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Cancer Cell Jun 2018Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a... (Review)
Review
Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.
Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Gastrointestinal Microbiome; Humans; Models, Biological; Rectum; Signal Transduction
PubMed: 29657127
DOI: 10.1016/j.ccell.2018.03.004 -
Journal of Controlled Release :... Jan 2023Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects.... (Review)
Review
Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.
Topics: Drug Delivery Systems; Colon; Pharmaceutical Preparations; Administration, Oral; Biological Availability
PubMed: 36528195
DOI: 10.1016/j.jconrel.2022.12.029 -
World Journal of Gastroenterology Jan 2019Differentiating Crohn's disease (CD) and intestinal tuberculosis (ITB) has remained a dilemma for most of the clinicians in the developing world, which are endemic for... (Review)
Review
Differentiating Crohn's disease (CD) and intestinal tuberculosis (ITB) has remained a dilemma for most of the clinicians in the developing world, which are endemic for ITB, and where the disease burden of inflammatory bowel disease is on the rise. Although, there are certain clinical (diarrhea/hematochezia/perianal disease common in CD; fever/night sweats common in ITB), endoscopic (longitudinal/aphthous ulcers common in CD; transverse ulcers/patulous ileocaecal valve common in ITB), histologic (caseating/confluent/large granuloma common in ITB; microgranuloma common in CD), microbiologic (positive stain/culture for acid fast-bacillus in ITB), radiologic (long segment involvement/comb sign/skip lesions common in CD; necrotic lymph node/contiguous ileocaecal involvement common in ITB), and serologic differences between CD and ITB, the only exclusive features are caseation necrosis on biopsy, positive smear for acid-fast bacillus (AFB) and/or AFB culture, and necrotic lymph node on cross-sectional imaging in ITB. However, these exclusive features are limited by poor sensitivity, and this has led to the development of multiple multi-parametric predictive models. These models are also limited by complex formulae, small sample size and lack of validation across other populations. Several new parameters have come up including the latest Bayesian meta-analysis, enumeration of peripheral blood T-regulatory cells, and updated computed tomography based predictive score. However, therapeutic anti-tubercular therapy (ATT) trial, and subsequent clinical and endoscopic response to ATT is still required in a significant proportion of patients to establish the diagnosis. Therapeutic ATT trial is associated with a delay in the diagnosis of CD, and there is a need for better modalities for improved differentiation and reduction in the need for ATT trial.
Topics: Antitubercular Agents; Biopsy; Colon; Colonoscopy; Crohn Disease; Diagnosis, Differential; Humans; Intestinal Mucosa; Mycobacterium tuberculosis; Predictive Value of Tests; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Gastrointestinal
PubMed: 30700939
DOI: 10.3748/wjg.v25.i4.418 -
Cell Stem Cell Jan 2022Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not...
Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5 adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.
Topics: Animals; Colon; Ileum; Intestinal Mucosa; Mice; Organoids; Stem Cells
PubMed: 34582804
DOI: 10.1016/j.stem.2021.09.004 -
Science (New York, N.Y.) Feb 2018Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with...
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of and Genes for colibactin () and toxin (), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with (expressing colibactin), and enterotoxigenic showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.
Topics: Adenomatous Polyposis Coli; Animals; Bacterial Toxins; Bacteroides fragilis; Biofilms; Carcinogenesis; Colon; Colonic Neoplasms; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Humans; Interleukin-17; Intestinal Mucosa; Metalloendopeptidases; Mice; Peptides; Polyketides; Precancerous Conditions
PubMed: 29420293
DOI: 10.1126/science.aah3648 -
Cell Stem Cell Nov 2023Most organs have tissue-resident immune cells. Human organoids lack these immune cells, which limits their utility in modeling many normal and disease processes. Here,...
Most organs have tissue-resident immune cells. Human organoids lack these immune cells, which limits their utility in modeling many normal and disease processes. Here, we describe that pluripotent stem cell-derived human colonic organoids (HCOs) co-develop a diverse population of immune cells, including hemogenic endothelium (HE)-like cells and erythromyeloid progenitors that undergo stereotypical steps in differentiation, resulting in the generation of functional macrophages. HCO macrophages acquired a transcriptional signature resembling human fetal small and large intestine tissue-resident macrophages. HCO macrophages modulate cytokine secretion in response to pro- and anti-inflammatory signals and were able to phagocytose and mount a robust response to pathogenic bacteria. When transplanted into mice, HCO macrophages were maintained within the colonic organoid tissue, established a close association with the colonic epithelium, and were not displaced by the host bone-marrow-derived macrophages. These studies suggest that HE in HCOs gives rise to multipotent hematopoietic progenitors and functional tissue-resident macrophages.
Topics: Humans; Mice; Animals; Pluripotent Stem Cells; Hematopoietic Stem Cells; Colon; Organoids; Macrophages
PubMed: 37922878
DOI: 10.1016/j.stem.2023.10.002 -
Cell Oct 2020The colon is primarily responsible for absorbing fluids. It contains a large number of microorganisms including fungi, which are enriched in its distal segment. The...
The colon is primarily responsible for absorbing fluids. It contains a large number of microorganisms including fungi, which are enriched in its distal segment. The colonic mucosa must therefore tightly regulate fluid influx to control absorption of fungal metabolites, which can be toxic to epithelial cells and lead to barrier dysfunction. How this is achieved remains unknown. Here, we describe a mechanism by which the innate immune system allows rapid quality check of absorbed fluids to avoid intoxication of colonocytes. This mechanism relies on a population of distal colon macrophages that are equipped with "balloon-like" protrusions (BLPs) inserted in the epithelium, which sample absorbed fluids. In the absence of macrophages or BLPs, epithelial cells keep absorbing fluids containing fungal products, leading to their death and subsequent loss of epithelial barrier integrity. These results reveal an unexpected and essential role of macrophages in the maintenance of colon-microbiota interactions in homeostasis. VIDEO ABSTRACT.
Topics: Animals; Colon; Epithelial Cells; Epithelium; Female; Gastrointestinal Microbiome; Homeostasis; Immunity, Innate; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Inbred C57BL; Microbiota; Signal Transduction
PubMed: 32970988
DOI: 10.1016/j.cell.2020.08.048 -
American Journal of Physiology.... Jan 2018We examined the role of macrophages in inflammation associated with colorectal cancer (CRC). Given the emerging evidence on immune-microbiota interactions in CRC, we...
We examined the role of macrophages in inflammation associated with colorectal cancer (CRC). Given the emerging evidence on immune-microbiota interactions in CRC, we also sought to examine the interaction between macrophages and gut microbiota. To induce CRC, male C57BL/6 mice ( n = 32) received a single injection of azoxymethane (AOM), followed by three cycles of dextran sodium sulfate (DSS)-supplemented water in weeks 1, 4, and 7. Prior to the final DSS cycle ( week 7) and twice weekly until euthanasia, mice ( n = 16/group) received either 200 μl ip of clodronate-filled liposomes (CLD) or phosphate-buffered saline (PBS) encapsulated liposomes to deplete macrophages. Colon tissue was analyzed for polyp burden, macrophage markers, transcription factors, and inflammatory mediators. Stool samples were collected, and DNA was isolated and subsequently sequenced for 16S rRNA. Clodronate liposomes decreased tumor number by ∼36% and specifically large (≥1 mm) tumors by ∼36% ( P < 0.05). This was consistent with a decrease in gene expression of EMR1 in the colon tissue and polyp tissue as well as expression of select markers associated with M1 (IL-6) and M2 macrophages (IL-13, IL-10, TGFβ, CCL17) in the colon tissue ( P < 0.05). Similarly, there was a decrease in STAT3 and p38 MAPK and ERK signaling in colon tissue. Clodronate liposomes increased the relative abundance of the Firmicutes phylum ( P < 0.05) and specifically Lactobacillaceae and Clostridiaceae families, which have been associated with reduced CRC risk. Overall, these data support the development of therapeutic strategies to target macrophages in CRC and provide support for further evaluation of immune-microbiota interactions in CRC. NEW & NOTEWORTHY We found that macrophage depletion during late-stage tumorigenesis is effective at reducing tumor growth. This was associated with a decrease in macrophage markers and chemokines in the colon tissue and a decrease in transcription factors that are linked to colorectal cancer. The macrophage-depleted group was found to have an increased abundance of Firmicutes, a phylum with documented anti-tumorigenic effects. Overall, these data support the development of therapeutic strategies to target macrophages in colorectal cancer.
Topics: Animals; Anticarcinogenic Agents; Azoxymethane; Biomarkers, Tumor; Cell Transformation, Neoplastic; Clodronic Acid; Colon; Colonic Polyps; Colorectal Neoplasms; Cytokines; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Host-Pathogen Interactions; Inflammation Mediators; Liposomes; Macrophages; Male; Mice, Inbred C57BL; Signal Transduction; Time Factors; Tumor Burden
PubMed: 29025731
DOI: 10.1152/ajpgi.00229.2017 -
Nature Medicine Jul 2017With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human...
With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.
Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Antibiotics, Antineoplastic; Blotting, Western; Cell Differentiation; Cell Proliferation; Colon; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Enteroendocrine Cells; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Profiling; Gentamicins; Germ-Line Mutation; Goblet Cells; Heterocyclic Compounds, 3-Ring; Human Embryonic Stem Cells; Humans; Immunohistochemistry; Induced Pluripotent Stem Cells; Microscopy, Confocal; Mutation; Organoids; Real-Time Polymerase Chain Reaction; Sirolimus; Wnt Signaling Pathway
PubMed: 28628110
DOI: 10.1038/nm.4355 -
Gut Microbes 2022The immune system in the large intestine is separated from commensal microbes and comparatively rare enteric pathogens by a monolayer of diverse epithelial cells... (Review)
Review
The immune system in the large intestine is separated from commensal microbes and comparatively rare enteric pathogens by a monolayer of diverse epithelial cells overlaid with a compact and adherent inner mucus layer and a looser outer mucus layer. Microorganisms, collectively referred to as the mucus-associated (MA) microbiota, physically inhabit this mucus barrier, resulting in a dynamic and incessant dialog to maintain both spatial segregation and immune tolerance. Recent major findings reveal novel features of the crosstalk between the immune system and mucus-associated bacteria in health and disease, as well as disease-related peripheral immune signatures indicative of host responses to these organisms. In this brief review, we integrate these novel observations into our overall understanding of host-microbiota mutualism at the colonic mucosal border and speculate on the significance of this emerging knowledge for our understanding of the prevention, development, and progression of chronic intestinal inflammation.
Topics: Colon; Gastrointestinal Microbiome; Humans; Immune System; Inflammation; Intestinal Mucosa; Mucus; Symbiosis
PubMed: 35239459
DOI: 10.1080/19490976.2022.2041342