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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 -
Nature Reviews. Gastroenterology &... Nov 2021The act of defaecation, although a ubiquitous human experience, requires the coordinated actions of the anorectum and colon, pelvic floor musculature, and the enteric,... (Review)
Review
The act of defaecation, although a ubiquitous human experience, requires the coordinated actions of the anorectum and colon, pelvic floor musculature, and the enteric, peripheral and central nervous systems. Defaecation is best appreciated through the description of four phases, which are, temporally and physiologically, reasonably discrete. However, given the complexity of this process, it is unsurprising that disorders of defaecation are both common and problematic; almost everyone will experience constipation at some time in their life and many will develop faecal incontinence. A detailed understanding of the normal physiology of defaecation and continence is critical to inform management of disorders of defaecation. During the past decade, there have been major advances in the investigative tools used to assess colonic and anorectal function. This Review details the current understanding of defaecation and continence. This includes an overview of the relevant anatomy and physiology, a description of the four phases of defaecation, and factors influencing defaecation (demographics, stool frequency/consistency, psychobehavioural factors, posture, circadian rhythm, dietary intake and medications). A summary of the known pathophysiology of defaecation disorders including constipation, faecal incontinence and irritable bowel syndrome is also included, as well as considerations for further research in this field.
Topics: Anal Canal; Colon; Constipation; Defecation; Defecography; Diet; Fecal Incontinence; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Intestine, Large; Magnetic Resonance Imaging; Magnetic Resonance Imaging, Cine; Manometry; Pelvic Floor; Rectum
PubMed: 34373626
DOI: 10.1038/s41575-021-00487-5 -
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 -
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 -
Biomaterials Dec 2021Although synthesized nanotherapeutics (NTs) are attractive for the oral treatment of colon diseases, their clinical translations are constrained by the unsatisfactory...
Although synthesized nanotherapeutics (NTs) are attractive for the oral treatment of colon diseases, their clinical translations are constrained by the unsatisfactory therapeutic outcomes, potential adverse effects, and high cost of mass production. Here, we report the development of tea leaf-derived natural NTs with desirable particle sizes (140.0 nm) and negative surface charge (-14.6 mV). These natural exosome-like NTs were found to contain large amounts of lipids, some functional proteins, and many bioactive small molecules. Specifically, galactose groups on the surface of NTs could mediate their specific internalization by macrophages via galactose receptor-mediated endocytosis. Moreover, these NTs were able to reduce the production of reactive oxygen species, inhibit the expression of pro-inflammatory cytokines, and increase the amount of anti-inflammatory IL-10 secreted by macrophages. Orally administered NTs could efficiently inhibit the inflammatory bowel responses, restore disrupted colonic barriers and enhance the diversity and overall abundance of gut microbiota, thereby preventing or alleviating inflammatory bowel disease and colitis-associated colon cancer. The present study brings new insights to the facile application of a versatile and robust natural nanoplatform for the prevention and treatment of colon diseases.
Topics: Animals; Colitis; Colon; Cytokines; Disease Models, Animal; Inflammatory Bowel Diseases; Plant Leaves; Tea
PubMed: 34656857
DOI: 10.1016/j.biomaterials.2021.121178 -
Journal of Agricultural and Food... Nov 2022Gut dysbiosis and bile acid (BA) metabolism disturbance are involved in the pathogenesis of ulcerative colitis. This study aimed to investigate the effect of fucoidan on...
Gut dysbiosis and bile acid (BA) metabolism disturbance are involved in the pathogenesis of ulcerative colitis. This study aimed to investigate the effect of fucoidan on BA metabolism and gut microbiota in dextran sulfate sodium-induced colitis mice. Our results showed that fucoidan effectively suppressed colonic inflammation and repaired the gut barrier. In addition, fucoidan increased the relative abundance of the Lachnospiraceae family, such as , , , and , followed by an increase in short-chain fatty acids, especially in butyrate. Moreover, fucoidan modulated bile acid metabolism by elevating cholic acid, ursodeoxycholic acid, deoxycholic acid, and lithocholic acid and decreasing β-muricholic acid, which led to activation of FXR and TGR5 and further enhanced the gut barrier and suppressed colonic inflammation. Our results revealed that the effect of fucoidan alleviating colitis was largely mediated by gut microbiota, which was confirmed by the fecal transplantation experiment. Collectively, these findings provided the basis for fucoidan as a potential functional food for colitis.
Topics: Mice; Animals; Gastrointestinal Microbiome; Dextran Sulfate; Colitis, Ulcerative; Disease Models, Animal; Colitis; Colon; Inflammation; Ursodeoxycholic Acid; Mice, Inbred C57BL
PubMed: 36378195
DOI: 10.1021/acs.jafc.2c06417 -
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 -
Clinical Anatomy (New York, N.Y.) May 2022The precaecocolic fascia, previously known as Jackson's membrane, is a variable vascular peritoneal fold between the ascending colon and the right posterolateral...
The precaecocolic fascia, previously known as Jackson's membrane, is a variable vascular peritoneal fold between the ascending colon and the right posterolateral abdominal wall. First described in 1913, it was originally thought to be of developmental or inflammatory origin and associated with abdominal pain. This investigation aimed to review its frequency, form and structure and look for evidence of association with malformation of the bowel, or previous inflammation. 26 dissecting room cadavers were studied to identify the precaecocolic fascia, any malrotation of the colon or signs of previous inflammation: adhesions, surgical scars, or absence of the appendix. Its structure was examined histologically and latex injections were used to trace the arteries. Membranes comparable with previous descriptions of the precaecocolic fascia occurred in 12 of 26 abdomens. They varied in form and size from long and translucent to short, thick, and opaque. In structure, the fascia resembled a fold of peritoneum containing a thickened fibrous lamina. Large thin-walled arteries in the fascia crossed the arteries in the wall of the colon at the point of attachment. No significant association with colonic malrotation or markers of previous inflammation were found. Attention should be paid to the definition of the precaecocolic fascia and "membrane" seems a more appropriate term than "fascia". It is one of a recognized group of peritoneal folds/bands, doubtful in origin but unlikely to be post-inflammatory. It may modify colonic mobility or complicate colonic operations.
Topics: Colon; Colon, Ascending; Fascia; Humans; Inflammation; Peritoneum
PubMed: 34535937
DOI: 10.1002/ca.23787 -
Current Opinion in Gastroenterology Sep 2022Colorectal cancer continues to be one of the most common causes of cancer-related death. Widespread dissemination of screening colonoscopy in the United States has led... (Review)
Review
PURPOSE OF REVIEW
Colorectal cancer continues to be one of the most common causes of cancer-related death. Widespread dissemination of screening colonoscopy in the United States has led to a significant reduction in the incidence and mortality. Here we review current literature with an aim to highlight recent improvements in the safety, efficiency, and effectiveness of screening colonoscopy.
RECENT FINDINGS
Colon capsule endoscopy is an emerging noninvasive method to capture images of colonic mucosa for select patients with appreciable sensitivity for polyp detection. Recent literature supports the use of the novel oral anticoagulant apixaban over other anticoagulants to reduce the risk of gastrointestinal bleeding related to colonoscopy. Cold snare polypectomy for smaller lesions and prophylactic clipping following resection of large polyps in the proximal colon may reduce the rate of delayed bleeding. Novel methods and devices for improving bowel preparation continue to emerge. Mechanical attachment devices and artificial intelligence represent recent innovations to improve polyp detection.
SUMMARY
Clinicians should be aware of relevant data and literature that continue to improve the quality and safety of screening colonoscopy and incorporate these findings into their clinical practice.
Topics: Artificial Intelligence; Colon; Colonic Polyps; Colonoscopy; Colorectal Neoplasms; Humans; Mass Screening
PubMed: 35894671
DOI: 10.1097/MOG.0000000000000860