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Nature Reviews. Gastroenterology &... Jun 2013Mucins--large, highly glycosylated proteins--are important for the luminal protection of the gastrointestinal tract. Enterocytes have their apical surface covered by... (Review)
Review
Mucins--large, highly glycosylated proteins--are important for the luminal protection of the gastrointestinal tract. Enterocytes have their apical surface covered by transmembrane mucins and goblet cells produce the secreted gel-forming mucins that form mucus. The small intestine has a single unattached mucus layer, which in cystic fibrosis becomes attached, accounting for the intestinal manifestations of this disease. The stomach and colon have two layers of mucus; the inner layer is attached and the outer layer is less dense and unattached. In the colon, the outer mucus layer is the habitat for commensal bacteria. The inner mucus layer is impervious to bacteria and is renewed every hour by surface goblet cells. The crypt goblet cells have the ability to restitute the mucus layer by secretion, for example after an ischaemic challenge. Proteases of certain parasites and some bacteria can cleave mucins and dissolve the mucus as part of their pathogenicity. The inner mucus layer can, however, also become penetrable to bacteria by several other mechanisms, including aberrations in the immune system. When bacteria reach the epithelial surface, the immune system is activated and inflammation is triggered. This mechanism might occur in some types of ulcerative colitis.
Topics: Colitis; Colon; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Intestine, Small; Mucus; Stomach
PubMed: 23478383
DOI: 10.1038/nrgastro.2013.35 -
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 -
Alimentary Pharmacology & Therapeutics Jan 2008Butyrate, a short-chain fatty acid, is a main end-product of intestinal microbial fermentation of mainly dietary fibre. Butyrate is an important energy source for... (Review)
Review
BACKGROUND
Butyrate, a short-chain fatty acid, is a main end-product of intestinal microbial fermentation of mainly dietary fibre. Butyrate is an important energy source for intestinal epithelial cells and plays a role in the maintenance of colonic homeostasis.
AIM
To provide an overview on the present knowledge of the bioactivity of butyrate, emphasizing effects and possible mechanisms of action in relation to human colonic function.
METHODS
A PubMed search was performed to select relevant publications using the search terms: 'butyrate, short-chain fatty acid, fibre, colon, inflammation, carcinogenesis, barrier, oxidative stress, permeability and satiety'.
RESULTS
Butyrate exerts potent effects on a variety of colonic mucosal functions such as inhibition of inflammation and carcinogenesis, reinforcing various components of the colonic defence barrier and decreasing oxidative stress. In addition, butyrate may promote satiety. Two important mechanisms include the inhibition of nuclear factor kappa B activation and histone deacetylation. However, the observed effects of butyrate largely depend on concentrations and models used and human data are still limited.
CONCLUSION
Although most studies point towards beneficial effects of butyrate, more human in vivo studies are needed to contribute to our current understanding of butyrate-mediated effects on colonic function in health and disease.
Topics: Animals; Butyrates; Carbohydrate Metabolism; Child, Preschool; Colon; Colonic Neoplasms; Dietary Fiber; Enema; Fatty Acids, Volatile; Humans; Infant, Newborn; Inflammation; Intestinal Mucosa; Oxidative Stress; Rabbits; Rats; Satiation
PubMed: 17973645
DOI: 10.1111/j.1365-2036.2007.03562.x -
Physiological Reviews Jul 2001Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure,... (Review)
Review
Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure, cooking of food, chemical modification, and food mastication. Human colonic bacteria ferment RS and nonstarch polysaccharides (NSP; major components of dietary fiber) to short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate. SCFA stimulate colonic blood flow and fluid and electrolyte uptake. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. Fermentation of some RS types favors butyrate production. Measurement of colonic fermentation in humans is difficult, and indirect measures (e.g., fecal samples) or animal models have been used. Of the latter, rodents appear to be of limited value, and pigs or dogs are preferable. RS is less effective than NSP in stool bulking, but epidemiological data suggest that it is more protective against colorectal cancer, possibly via butyrate. RS is a prebiotic, but knowledge of its other interactions with the microflora is limited. The contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP. However, the lack of a generally accepted analytical procedure that accommodates the major influences on RS means this is yet to be established.
Topics: Colon; Dietary Fiber; Digestion; Fatty Acids, Volatile; Fermentation; Humans; Intestinal Absorption; Intestine, Small; Polysaccharides; Starch
PubMed: 11427691
DOI: 10.1152/physrev.2001.81.3.1031 -
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 -
Proceedings of the National Academy of... Sep 2008We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is...
We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 mum above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2(-/-) mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation.
Topics: Animals; Colitis; Colon; Intestinal Mucosa; Mice; Mice, Mutant Strains; Mucin-2; Mucins; Mucus; Rats; Rats, Sprague-Dawley; Symbiosis
PubMed: 18806221
DOI: 10.1073/pnas.0803124105 -
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 -
Nutrients Jan 2015Globally, zinc deficiency is widespread, despite decades of research highlighting its negative effects on health, and in particular upon child health in low-income... (Review)
Review
Globally, zinc deficiency is widespread, despite decades of research highlighting its negative effects on health, and in particular upon child health in low-income countries. Apart from inadequate dietary intake of bioavailable zinc, other significant contributors to zinc deficiency include the excessive intestinal loss of endogenously secreted zinc and impairment in small intestinal absorptive function. Such changes are likely to occur in children suffering from environmental (or tropical) enteropathy (EE)-an almost universal condition among inhabitants of developing countries characterized by morphologic and functional changes in the small intestine. Changes to the proximal gut in environmental enteropathy will likely influence the nature and amount of zinc delivered into the large intestine. Consequently, we reviewed the current literature to determine if colonic absorption of endogenous or exogenous (dietary) zinc could contribute to overall zinc nutriture. Whilst we found evidence that significant zinc absorption occurs in the rodent colon, and is favoured when microbially-fermentable carbohydrates (specifically resistant starch) are consumed, it is unclear whether this process occur in humans and/or to what degree. Constraints in study design in the few available studies may well have masked a possible colonic contribution to zinc nutrition. Furthermore these few available human studies have failed to include the actual target population that would benefit, namely infants affected by EE where zinc delivery to the colon may be increased and who are also at risk of zinc deficiency. In conducting this review we have not been able to confirm a colonic contribution to zinc absorption in humans. However, given the observations in rodents and that feeding resistant starch to children is feasible, definitive studies utilising the dual stable isotope method in children with EE should be undertaken.
Topics: 6-Phytase; Animals; Biological Availability; Colon; Homeostasis; Humans; Hydrolysis; Intestine, Small; Models, Animal; Phytic Acid; Zinc
PubMed: 25594440
DOI: 10.3390/nu7010572 -
Comprehensive Physiology Sep 2018The colon has large capacities for K absorption and K secretion, but its role in maintaining K homeostasis is often overlooked. For many years, passive diffusion and/or... (Review)
Review
The colon has large capacities for K absorption and K secretion, but its role in maintaining K homeostasis is often overlooked. For many years, passive diffusion and/or solvent drag were thought to be the primary mechanisms for K absorption in human and animal colon. However, it is now clear that apical H ,K -ATPase, in coordination with basolateral K -Cl cotransport and/or K and Cl channels operating in parallel, mediate electroneutral K absorption in animal colon. We now know that K absorption in rat colon reflects ouabain-sensitive and ouabain-insensitive apical H ,K -ATPase activities. Ouabain-insensitive and ouabain-sensitive H ,K -ATPases are localized in surface and crypt cells, respectively. Colonic H ,K -ATPase consists of α- (HKC ) and β- (HKC ) subunits which, when coexpressed, exhibit ouabain-insensitive H ,K -ATPase activity in HEK293 cells, while HKC coexpressed with the gastric β-subunit exhibits ouabain-sensitive H ,K -ATPase activity in Xenopus oocytes. Aldosterone enhances apical H ,K -ATPase activity, HKC specific mRNA and protein expression, and K absorption. Active K secretion, on the other hand, is mediated by apical K channels operating in a coordinated way with the basolateral Na -K -2Cl cotransporter. Both Ca -activated intermediate conductance K (IK) and large conductance K (BK) channels are located in the apical membrane of colonic epithelia. IK channel-mediated K efflux provides the driving force for Cl secretion, while BK channels mediate active (e.g., cAMP-activated) K secretion. BK channel expression and activity are increased in patients with end-stage renal disease and ulcerative colitis. This review summarizes the role of apical H ,K -ATPase in K absorption, and apical BK channel function in K secretion in health and disease. © 2018 American Physiological Society. Compr Physiol 8:1513-1536, 2018.
Topics: Animals; Colon; Humans; Intestinal Absorption; Potassium; Potassium Channels
PubMed: 30215859
DOI: 10.1002/cphy.c170030 -
The Veterinary Clinics of North... Aug 1997Displacements and intraluminal obstructions of the large colon carry a good to excellent prognosis for long-term recovery, and surgery for these diseases is rarely... (Review)
Review
Displacements and intraluminal obstructions of the large colon carry a good to excellent prognosis for long-term recovery, and surgery for these diseases is rarely followed by short-term or long-term complications. Entrapment of the large colon over the renosplenic ligament is amenable to medical therapies so that surgery can be avoided in many cases. However, preoperative diagnosis of all nonstrangulating diseases of the large colon can be difficult. Vascular diseases of the large colon, such as thromboembolic diseases and large colon volvulus, are more difficult to treat and carry a poorer prognosis for survival.
Topics: Animals; Bezoars; Colitis; Colon; Colonic Diseases; Horse Diseases; Horses; Infarction; Intestinal Obstruction; Postoperative Care; Prognosis
PubMed: 9290186
DOI: 10.1016/s0749-0739(17)30242-0