Distinct Colon Mucosa Microbiomes associated with Tubular Adenomas and Serrated Polyps

Background: Colorectal cancer is the second most deadly and third most common cancer in the world. Its development is heterogenous, with multiple mechanisms of carcinogenesis. Two distinct mechanisms include the adenoma-carcinoma sequence and the serrated pathway. The gut microbiome has been identified as a key player in the adenoma-carcinoma sequence, but its role in serrated carcinogenesis is unclear. In this study, we characterized the gut microbiome of 140 polyp-free and polyp-bearing individuals using colon mucosa and fecal samples to determine if microbiome composition was associated with each of the two key pathways. Results: We discovered significant differences between colon mucosa and fecal samples, explaining 14% of the variation observed in the microbiome. Multiple mucosal samples were collected from each individual to investigate the gut microbiome for differences between polyp and healthy intestinal tissue, but no such differences were found. Colon mucosa sampling revealed that the microbiomes of individuals with tubular adenomas and serrated polyps were significantly different from each other and polyp-free individuals, explaining 2-10% of the variance in the microbiome. Further analysis revealed differential abundances of Eggerthella lenta, Clostridium scindens, and three microbial genes across tubular adenoma, serrated polyp, and polyp-free cases. Conclusion: By directly sampling the colon mucosa and distinguishing between the different developmental pathways of colorectal cancer, this study helps characterize potential mechanistic targets and diagnostic biomarkers for serrated carcinogenesis. This research also provides insight into multiple microbiome sampling strategies by assessing each methods practicality and effect on microbial community composition.

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Interaction between Host MicroRNAs and the Gut Microbiota in Colorectal Cancer

mSystems ◽

10.1128/msystems.00205-17 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 35

Author(s):

Ce Yuan ◽

Michael B. Burns ◽

Subbaya Subramanian ◽

Ran Blekhman

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Gut Microbiota ◽

Mirna Expression ◽

Gut Microbiome ◽

Noncoding Rna ◽

Microbial Community Composition ◽

Host Cells ◽

Microbiome Composition ◽

Small Noncoding Rna

ABSTRACT Although variation in gut microbiome composition has been linked with colorectal cancer (CRC), the factors that mediate the interactions between CRC tumors and the microbiome are poorly understood. MicroRNAs (miRNAs) are known to regulate CRC progression and are associated with patient survival outcomes. In addition, recent studies suggested that host miRNAs can also regulate bacterial growth and influence the composition of the gut microbiome. Here, we investigated the association between miRNA expression and microbiome composition in human CRC tumor and normal tissues. We identified 76 miRNAs as differentially expressed (DE) in tissue from CRC tumors and normal tissue, including the known oncogenic miRNAs miR-182, miR-503, and mir-17~92 cluster. These DE miRNAs were correlated with the relative abundances of several bacterial taxa, including Firmicutes , Bacteroidetes , and Proteobacteria . Bacteria correlated with DE miRNAs were enriched with distinct predicted metabolic categories. Additionally, we found that miRNAs that correlated with CRC-associated bacteria are predicted to regulate targets that are relevant for host-microbiome interactions and highlight a possible role for miRNA-driven glycan production in the recruitment of pathogenic microbial taxa. Our work characterized a global relationship between microbial community composition and miRNA expression in human CRC tissues. IMPORTANCE Recent studies have found an association between colorectal cancer (CRC) and the gut microbiota. One potential mechanism by which the microbiota can influence host physiology is through affecting gene expression in host cells. MicroRNAs (miRNAs) are small noncoding RNA molecules that can regulate gene expression and have important roles in cancer development. Here, we investigated the link between the gut microbiota and the expression of miRNA in CRC. We found that dozens of miRNAs are differentially regulated in CRC tumors and adjacent normal colon and that these miRNAs are correlated with the abundance of microbes in the tumor microenvironment. Moreover, we found that microbes that have been previously associated with CRC are correlated with miRNAs that regulate genes related to interactions with microbes. Notably, these miRNAs likely regulate glycan production, which is important for the recruitment of pathogenic microbial taxa to the tumor. This work provides a first systems-level map of the association between microbes and host miRNAs in the context of CRC and provides targets for further experimental validation and potential interventions.

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Interaction Between Host MicroRNAs and the Gut Microbiota in Colorectal Cancer

10.1101/192401 ◽

2017 ◽

Author(s):

Ce Yuan ◽

Michael Burns ◽

Subbaya Subramanian ◽

Ran Blekhman

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Normal Tissue ◽

Microbial Community Composition ◽

Taxonomic Composition ◽

Integrated Analysis ◽

Tissue Samples ◽

Microbiome Composition ◽

Normal Tissues ◽

Mirnas Expression

AbstractBackgroundAlthough variation in gut microbiome composition has been linked with colorectal cancer (CRC), the factors that mediate the interactions between CRC tumors and the microbiome are poorly understood. MicroRNAs (miRNAs) are known to regulate CRC progression and patient survival outcomes. In addition, recent studies suggested that host miRNAs can also regulate bacterial growth and influence the composition of the gut microbiome. Here, we investigated the association between miRNAs expression in human CRC tumor and normal tissues and the microbiome composition associated with these same tissues.MethodWe sequenced the small RNAs from patient-matched tumor and normal tissue samples collected from 44 human CRC patients performed an integrated analysis with microbiome taxonomic composition data from these same samples. We then interrogated the functions of the bacteria correlated with miRNAs that were differentially expressed (DE) between tumor and matched normal tissues, as well as the functions of miRNAs correlated with bacterial taxa that have been previously associated with CRC, including Fusobacterium, Providencia, Bacteroides, Akkermansia, Roseburia, Porphyromonas, and Peptostreptococcus.ResultsWe identified 76 miRNAs as DE between CRC and normal tissue, including known oncogenic miRNAs miR-182, miR-503, and miR-17∼92. These DE miRNAs were correlated with the relative abundance of several bacterial taxa, including Firmicutes, Bacteroidetes, and Proteobacteria. Bacteria correlated with DE miRNAs were enriched with distinct predicted metabolic categories. Additionally, we found that miRNAs correlated with CRC-associated bacteria are predicted to regulate targets that are relevant for host-microbiome interactions, and highlight a possible role for miRNA-driven glycan production in the recruitment of pathogenic microbial taxa.ConclusionsOur work characterized a global relationship between microbial community composition and miRNA expression in human CRC tissues. Our results support a role for miRNAs in mediating a bi-directional host-microbiome interaction in CRC. In addition, we highlight sets of potentially interacting microbes and host miRNAs, suggesting several pathways that can be targeted via future therapies.

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Bacterial community structure alterations within the colorectal cancer gut microbiome

BMC Microbiology ◽

10.1186/s12866-021-02153-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mark Loftus ◽

Sayf Al-Deen Hassouneh ◽

Shibu Yooseph

Keyword(s):

Colorectal Cancer ◽

Community Structure ◽

Bacterial Community ◽

Gut Microbiome ◽

Late Stage ◽

Bacterial Community Structure ◽

Whole Genome ◽

Human Gut ◽

Fecal Samples ◽

Human Gut Microbiome

Abstract Background Colorectal cancer is a leading cause of cancer-related deaths worldwide. The human gut microbiome has become an active area of research for understanding the initiation, progression, and treatment of colorectal cancer. Despite multiple studies having found significant alterations in the carriage of specific bacteria within the gut microbiome of colorectal cancer patients, no single bacterium has been unequivocally connected to all cases. Whether alterations in species carriages are the cause or outcome of cancer formation is still unclear, but what is clear is that focus should be placed on understanding changes to the bacterial community structure within the cancer-associated gut microbiome. Results By applying a novel set of analyses on 252 previously published whole-genome shotgun sequenced fecal samples from healthy and late-stage colorectal cancer subjects, we identify taxonomic, functional, and structural changes within the cancer-associated human gut microbiome. Bacterial association networks constructed from these data exhibited widespread differences in the underlying bacterial community structure between healthy and colorectal cancer associated gut microbiomes. Within the cancer-associated ecosystem, bacterial species were found to form associations with other species that are taxonomically and functionally dissimilar to themselves, as well as form modules functionally geared towards potential changes in the tumor-associated ecosystem. Bacterial community profiling of these samples revealed a significant increase in species diversity within the cancer-associated gut microbiome, and an elevated relative abundance of species classified as originating from the oral microbiome including, but not limited to, Fusobacterium nucleatum, Peptostreptococcus stomatis, Gemella morbillorum, and Parvimonas micra. Differential abundance analyses of community functional capabilities revealed an elevation in functions linked to virulence factors and peptide degradation, and a reduction in functions involved in amino-acid biosynthesis within the colorectal cancer gut microbiome. Conclusions We utilize whole-genome shotgun sequenced fecal samples provided from a large cohort of late-stage colorectal cancer and healthy subjects to identify a number of potentially important taxonomic, functional, and structural alterations occurring within the colorectal cancer associated gut microbiome. Our analyses indicate that the cancer-associated ecosystem influences bacterial partner selection in the native microbiota, and we highlight specific oral bacteria and their associations as potentially relevant towards aiding tumor progression.

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Maternal effects on early-life gut microbiome maturation in a wild nonhuman primate

10.1101/2021.11.06.467515 ◽

2021 ◽

Author(s):

Alice Baniel ◽

Lauren Petrullo ◽

Arianne Mercer ◽

Laurie Reitsema ◽

Sierra Sams ◽

...

Keyword(s):

Maternal Effects ◽

Gut Microbiome ◽

Early Life ◽

Amplicon Sequencing ◽

Microbial Colonization ◽

Fecal Samples ◽

Microbiome Composition ◽

16S Rrna Amplicon Sequencing ◽

Gut Colonization ◽

First Time

Early-life gut microbial colonization is an important process shaping host physiology, immunity and long-term health outcomes in humans and other animals. However, our understanding of this dynamic process remains poorly investigated in wild animals, where developmental mechanisms can be better understood within ecological and evolutionary relevant contexts. Using 16s rRNA amplicon sequencing on 525 fecal samples from a large cohort of infant and juvenile geladas (Theropithecus gelada), we characterized gut microbiome maturation during the first three years of life and assessed the role of maternal effects in shaping offspring microbiome assembly. Microbial diversity increased rapidly in the first months of life, followed by more gradual changes until weaning. As expected, changes in gut microbiome composition and function with increasing age reflected progressive dietary transitions: in early infancy when infants rely heavily on their mother's milk, microbes that facilitate milk glycans and lactose utilization dominated, while later in development as graminoids are progressively introduced into the diet, microbes that metabolize plant complex polysaccharides became dominant. Furthermore, the microbial community of nursing infants born to first-time (primiparous) mothers was more "milk-oriented" compared to similarly-aged infants born to experienced (multiparous) mothers. Comparisons of matched mother-offspring fecal samples to random dyads did not support vertical transmission as a conduit for these maternal effects, which instead could be explained by slower phenotypic development (and associated slower gut microbiome maturation) in infants born to first-time mothers. Together, our findings highlight the dynamic nature of gut colonization

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The Western Dietary Pattern Combined with Vancomycin-Mediated Changes to the Gut Microbiome Exacerbates Colitis Severity and Colon Tumorigenesis

Nutrients ◽

10.3390/nu13030881 ◽

2021 ◽

Vol 13 (3) ◽

pp. 881

Author(s):

Niklas D. Aardema ◽

Daphne M. Rodriguez ◽

Arnaud J. Van Wettere ◽

Abby D. Benninghoff ◽

Korry J. Hintze

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Tumor Development ◽

Alpha Diversity ◽

Basal Diet ◽

Plain Water ◽

Microbiome Composition ◽

Colon Tumorigenesis ◽

Induced Changes ◽

The Impact

Previous work by our group using a mouse model of inflammation-associated colorectal cancer (CAC) showed that the total Western diet (TWD) promoted colon tumor development. Others have also shown that vancomycin-mediated changes to the gut microbiome increased colorectal cancer (CRC). Therefore, the objective of this study was to determine the impact of vancomycin on colon tumorigenesis in the context of a standard mouse diet or the TWD. A 2 × 2 factorial design was used, in which C57Bl/6J mice were fed either the standard AIN93G diet or TWD and with vancomycin in the drinking water or not. While both the TWD and vancomycin treatments independently increased parameters associated with gut inflammation and tumorigenesis compared to AIN93G and plain water controls, mice fed the TWD and treated with vancomycin had significantly increased tumor multiplicity and burden relative to all other treatments. Vancomycin treatment significantly decreased alpha diversity and changed the abundance of several taxa at the phylum, family, and genus levels. Conversely, basal diet had relatively minor effects on the gut microbiome composition. These results support our previous research that the TWD promotes colon tumorigenesis and suggest that vancomycin-induced changes to the gut microbiome are associated with higher tumor rates.

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Black Raspberry Supplementation Alters the Gut Microbiome and Improves Alpha Diversity in a Mouse Model of Inflammation-Associated Colorectal Cancer

Current Developments in Nutrition ◽

10.1093/cdn/nzab054_032 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1177-1177

Author(s):

Daphne Rodriguez ◽

Eliza Owens ◽

Sam Vassar ◽

Ashley Bartlett ◽

Emily Mortensen ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Dietary Intervention ◽

Alpha Diversity ◽

Basal Diet ◽

Recovery Phase ◽

Protective Effects ◽

Linear Discriminant ◽

Microbiome Composition ◽

Freeze Dried

Abstract Objectives Anti-inflammatory bioactives in black raspberries (BRB) have been shown to have protective effects on the colon epithelium and may influence gut microbiome. The goal of this study was to determine the effects of dietary intervention with BRB on the dynamic composition of the gut microbiome composition in mice. Methods Using a 2 × 2 factorial design, C57BL/6J male mice were fed the standard AIN93G diet or the total Western diet (TWD) for 16 weeks with or without 10% (w/w) whole, freeze-dried BRB powder. The azoxymethane + dextran sodium sulfate model of inflammation-associated colorectal cancer was employed to assess the dynamic response of the gut microbiome to basal diet and BRB treatment prior to, during, and after active colitis and at the study end. Microbiome composition was determined using 16s rRNA sequencing followed by diversity analyses (alpha and beta) and identification of discriminating taxa by with linear discriminant analyses by effect size (lefse). Results Alpha diversity was markedly reduced during colitis for mice consuming either AIN93G or TWD, with some improvement noted by the recovery phase. Of note, consumption of BRB for two weeks significantly increased alpha diversity measures, and BRB improved alpha diversity in mice fed the AIN93G diet during colitis. Alternatively, BRB appeared less effective in mice fed TWD. Beta diversity was also significantly affected with notable clustering of microbiomes by BRB treatment during and after colitis. Consumption of BRB affected the relative abundance of several key taxa over the course of colitis and recovery from gut injury, including Erysipelotrichaceae, Bifidobacteriaceae, Streptococcaceae, Rikenellaceae, Ruminococcaceae and Akkermansiaceae, among others. Conclusions Dietary supplementation with BRB shifted the composition of the gut microbiome during colitis and recovery from gut injury, though the effects were inconsistent with respect to the basal diet consumed. Funding Sources USDA NIFA AFRI grant no. 2018-67017-27,516 and 2014-67017-21755.

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Changes in Microbial Community Composition Related to Sex and Colon Cancer by Nrf2 Knockout

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.636808 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chin-Hee Song ◽

Nayoung Kim ◽

Ryoung Hee Nam ◽

Soo In Choi ◽

Jeong Eun Yu ◽

...

Keyword(s):

Gut Microbiome ◽

Microbial Community Composition ◽

Alpha Diversity ◽

16S Rrna Gene Sequencing ◽

Rrna Gene ◽

Related Factor ◽

Invasive Adenocarcinoma ◽

Linear Discriminant ◽

Microbiome Composition ◽

Male Control

The frequency of azoxymethane/dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in male mice is higher than that in female mice. Previous studies have reported that 17β-estradiol inhibits tumorigenesis in males by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2). This study aimed to investigate the changes in mouse gut microbiome composition based on sex, AOM/DSS-induced colorectal cancer (CRC), and Nrf2 genotype. The gut microbiome composition was determined by 16S rRNA gene sequencing fecal samples obtained at week 16 post-AOM administration. In terms of sex differences, our results showed that the wild-type (WT) male control mice had higher alpha diversity (i.e. Chao1, Shannon, and Simpson) than the WT female control mice. The linear discriminant analysis effect size (LEfSe) results revealed that the abundances of Akkermansia muciniphila and Lactobacillus murinus were higher in WT male control mice than in WT female controls. In terms of colon tumorigenesis, the alpha diversity of the male CRC group was lower than that of the male controls in both WT and Nrf2 KO, but did not show such changes in females. Furthermore, the abundance of A. muciniphila was higher in male CRC groups than in male controls in both WT and Nrf2 KO. The abundance of Bacteroides vulgatus was higher in WT CRC groups than in WT controls in both males and females. However, the abundance of L. murinus was lower in WT female CRC and Nrf2 KO male CRC groups than in its controls. The abundance of A. muciniphila was not altered by Nrf2 KO. In contrast, the abundances of L. murinus and B. vulgatus were changed differently by Nrf2 KO depending on sex and CRC. Interestingly, L. murinus showed negative correlation with tumor numbers in the whole colon. In addition, B. vulgatus showed positive correlation with inflammatory markers (i.e. myeloperoxidase and IL-1β levels), tumor numbers, and high-grade adenoma, especially, developed mucosal and submucosal invasive adenocarcinoma at the distal part of the colon. In conclusion, Nrf2 differentially alters the gut microbiota composition depending on sex and CRC induction.

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Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.806680 ◽

2022 ◽

Vol 11 ◽

Author(s):

Giuseppe Privitera ◽

Nitish Rana ◽

Franco Scaldaferri ◽

Alessandro Armuzzi ◽

Theresa T. Pizarro

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Active Role ◽

Current Evidence ◽

Microbiome Composition ◽

Downstream Effectors ◽

Intestinal Dysbiosis ◽

Causative Relationship ◽

Colonic Carcinogenesis ◽

And Function

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countries. Inflammation is a well-known driver of colonic carcinogenesis; however, its role in CRC extends beyond colitis-associated cancer. Over the last decades, numerous associations between intestinal dysbiosis and CRC have been identified, with more recent studies providing mechanistic evidence of a causative relationship. Nonetheless, much remains to be discovered regarding the precise implications of microbiome alterations in the pathogenesis of CRC. Research confirms the importance of a bidirectional crosstalk between the gut microbiome and the mucosal immune system in which inflammasomes, multiprotein complexes that can sense “danger signals,” serve as conduits by detecting microbial signals and activating innate immune responses, including the induction of microbicidal activities that can alter microbiome composition. Current evidence strongly supports an active role for this “inflammasome–microbiome axis” in the initiation and development of CRC. Furthermore, the gasdermin (GSDM) family of proteins, which are downstream effectors of the inflammasome that are primarily known for their role in pyroptosis, have been recently linked to CRC pathogenesis. These findings, however, do not come without controversy, as pyroptosis is reported to exert both anti- and protumorigenic functions. Furthermore, the multi-faceted interactions between GSDMs and the gut microbiome, as well as their importance in CRC, have only been superficially investigated. In this review, we summarize the existing literature supporting the importance of the inflammasome–microbiota axis, as well as the activation and function of GSDMs, to gain a better mechanistic understanding of CRC pathogenesis.

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Serrated Polyposis: An Enigmatic Model of Colorectal Cancer Predisposition

Pathology Research International ◽

10.4061/2011/157073 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 18

Author(s):

Christophe Rosty ◽

Susan Parry ◽

Joanne P. Young

Keyword(s):

Colorectal Cancer ◽

Familial Risk ◽

Gene Promoter ◽

Promoter Hypermethylation ◽

Normal Mucosa ◽

Premature Aging ◽

Neoplastic Progression ◽

Serrated Polyps ◽

Serrated Polyp ◽

Molecular Features

Serrated polyposis has only recently been accepted as a condition which carries an increased personal and familial risk of colorectal cancer. Described over four decades ago, it remains one of the most underrecognized and poorly understood of all the intestinal polyposes. With a variety of phenotypic presentations, it is likely that serrated polyposis represents a group of diseases rather than a single entity. Further, neoplastic progression in serrated polyposis may be associated with premature aging in the normal mucosa, typified by widespread gene promoter hypermethylation. From this epigenetically altered field, arise diverse polyps and cancers which show a range of molecular features. Despite a high serrated polyp count, only one-third of colorectal cancers demonstrate a BRAF V600E mutation, the molecular hallmark of the canonical serrated pathway, suggesting that though multiple serrated polyps act as a marker of an abnormal mucosa, the majority of CRC in these patients arise within lesions other than BRAF-mutated serrated polyps.

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