < 0.001) and Fn (19.47 [13.32-28.87], P < 0.001) were significantly enriched in LS CRCs when compared with sporadic CRCs. Pks+ E. coli in the initial CRC was associated with an increased risk of metachronous CRC (hazard ratio [95% confidence interval] = 2.32 [1.29-4.17], P = 0.005) and metachronous colorectal neoplasia (1.51 [1.02-2.23], P = 0.040) when compared with CRCs without pks+ E. coli.

Pks+ E. coli, pks-E. coli, and Fn are enriched within LS CRCs, suggesting possible roles in CRC development in LS. Having intratumoural pks+ E. coli is associated with increased risk of metachronous CRC, suggesting that, if validated, people with LS might benefit from pks+ E. coli screening and eradication.

This work was funded by an NHMRC Investigator grant (GNT1194896) and a Cancer Australia/Cancer Council NSW co-funded grant (GNT2012914).

Microsatellite instability (MSI) is a hallmark of DNA mismatch repair (MMR) deficiency that leads to genomic instability and increased cancer risk. The tumor microenvironment (TME) significantly influences MSI-driven tumorigenesis, and emerging evidence points to a critical role of the microbiome in shaping this complex interplay.

This review comprehensively examines the existing literature on the intricate relationship between MSI, microbiome, and cancer development, with a particular focus on the impact of microbial dysbiosis on the TME.

MSI-high tumors exhibited increased immune cell infiltration owing to the generation of neoantigens. However, immune evasion mechanisms such as PD-1/CTLA-4 upregulation limit the efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients. Pathobionts, such as Fusobacterium nucleatum and Bacteroides fragilis, contribute to MSI through the production of genotoxins, further promoting inflammation and oxidative stress within the TME.

The microbiome profoundly affects MSI-driven tumorigenesis. Modulation of the gut microbiota through interventions such as fecal microbiota transplantation, probiotics, and dietary changes holds promise for improving ICI response rates. Further research into cancer pharmacomicrobiomics, investigating the interplay between microbial metabolites and anticancer therapies, is crucial for developing personalized treatment strategies.

Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used Il10-/- mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus or colibactin-producing (polyketide synthase-positive (pks+)) Escherichia coli and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet. Mechanistically, mucosal inflammation was increased in the LC-diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. The pks+ E. coli also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.