ArticleLiterature Review

Surface area of the digestive tract—Revisited

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Abstract

Background: According to textbooks, the human gut mucosa measures 260-300 m(2), that is, in the order of a tennis court. However, the quantitative data are incomplete and sometimes conflicting. Objectives: To review the literature regarding the mucosal surface area of the human digestive tract; to collect morphometric data from the parts of the gut where such data are missing; and to recalculate the mucosal surface area of the intestine in man. Methods: With focus on the intestine, we carried out morphometry by light and electron microscopy on biopsies from healthy adult volunteers or patients with endoscopically normal mucosae. Results: Literature review of intubation or radiological methods indicates an oroanal length of ∼5 m, two-third of which refers to the small intestine. However, there is a considerable variation between individuals. The inner diameter of the small intestine averages 2.5 cm and that of the large intestine averages 4.8 cm. The mucosa of the small intestine is enlarged ∼1.6 times by the plicae circulares. Morphometric data obtained by light and electron microscopy of biopsies demonstrate that villi and microvilli together amplify the small intestinal surface area by 60-120 times. Surface amplification due to microvilli in the colon is ∼6.5 times. The mean total mucosal surface of the digestive tract interior averages ∼32 m(2), of which about 2 m(2) refers to the large intestine. Conclusion: The total area of the human adult gut mucosa is not in the order of tennis lawn, rather is that of half a badminton court.

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... The gastrointestinal tract (GI) consisting of the esophagus, stomach, small intestine and the large intestine (Figure 1.1A) represents one of the biggest organ systems in humans and rodents [1,2] with a mean length of about 7.62 m [1] and an average mucosal surface area of ~ 32 m² in humans [3]. In comparison, the murine GI tract is about 55.5 cm in length with a surface area of ~ 402.31 cm² [4]. ...
... The tunica serosa as outermost sheet is comprised of connective [7,10,11] (Figure 1.1B). Together, the submucosa and the mucosa build protrusions called villi towards the lumen thereby enhancing the apical surface, which implicates an increased nutrient uptake capacity of the epithelium [3,7]. Of note, those villi structures are intermingled by crypt regions representing the germinal zone of the small intestinal epithelium where continuous cell renewal and proliferation occurs (discussed in more detail in the next section). ...
... In contrast to the crypt, the villus domain represents an elongated structure with differentiated enterocytes as most prominent cell population (Figure 1.3A) that play a major role in nutrient digestion and nutrient absorption secreting digestive enzymes and presenting specialized transporter proteins for molecule absorption on the apical cell surface, also known as brush border membrane. To increase nutrient absorption and enzyme secretion at the luminal surface, the villus epithelium is further enlarged by microscopic membrane protrusions called microvilli [3,44]. Next to the enterocytes, the villus epithelium contains hormone-secreting enteroendocrine cells (EECs) and mucin-producing goblet cells. ...
Thesis
The small intestine represents a strong barrier separating the lumen from blood circulation thereby playing a major role in the absorption and the transport of pharmacological agents prior to their arrival on the respective target site. In order to gain more knowledge about specialized uptake mechanisms and risk assessment for the patient after oral admission of drugs, intestinal in vitro models demonstrating a close similarity to the in vivo situation are needed. In the past, cell line-based in vitro models composed of Caco-2 cells cultured on synthetic cell carriers represented the “gold standard” in the field of intestinal tissue engineering. Expressive advantages of these models are a reproducible, cost-efficient and standardized model set up, but cell function can be negatively influenced by the low porosity or unwanted molecular adhesion effects of the artificial scaffold material. Natural extracellular matrices (ECM) such as the porcine decellularized small intestinal submucosa (SIS) are used as alternative to overcome some common drawbacks; however, the fabrication of these scaffolds is time- and cost-intensive, less well standardized and the 3Rs (replacement, reduction, refinement) principle is not entirely fulfilled. Nowadays, biopolymer-based scaffolds such as the bacterial nanocellulose (BNC) suggest an interesting option of novel intestinal tissue engineered models, as the BNC shows comparable features to the native ECM regarding fiber arrangement and hydrophilic properties. Furthermore, the BNC is of non-animal origin and the manufacturing process is faster as well as well standardized at low costs. In this context, the first part of this thesis analyzed the BNC as alternative scaffold to derive standardized and functional organ models in vitro. Therefore, Caco-2 cells were cultured on two versions of BNC with respect to their surface topography, the unmodified BNC as rather smooth surface and the surface-structured BNC presenting an aligned fiber arrangement. As controls, Caco-2 in vitro models were set up on PET and SIS matrices. In this study, the BNC-based models demonstrated organ-specific properties comprising typical cellular morphologies, a characteristic tight junction protein expression profile, representative ultrastructural features and the formation of a tight epithelial barrier together with a corresponding transport activity. In summary, these results validated the high quality of the BNC-based Caco-2 models under cost-efficient conditions and their suitability for pre-clinical research purposes. However, the full functional diversity of the human intestine cannot be presented by Caco-2 cells due to their tumorigenic background and their exclusive representation of mature enterocytes. Next to the scaffold used for the setup of in vitro models, the cellular unit mainly drives functional performance, which demonstrates the crucial importance of mimicking the cellular diversity of the small intestine in vitro. In this context, intestinal primary organoids are of high interest, as they show a close similarity to the native epithelium regarding their cellular diversity comprising enterocytes, goblet cells, enteroendocrine cells, paneth cells, transit amplifying cells and stem cells. In general, such primary organoids grow in a 3D Matrigel® based environment and a medium formulation supplemented with a variety of growth factors to maintain stemness, to inhibit differentiation and to stimulate cell migration supporting long term in vitro culture. Intestinal primary spheroid/organoid cultures were set up as Transwell®-like models on both BNC variants, which resulted in a fragmentary cell layer and thereby unfavorable properties of these scaffold materials under the applied circumstances. As the BNC manufacturing process is highly flexible, surface properties could be adapted in future studies to enable a good cell adherence and barrier formation for primary intestinal cells, too. However, the application of these organoid cultures in pre-clinical research represents an enormous challenge, as the in vitro culture is complex and additionally time- and cost-intensive. With regard to the high potential of primary intestinal spheroids/organoids and the necessity of a simplified but predictive model in pre-clinical research purposes, the second part of this thesis addressed the establishment of a primary-derived immortalized intestinal cell line, which enables a standardized and cost-efficient culture (including in 2D), while maintaining the cellular diversity of the organoid in vitro cultures. In this study, immortalization of murine and human intestinal primary organoids was induced by ectopic expression of a 10- (murine) or 12 component (human) pool of genes regulating stemness and the cell cycle, which was performed in cooperation with the InSCREENeX GmbH in a 2D- and 3D-based transduction strategy. In first line, the established cell lines (cell clones) were investigated for their cell culture prerequisites to grow under simplified and cost-efficient conditions. While murine cell clones grew on uncoated plastic in a medium formulation supplemented with EGF, Noggin, Y-27632 and 10% FCS, the human cell clones demonstrated the necessity of a Col I pre coating together with the need for a medium composition commonly used for primary human spheroid/organoid cultures. Furthermore, the preceding analyses resulted in only one human cell clone and three murine cell clones for ongoing characterization. Studies regarding the proliferative properties and the specific gene as well as protein expression profile of the remaining cell clones have shown, that it is likely that transient amplifying cells (TACs) were immortalized instead of the differentiated cell types localized in primary organoids, as 2D, 3D or Transwell®-based cultures resulted in slightly different gene expression profiles and in a dramatically reduced mRNA transcript level for the analyzed marker genes representative for the differentiated cell types of the native epithelium. Further, 3D cultures demonstrated the formation of spheroid-like structures; however without forming organoid-like structures due to prolonged culture, indicating that these cell populations have lost their ability to differentiate into specific intestinal cell types. The Transwell®-based models set up of each clone exhibit organ-specific properties comprising an epithelial-like morphology, a characteristic protein expression profile with an apical mucus-layer covering the villin-1 positive cell layer, thereby representing goblet cells and enterocytes, together with representative tight junction complexes indicating an integer epithelial barrier. The proof of a functional as well as tight epithelial barrier in TEER measurements and in vivo-like transport activities qualified the established cell clones as alternative cell sources for tissue engineered models representing the small intestine to some extent. Additionally, the easy handling and cell expansion under more cost-efficient conditions compared to primary organoid cultures favors the use of these newly generated cell clones in bioavailability studies. Altogether, this work demonstrated new components, structural and cellular, for the establishment of alternative in vitro models of the small intestinal epithelium, which could be used in pre-clinical screenings for reproducible drug delivery studies.
... The small intestine is located between the stomach and the colon and is in average 2.5 cm in diameter and 291cm long (Helander et al., 2014). This part of the digestive tract has three successive sections: the duodenum (0.25 m), the jejunum (2.5 m) (Collins et al., 2021), and the ileum (3.5 m) (Zhan et al., 2004). ...
Thesis
The human intestinal microbiota is composed of several types of microorganisms, including bacteria, archaea, fungi, unicellular eukaryotes and viruses. Among them, bacteria are the most diverse and abundant with a gene catalog 150 times larger than the genes present in the human genome, which represents a tremendous metabolic potential. These bacteria actively participate in the maintenance of intestinal homeostasis. Dysbiosis of the gut microbiota could be observed at course of many human pathologies, particularly inflammatory diseases intestinal chronic diseases (IBD), such as Crohn's disease (CD) or Ulcerative colitis (UC). These dysbiosis could contribute to the onset and progression of diseases. For example, gut microbiota transplantation experiments in murine model have allowed to show that a dysbiotic microbiota is sufficient to induce chronic inflammation in the colon and thus lead to the development of a metabolic syndrome or colitis. Different intervention strategies, including fecal transplantation, administration of probiotics or even special nutritional diets have been developed to act on the microbial communities of the digestive tract and to restore homeostasis of host tissues. The success of some interventions like Fecal transplantation represent a proof of concept in humans that acting on the composition of the intestinal microbiota is a strong lever to resolve certain physio pathological situations associated with gut microbiota dysbiosis. Diet is another important method for modulating the gut microbiota since it is the most important factor influencing its composition. In fact, the nutrients ingested can act directly on the composition of the microbiota by serving as substrates for microorganisms and indirectly by modulating intestinal homeostasis and components of the immune system associated, themselves contributing to regulate the composition microbiota. It is expected that ingestion of these beneficial microorga nisms can stimulate the immune system, promote intestinal homeostasis and to some extent contribute to the balance of the microbiota intestinal. The use of probiotic microorganisms is found to be very effective in some studies to treat different physiopathological situations (colitis, metabolic syndrome) in laboratory model organisms (rats, mice), however the use of these same probiotics in humans have given relatively disappointing clinical results, with poorly reproducible results across cohorts of patients. Except for the treatment of antibiotic-associated diarrhea. These discrepancies in results between pre-clinical models and clinical trials encourage better characterization of the molecular mechanisms used by probiotics to exert their beneficial effects and especially better understand the relationship of these probiotic microorganisms with the resident microbiota and diet.Among the different rising intervention strategies practiced nowadays in the purpose to shape the microbiota, a growing interest is given to other dietary interventions, like caloric restriction (CR) which has demonstrated several beneficial effects on various physiological systems, including the gastro-intestinal system, by modulating the innate and adaptative immune responses. In fact, emerging evidence suggests that the immune system function might be heavily influenced by the sensing of nutrient, reinforcing the idea that diet can deeply influence the inflammatory responses.
... 17 Furthermore, research in animal models has suggested that the target depth to which the stomach wall can be penetrated is 4-5 mm, with wall thicknesses of 4-8 mm depending on the location. 7,[18][19][20][21][22][23][24] The size of the device is an important safety consideration that must be taken into account to avoid device interruption or cessation. Capsule-shaped devices of 9 mm in diameter and 15 mm in length set a safe standard for ingestible oral devices. ...
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Oral delivery is preferred over other routes of drug administration by both patients and physicians. The bioavailability of some therapeutics that are delivered via the oral route is restricted due to the protease- and bacteria-rich environment in the gastrointestinal tract, and by the pH variability along the delivery route. Given these harsh environments, the oral delivery of therapeutic macromolecules is complicated and remains challenging. Various formulation approaches, including the use of permeation enhancers and nanosized carriers, as well as chemical alteration of the drug structure, have been studied as ways to improve the oral absorption of macromolecular drugs. Nevertheless, the bioavailability of marketed oral peptide medicines is often relatively poor. This review highlights the most recent and promising physical methods for improving the oral bioavailability of macromolecules such as peptides. These methods include microneedle injections, high-speed stream injectors, magnetic drug targeting, expandable hydrogels, and iontophoresis. We highlight the potential and challenges of these new technologies, which may impact the future approaches used by pharmaceutical companies to create more efficient and safer orally administered macromolecules. Teaser: Despite substantial effort, the oral delivery of macromolecules remains challenging due to their low bioavailability. This review discusses the potential, challenges, and safety concerns associated with new technologies and devices for oral macromolecule delivery.
... The orchestration of the full system is demanding enough that the gut has dedicated to this task its own bespoke nervous system. Hinting at its importance, this "enteric" nervous system evolved before the central one did (Snoek et al., 2010;Furness, 2012;Cryan et al., 2019;Niesler et al., 2021) and comprises between 400 and 600 million neurons, covering the entire 32 m 2 inside surface of the intestines (Helander and Fändriks, 2014). ...
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Alzheimer’s and Parkinson’s are the two best-known neurodegenerative diseases. Each is associated with the excessive aggregation in the brain and elsewhere of its own characteristic amyloid proteins. Yet the two afflictions have much in common and often the same amyloids play a role in both. These amyloids need not be toxic and can help regulate bile secretion, synaptic plasticity, and immune defense. Moreover, when they do form toxic aggregates, amyloids typically harm not just patients but their pathogens too. A major port of entry for pathogens is the gut. Keeping the gut’s microbe community (microbiota) healthy and under control requires that our cells’ main energy producers (mitochondria) support the gut-blood barrier and immune system. As we age, these mitochondria eventually succumb to the corrosive byproducts they themselves release, our defenses break down, pathogens or their toxins break through, and the side effects of inflammation and amyloid aggregation become problematic. Although it gets most of the attention, local amyloid aggregation in the brain merely points to a bigger problem: the systemic breakdown of the entire human superorganism, exemplified by an interaction turning bad between mitochondria and microbiota.
... The latter constitute the majority of bacteria in the colon. Indeed, the surface area of the large intestine, including its folds, is about 2 m 2 (43), while the mucus layer is about 100-to 300-μm thick (44) and typically comprises a few 10 8 bacteria per milliliter in healthy samples (45), which leads to an order of magnitude of 10 11 bacteria associated with mucus. This number is small compared with the total colon content, which is around 10 14 bacteria (1). ...
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The gut microbiota features important genetic diversity, and the specific spatial features of the gut may shape evolution within this environment. We investigate the fixation probability of neutral bacterial mutants within a minimal model of the gut that includes hydrodynamic flow and resulting gradients of food and bacterial concentrations. We find that this fixation probability is substantially increased, compared with an equivalent well-mixed system, in the regime where the profiles of food and bacterial concentration are strongly spatially dependent. Fixation probability then becomes independent of total population size. We show that our results can be rationalized by introducing an active population, which consists of those bacteria that are actively consuming food and dividing. The active population size yields an effective population size for neutral mutant fixation probability in the gut.
... The ileum and jejunum have a large surface area to allow absorption of the small molecules produced. In fact, the digestive tract is the organ with the largest area facing the "external" environment, with an absorptive area of approximately 30-35 m 2 , of which about 30 m 2 is the surface of the small intestine (Helander and Fandriks 2014). This large area is due to the intensively convoluted surface of the intestines and the structures of villi and microvilli that line the surface, giving an effective 60 to 120-fold enhancement of surface area. ...
Chapter
Novel physic and chemical properties can be obtained by the micro and nanoengineering of food-grade compounds and ingredients to obtain fibres, nanotubes, films, coatings, and 3D structures, such as micro and nanoparticles, emulsions and oleogels. These new properties allow enhancing the stability and the controlled release of bioactive compounds. In this chapter, nano and microstructures that can be used in the food industry for the development of foods with high quality and safety, and new food structures are presented. The explored structures are fibres and nanotubes (1D), films and coatings (2D), micro and nanoparticles, emulsions, oleogels and food printing (3D). In the end, is presented an overview of how the toxicity of micro and nano-engineered structures should be assessed to be applied in the food industry.
... Microbiome on the other hand refers to the total genes they encode [34]. Human gastrointestinal tract (GIT) has one of the largest surface areas of any organ in the body [35] and is the home to a numbers of species of microbiota [36] ranging from 250 to 400 m 2 . The microbiome of human gut comprises more than 100 trillion microbial organisms that include bacteria, fungi, viruses, and protozoa [37]. ...
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Inflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal (GI) tract with dysregulated mucosal immune functions and disturbed commensal ecosystem of the intestinal lumen. IBD is categorized into two major subsets: Crohn’s disease (CD) and ulcerative colitis (UC). Though advent of biologics has shifted the treatment with relatively longer remission compared to small molecule pharmaceuticals, patients still suffer from long-term complications. Since gut-microbiome is now accepted as another human organ holding potential for long-lasting human health, probiotics, and its engineering hold great promises to treat several previously untreatable chronic inflammatory conditions including IBD. Several emerging biological engineering tools have unlimited potential to manipulate probiotic bacterial system. These can produce useful therapeutic biologics with a goal to either ameliorate and/or treat previously untreatable chronic inflammatory conditions. As gut-microbiome is diverse and vary in different ethnic, geographic, and cultural human population, it will be important to develop vision for personalized probiotic treatment and develop the technology thereof to make personalized probiotic options a reality. The aim of this review paper is to present an overview of the current knowledge on both pharmacological and nonpharmacological IBD treatment modalities with a special emphasis on probiotic strains that are developed through the probiotic engineering. These engineered probiotics contain the most anti-inflammatory cytokines found within the human immune response and are currently being used to treat the intestinal inflammation in IBD for the IBD treatment.
... The intestine is a remarkable organ that carries out diverse and necessary physiological roles for human survival including nutrient uptake, hormone production, and host immunity. To optimize absorption, the human intestine has an expansive surface area that is estimated to be between 30 and 40m 2 (Helander and Fändriks, 2014). To achieve such a large surface area, the epithelium is highly folded into stereotypic fingerlike projections known as villi (Walton et al., 2018). ...
Thesis
The human intestine is a remarkable organ that performs diverse and necessary functions for survival including nutrient uptake, hormone production, and host immunity. Given the prevalence and severity of gastrointestinal diseases in human health, there has been great interest in developing in vitro models to enable the study of human intestinal development, disease, and regeneration. To address this need, methods have been developed to generate complex three-dimensional in vitro intestinal cultures (organoids) from primary human donor tissue or human pluripotent stem cells (hPSCs). These organoid cultures partially recapitulate the cellular diversity and tissue organization of the native human intestine. Research is now focused on advancing existing systems towards more faithfully recapitulating the native organ and utilizing intestinal organoids for biological discovery. In this dissertation, I present an in-depth characterization of in vivo human intestinal development from 7–21 weeks post conception and of corresponding organoid models using single cell mRNA-sequencing (scRNA-seq). One focus of this dissertation was to characterize the developing human intestinal stem cell (ISC) niche—a specialized microenvironment that supports ISC survival and function. This work examined the expression and localization of intestinal stem cell (ISC) niche factors inferred from murine studies, including Epidermal Growth Factor (EGF), WNTs, and R-spondins, to determine their relevance during human intestinal development. Both molecular and spatial characterization of the in vivo human intestine revealed that EGF, a prominent niche factor in mice, is expressed outside of the ISC crypt niche during human development. However, the EGF ligand family member Neuregulin 1 (NRG1) is expressed in a subepithelial PDGFRAHI/F3HI/DLL1HI mesenchymal population that lines the crypt-villus axis of the developing human intestine. Exogenously supplied NRG1, but not EGF, improved cellular diversity in human epithelial organoids by permitting differentiation of secretory lineages. This work illuminates the complexities of intestinal EGF/ERBB signaling and delineates key niche cells and signals of the developing intestine. Another focus of this thesis was to investigate the cellularity of hPSC-derived human intestinal organoids (HIOs), as HIOs lack several cellular populations found in the native organ, including vasculature. scRNA-seq of HIOs identified a population of endogenous endothelial cells (ECs) present early in HIO differentiation that declines over time in culture. In this thesis, I developed a method to expand and maintain this endogenous population of ECs within HIOs. Given that ECs possess organ-specific gene expression, morphology, and function, we used bulk RNA-seq and scRNA-seq to interrogate the developing human intestine, lung, and kidney to identify organ-enriched EC gene signatures. By comparing these gene signatures and validated markers of HIO ECs, I found that HIO ECs grown in vitro share the highest similarity with native intestinal ECs relative to kidney and lung. Together, these data demonstrate that HIOs can co-differentiate a native EC population that is partially patterned with an intestine-specific EC transcriptional signature in vitro. Collectively, this thesis provides new single cell resolution insights into in vivo human intestinal development and corresponding organoid model systems. Characterization of the native tissue helps define a more physiologically relevant niche environment to both improve fidelity of corresponding epithelial organoid model systems and deepen our understanding of human intestinal development. Additionally, a native population of ECs is documented and expanded within hPSC-derived human intestinal organoid models. This thesis advances human intestinal organoid models to more faithfully recapitulate the complexity of the native tissue.
... Most sources in our literature search provide the range of estimates between 200 m 2 and 400 m 2 and have been listed in Table 2 along with the parallel drawn to tennis courts [8,[23][24][25][26][27][28][29]. Thus, the combination of the folds of Kerckring, the villi, and the microvilli increases the total absorptive area of the mucosa perhaps 1000-fold, making a tremendous total area of 250 or more square meters for the entire small intestine-about the surface area of a tennis court. ...
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... Once emptied, luminal contents reach the upper small intestine where both, longer transit times (mean 3.5 ± 1.0 h) [13] and enhanced surface area (32-140 m 2 ) [14,15], promote the absorption process. Unlike gastric residence, intestinal transit remains mostly invariable regardless of the ingested material, e.g., food, tablets, pellets or fluids [16,17]. ...
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... Microvilli are actin-based structures that serve to increase the membrane surface area for nutrient absorption and to sense the extracellular environment [152]. For example, Ano1 increases microvilli length in the frog oocyte, which is beneficial to the exchange capacity of the cell [153]. ...
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... However, 3 out of 4 the dogs included in this analysis (nlab=3, ndo=1) were laboratory dogs that were all fasted for 24h before euthanasia, and hence, these lipids may derive from sloughed off epithelial cells. In the small intestine, the cellular turnover rate is around 2 days shorter [48,49] than in the large intestine of mice and the number of cells per cm 2 in humans is also higher [50]. It is therefore reasonable to expect more epithelial cells to be shed into the mucus of the jejunum than the colon. ...
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... No models currently exist for the epithelia of the gastrointestinal tract. The gut makes up a large portion of the body's external surface (Helander and Fändriks 2014) and the small intestine is where around 90% of the digestion and adsorption of food occurs (Borgstrom et al. 1957), thus it is a major exposure site of ingested genotoxicants. ...
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The micronucleus (MN) assay is widely used as part of a battery of tests applied to evaluate the genotoxic potential of chemicals, including new food additives and novel food ingredients. Micronucleus assays typically utilise homogenous in vitro cell lines which poorly recapitulate the physiology, biochemistry and genomic events in the gut, the site of first contact for ingested materials. Here we have adapted and validated the MN endpoint assay protocol for use with complex 3D reconstructed intestinal microtissues; we have named this new protocol the reconstructed intestine micronucleus cytome (RICyt) assay. Our data suggest the commercial 3D microtissues replicate the physiological, biochemical and genomic responses of native human small intestine to exogenous compounds. Tissues were shown to maintain log-phase proliferation throughout the period of exposure and expressed low background MN. Analysis using the RICyt assay protocol revealed the presence of diverse cell types and nuclear anomalies (cytome) in addition to MN, indicating evidence for comprehensive DNA damage and mode(s) of cell death reported by the assay. The assay correctly identified and discriminated direct-acting clastogen, aneugen and clastogen requiring exogenous metabolic activation, and a non-genotoxic chemical. We are confident that the genotoxic response in the 3D microtissues more closely resembles the native tissues due to the inherent tissue architecture, surface area, barrier effects and tissue matrix interactions. This proof-of-concept study highlights the RICyt MN cytome assay in 3D reconstructed intestinal microtissues is a promising tool for applications in predictive toxicology.
... In vivo, C. parvum stages (i.e., sporozoites, trophozoites, merozoites, and gametocytes) reside in a very specialized niche through their epicellular intracellular but extracytoplasmic location, thereby being separated only by a thin membrane from the intestinal contents. There are many commensal and pathogenic microorganisms [70] in the gut that make it a unique ecosystem with its own physiological oxygen pressure atmosphere known as "physioxia/normoxia," and which is one of the largest human organ surfaces [48,71]. With numerous studies proving the value of physioxic circumstances in the NETs production [72], the metabolism of gut epithelium [73,74], as well as on the metabolic signatures of C. parvum-infected primary bovine small intestinal epithelial cells (BSIEC) and ex vivo explants of bovine small intestine (BSI), the concern of intrinsic pathological environment has achieved significant importance in recent years [4,12]. ...
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Simple Summary: Cryptosporidium parvum, a zoonotic apicomplexan, is one of the leading causes of severe diarrheal disease worldwide and a major contributor to early infant and neonatal mortality. In vivo, sporozoites of C. parvum must invade enterocytes where they develop in a unique in-tracellular extracytoplasmic niche. Polymorphonuclear neutrophils (PMN) are the most common leukocytes in the immune defense system of the host, the first to be transferred to C. parvum-infected gut mucosa, and are increasingly recognized as important cells in the fight against other intestinal parasites. We investigated the role of ATP purinergic receptor P2X1, glycolysis, plasma membrane monocarboxylate transporters (MCTs) of lactate, extracellular acidification rates (ECAR), and mito-chondrial oxygen consumption rates (OCR), as well as Notch signaling in C. parvum-triggered NETs formation in exposed bovine PMN under intestinal physioxic (5% O2) as well as hyperoxic (21% O2) conditions. Both C. parvum stages, i.e., sporozoites and oocysts, strongly induce suicidal NETosis in a P2X1-dependent manner, suggesting anti-cryptosporidial effects not only through firm sporozoite entrapment and hampered sporozoite excystation, but also probably through direct exposure to NETs-derived toxic molecules. Abstract: Cryptosporidiosis is a zoonotic intestinal disease that affects humans, wildlife, and neo-natal cattle, caused by Cryptosporidium parvum. Neutrophil extracellular traps (NETs), also known as suicidal NETosis, are a powerful and ancient innate effector mechanism by which polymorpho-nuclear neutrophils (PMN) battle parasitic organisms like protozoa and helminths. Here, C. parvum oocysts and live sporozoites were utilized to examine suicidal NETosis in exposed bovine PMN beneath both 5% O2 (physiological conditions within small intestinal tract) and 21% O2 (normal hy-peroxic conditions in research facilities). Both sporozoites and oocysts induced suicidal NETosis in exposed PMN under physioxia (5% O2) and hyperoxia (21% O2). Besides, C. parvum-induced suicidal NETosis was affirmed by total break of PMN, co-localization of extracellular DNA decorated with pan-histones (H1A, H2A/H2B, H3, H4) and neutrophil elastase (NE) by means of confocal-and immunofluorescence microscopy investigations. C. parvum-triggered NETs entrapped sporozoites and impeded sporozoite egress from oocysts covered by released NETs, according to scanning electron microscopy (SEM) examination. Live cell 3D-holotomographic microscopy analysis visualized early parasite-induced PMN morphological changes, such as the formation of membrane protru-sions towards C. parvum while undergoing NETosis. Significant reduction of C. parvum-induced suicidal NETosis was measured after PMN treatments with purinergic receptor P2X1 inhibitor Citation: Hasheminasab, S.S.; Conejeros, I.; Velásquez, Z.D.; Borggrefe, T.; Gärtner, U.; Kamena, F.; Taubert, A.; Hermosilla, C. ATP Purinergic Receptor P2X1-Dependent Suicidal NETosis Induced by Cryptosporidium parvum under Physioxia Conditions. Biology 2022, 11, 442. https://doi. Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons At-tribution (CC BY) license (https://cre-ativecommons.org/licenses/by/4.0/). Biology 2022, 11, 442 2 of 20 NF449, under both oxygen circumstances, this receptor was found to play a critical role in the induction of NETs, indicating its importance. Similarly, inhibition of PMN glycolysis via 2-deoxy glucose treatments resulted in a reduction of C. parvum-triggered suicidal NETosis but not significantly. Extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) were not increased in C. parvum-exposed cells, according to measurements of PMN energetic state. Treatments with inhibitors of plasma membrane monocarboxylate transporters (MCTs) of lactate failed to significantly reduce C. parvum-mediated NET extrusion. Concerning Notch signaling, no significant reduction was detected after PMN treatments with two specific Notch inhibitors, i.e., DAPT and compound E. Overall, we here describe for the first time the pivotal role of ATP purinergic receptor P2X1 in C. parvum-mediated suicidal NETosis under physioxia (5% O2) and its anti-cryptosporidial properties.
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Thesis
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Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment. The following discussion presents an expansive review of intestinal oxalate transport. We begin with an overview of the fate of oxalate, focusing on the sources, rates, and locations of absorption and secretion along the GI tract. We then consider the mechanisms and pathways of transport across the epithelial barrier, discussing the transcellular, and paracellular components. There is an emphasis on the membrane-bound anion transporters, in particular, those belonging to the large multifunctional Slc26 gene family, many of which are expressed throughout the GI tract, and we summarize what is currently known about their participation in oxalate transport. In the final section, we examine the physiological stimuli proposed to be involved in regulating some of these pathways, encompassing intestinal adaptations in response to chronic kidney disease, metabolic acid-base disorders, obesity, and following gastric bypass surgery. There is also an update on research into the probiotic, Oxalobacter formigenes, and the basis of its unique interaction with the gut epithelium. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.
Thesis
Hintergrund und Ziele Knapp eine halbe Millionen Menschen in Deutschland leiden an Morbus Crohn (MC) oder Colitis Ulcerosa (CU). Diese chronisch entzündlichen Darmerkrankungen (CED) beeinträchtigen Patienten oft über lange Zeiträume hinweg, da sie in Schüben verlaufen, mit Schmerzen, Diarrhöen und einer Reihe von Komplikationsrisiken einhergehen und häufig bereits im jungen Alter auftreten. [1,2] Das therapeutische Management dieser komplexen und vielschichtigen Erkrankungen ist mit einer Reihe von Herausforderungen verbunden. Immer mehr Wirkstoffe stehen zur Verfügung, aber es gibt keinen verlässlichen und evidenzbasierten Algorithmus, um die Reihenfolge ihres Einsatzes bei der Behandlung von CU und MC priorisieren zu können bzw. im individuellen Patientenfall das Ansprechen vorhersagen zu können. [1] Zu den neueren Medikamenten zählen Biologicals (gentechnisch hergestellte Therapeutika). Biologicals richten sich zielgerichtet gegen bestimmte Zytokine und Entzündungsmediatoren und haben der CED-Behandlung neue Möglichkeiten eröffnet. Jedoch kommt es weiterhin bei vielen Patienten zu einem primären Nichtansprechen oder einem sekundären Wirkverlust während der Therapie und es kommen verschiedene, zum Teil schwere Nebenwirkungen vor. [1–3] Auch der seit 2014 zugelassene anti-α4β7-Antikörper Vedolizumab (VDZ) zählt zu den Biologicals. In Studien konnte für VDZ gezeigt werden, dass es die Adhäsion von α4β7-exprimierenden-T-Lymphozyten an das endotheliale Mucosal vascular Addressin Cell Adhesion Molecule-1 (MAdCAM-1) blockiert. Dadurch wird das Auswandern von entzündungsfördernden Lymphozyten in den Darm verhindert und so die Entzündungsreaktion reduziert. Da MAdCAM-1 beinahe ausschließlich im Darm exprimiert ist, führt das Medikament höchst spezifisch zu einer Unterdrückung der Einwanderung von Lymphozyten (Homing) in den Darm ohne relevanten Einfluss auf andere Organe. [4–6] Da jedoch nur der Nachschub an pro-inflammatorischen Lymphozyten, nicht aber der Entzündungsprozess im Darm an sich beeinflusst werden, tritt die Wirkung von VDZ in vielen Fällen erst nach mehreren Wochen ein. Zudem spricht, wie auch bei allen anderen bei CED eingesetzten Biologika, nur ein Teil der Patienten auf das Medikament an. [3] Eine Möglichkeit, den Erfolg einer Therapie mit dem anti-α4β7-Integrin-Antikörper VDZ mittels eines Biomarkers vorhersagen zu können, wäre daher aus klinischer Sicht äußerst wünschenswert, fehlt allerdings bislang. Ziel dieses Promotionsvorhabens war es daher, mögliche Biomarker, insbesondere der Integrin-Expression und -Funktion, zur Unterstützung von 2 Behandlungsentscheidungen zu identifizieren und auf ihre mögliche Eignung zur Prädiktion des Therapieerfolgs von VDZ bei CED zu untersuchen. Methoden Wir führten eine retrospektive Kohortenstudie bei 21 Patienten mit CU durch, die erstmalig eine Therapie mit VDZ erhielten. CD4+ T-Zellen wurden aus dem peripheren Blut isoliert und die dynamische Adhäsion an MAdCAM-1 in vitro bestimmt sowie die Wirkung von VDZ auf diese Adhäsion in vitro. Zusätzlich wurde die Expression von α4β1-Integrin auf CD4+ T-Zellen des peripheren Blutes mittels Durchflusszytometrie quantifiziert. Anhand der elektronischen Patientenakten wurde mittels des Mayo Clinical Subscore (MCS) retrospektiv das klinische Ansprechen auf VDZ erhoben. Klinische und experimentelle Daten wurden korreliert. Ergebnisse und Beobachtungen Bei Patienten mit einem Ansprechen auf die VDZ-Therapie (Responder) beobachteten wir im Vergleich zu Patienten ohne Ansprechen (Non-Responder) in dynamischen Adhäsionassays eine höhere Anzahl von CD4+ T-Zellen aus dem peripheren Blut, die an MAdCAM-1 adhärierten. Zudem bestätigten und erweiterten wir frühere Beobachtungen, dass die dynamische Änderung der α4β1-Expression auf CD4+ T-Zellen zwischen Woche 0 und Woche 6 der VDZ-Behandlung mit dem späteren klinischen Ansprechen korreliert. [7] Eine Heraufregulation der α4β1-Expression auf CD4+ T-Zellen wurde bei Patienten mit stabiler oder zunehmender klinischer Aktivität erfasst, während eine Herunterregulation überwiegend bei Patienten mit einem klinischen Ansprechen in der 15. Therapiewoche beobachtet werden konnte. Diese Responder konnten mit hoher Spezifität und hohem positivem Vorhersagewert identifiziert werden. Schlussfolgerungen Die Bestimmung der dynamischen Adhäsion von CD4+ T-Zellen an MAdCAM-1 und der in vitro-Wirkung von VDZ auf die dynamische T-Zell-Adhäsion vor Behandlungsbeginn sowie die Erfassung der dynamischen Integrin-Regulation im frühen Verlauf der Behandlung scheinen vielversprechende Ansätze zu sein, um das klinische Ansprechen von CU-Patienten auf die VDZ-Therapie vorherzusagen. Unsere Studie legt somit erstmals ein Konzept zur Vorhersage des Erfolgs einer VDZ-Behandlung mit Hilfe von peripheren Blutproben vor und liefert die Rationale für die Durchführung größerer prospektiver Studien.
Article
The prevalence of inflammatory bowel disease (IBD) is increasing, which is concerning because IBD is a known risk factor for the development of colorectal cancer. Emerging evidence highlights environmental factors, particularly dietary factors and gut microbiota dysbiosis, as pivotal inducers of IBD onset. Goji berry, an ancient tonic food and a nutraceutical supplement, contains a range of phytochemicals such as polysaccharides, carotenoids, and polyphenols. Among these phytochemicals, L. barbarum polysaccharides (LBPs) are the most important functional constituents, which have protective effects against oxidative stress, inflammation, and neurodegeneration. Recently, the beneficial effects of goji berry and associated LBPs consumption were linked to prebiotic effects, which can prevent dysbiosis associated with IBD. This review assessed pertinent literature on the protective effects of goji berry against IBD focusing on the gut microbiota and their metabolites in mediating the observed beneficial effects.
Thesis
Chronisch entzündliche Darmerkrankungen (CED) sind Erkrankungen, die den gesamten Gastrointestinaltrakt betreffen können. Sie werden unterteilt in die Hauptklassen Morbus Crohn (MC) und Colitis ulcerosa (CU). Da die Inzidenz dieser Erkrankungen weltweit steigt, ist es von besonderem Interesse, die Pathophysiologie sowie zugrundeliegende Signalwege und Zielantigene zu verstehen. Bisher wird vermutet, dass Umweltfaktoren, eine Fehlfunktion der Darmschleimhautbarriere und ein fehlreguliertes Immunsystem in genetisch prädisponierten Individuen bei der Manifestation der CED eine Rolle spielen. Eine Beteiligung der Immunantwort wird durch die Tatsache gestützt, dass krank-heitsspezifische Antikörper gegen körpereigene Bestandteile sowie gegen mikrobielle Antigene gefunden wurden. In dieser Arbeit waren Anti-Neutrophile zytoplasmatische Antikörper (ANCA) von besonderem Interesse. ANCA erzeugen, abhängig vom Antigen, ein spezifisches Fluoreszenzmuster auf neutrophilen Granulozyten und können dadurch für die Diagnose bestimmter Erkrankungen genutzt werden. Eine spezielle Untergruppe, die atypischen ANCA, wurden mit CED und speziell CU assoziiert. Für atpyische ANCA wurde eine Vielzahl von neutrophilen Antigenen beschrieben, jedoch ist unklar, ob das Hauptantigen bereits identifiziert wurde. Daher war das Ziel dieser Arbeit, neue neutrophile antigene Ziele zu identifizieren, die möglicherweise an der Erkennung der Darmmikrobiota sowie der Entzündung bei CED beteiligt sind. Dafür sollten neutrophile Granulozyten isoliert und ihre Proteine mittels verschiedener Methoden der Proteomik untersucht werden. Identifizierte Antigene sollten rekombinant exprimiert und für die Entwicklung eines immunologischen Testsystems genutzt werden. Bei der Untersuchung der neutrophilen Proteine wurde das Molekül Chitinase-3-Like Protein 1 (CHI3L1) identifiziert und für die Entwicklung eines Enzyme-linked Immunosorbent Assay (ELISA) genutzt. Dieser wurde genutzt, um das Serum von Patienten mit MC, CU oder Zöliakie sowie gesunde Kontrollen zu untersuchen. In Patienten mit MC zeigten sich signifikant höhere IgG-Reaktivitäten gegen CHI3L1 als in Patienten mit CU oder Zöliakie. IgA- und sekretorisches IgA (sIgA)-Reaktivitäten gegen CHI3L1 waren ebenfalls in Patienten mit MC signifikant höher als in CU, Zöliakie oder gesunden Kontrollen. Diese Daten zeigten, dass CHI3L1 ein neues neutrophiles antigenes Ziel in CED und speziell MC ist. Es konnte keine Korrelation von CHI3L1-Antikörpern mit MC-spezifischen Anti-Saccharomyces cerevisiae-Antikörpern (ASCA) gezeigt werden. Die ROC-Analyse verschiedener klinischer Szenarien ergab, dass CHI3L1-Antikörper allein nicht für die klinische Anwendung geeignet sind. Allerdings könnten CHI3L1-Antikörper bestehende serologische Marker ergänzen und so zum Beispiel die Diagnostik verbessern. Ungeklärt bleibt, ob CHI3L1 eine Rolle in der Pathophysiologie von CED spielen könnte. Das Auftreten von Antikörpern gegen CHI3L1 deutet jedoch darauf hin.
Article
The prevalence of microplastics (MPs) contamination in a broad spectrum of potable water sources has raised significant environmental and public health concerns. While evidence of ingested MPs bioaccumulation in the gastrointestinal tract (GIT) of aquatic and terrestrial organisms is mounting, our understanding of the effects of MPs on human gastrointestinal health remains scant. Herein, the potential deleterious biological effects of pristine and in vitro digested polystyrene (PS) MPs of varying sizes (i.e., 0.1 μm, 1 μm, and 10 μm) were systematically examined over a wide concentration range of 25 μg ml–1 to 400 μg ml–1 on two human intestinal cell lines, namely Caco‐2 and NCM 460. Specifically, significant internalization of 0.1 μm and 1 μm PS MPs have been observed in both cell types 24 h post‐exposure. However, multi‐parametric dose and time‐dependent analysis encompassing cell viability, reactive oxygen species (ROS), and nutrient absorption/ metabolism measurement revealed no significant adversarial outcomes. Interestingly, we found that the 0.1μm PS‐MPs could perturb redox homeostasis in NCM460 but not in Caco‐2 cells. Based on our in vitro experimental boundaries and findings, we concluded that ingested PS‐MPs poses little acute cytotoxic harm to human gastrointestinal health. This article is protected by copyright. All rights reserved
Article
Objective: To develop a physiologically based pharmacokinetic (PBPK) model for amiloride, an acid-sensing ion channel (ASIC) antagonist, and to simulate its pharmacokinetics in plasma and the central nervous system following intranasal administration in a virtual human population. Materials and methods: We first developed a PBPK model of amiloride after oral administration and optimized the model using data from five clinical studies. Next, we added a nasal compartment to the amiloride oral PBPK model and parameterized using data from previous clinical studies. We simulated amiloride's pharmacokinetics in plasma, brain, and cerebrospinal fluid (CSF) after intranasal administration of amiloride at various doses in a virtual human population. Results: The target amiloride concentration in the central nervous system required for maximal ASIC inhibition was achieved with a 75-mg intranasal amiloride dose. However, this finding is based on simulations performed using a mathematical model and needs to be further validated with appropriate clinical data. Conclusion: The nasal PBPK model of amiloride could be used to design future clinical studies and allow for successful clinical translation of intranasal amiloride formulation.
Article
Nanomaterials are at the forefront of health research and development. Among different nanomaterials, nanoparticles are especially promising for cancer theranostics. However, despite great potential, the clinical translation of nano-based applications continues to face obstacles. A major hurdle to the localized eradication of tumors is the efficient targeting of nanomaterials to the desired tissues and cells. In particular, nanoparticle properties and the route of administration impact the efficacy of precision nanomedicine. This review focuses on nanoparticles that have been produced for the detection and treatment of cancer. Common and tissue-specific barriers that limit the accumulation of nanoparticles in malignant tumors are discussed. The in-depth discussion focuses on the physicochemical properties of nanoparticles and the surface modifications that achieve efficient accumulation at tumor sites. Furthermore, limitations of current strategies and open questions are presented. The review concludes with an outlook on future directions and the trajectories that will drive the field forward to advance nano-oncology in the clinic. Free link until April 24, 2022: https://authors.elsevier.com/a/1ehYl,6w-FydMQ
Article
Crohn’s disease and ulcerative colitis are the two most frequent types of chronic inflammatory bowel disease (IBD) in childhood. They are characterized by a multifactorial trigger of chronic inflammation of the gastrointestinal tract (GIT). The cause is a disrupted interplay of immune regulation, nutrition, lifestyle, microbiota and leaky epthithelial barrier on the basis of a (poly)genetic predisposition; however, only a very small number of IBD patients are found to have a monogenetic cause of the disorder, including primary immune defects (PID). As the symptoms of IBD can be the first or only manifestation of a superordinate monogenetic disease, the correct diagnosis is challenging but decisive for the further diagnostics, treatment and prognosis of the patients. The gastrointestinal symptoms, the macroscopic and microscopic endoscopic findings frequently do not enable a clinical differentiation between polygenetic IBD and monogenetic diseases. Therefore, a sensitization for rare monogenetic causes is the prerequisite for risk estimation and initiation of targeted diagnostic steps. This article provides help on this matter and is based on the current position paper of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).
Article
Postbiotics have recently emerged as critical effectors of the activity of probiotics and, because of their safety profile, they are considered potential therapeutics for the treatment of fragile patients. Here, we present recent studies on probiotics and postbiotics in the context of novel discovery tools, such as organoids and organoid-based platforms, and nontransformed preclinical models, that can be generated from intestinal stem cells. The implementation of organoid-related techniques is the next gold standard for unraveling the effect of microbial communities on homeostasis, inflammation, idiopathic diseases, and cancer in the gut. We also summarize recent studies on biotics in organoid-based models and offer our perspective on future directions.
Chapter
This chapter focuses on the pulmonary application of drugs, which is of great importance for the local treatment of lung-related diseases like asthma and COPD but has also been put more into the focus for systemic treatment of a multitude of diseases lately. An important aspect for inhalation is the geometry and anatomy of the respiratory tract. The system of airways, best imagined as branches, is the root of the aerodynamic properties that are used to apply drugs through inhalation and explain the various ways particles are deposited in the lungs. In order to maximize the drug delivery efficiency, the properties of the aerosol need to be optimized in order to profit off this innate aerodynamic setup. Systems to qualify aerosols related to their aerodynamic properties have been implemented but come with their downfalls, especially when it comes to transferring the results onto the human respiratory system. This needs to be taken into account when developing new inhalation devices. As the number of inhalation devices grows, it is important to understand the basic mechanism and the advantages of each system in order to optimize treatment for patients.
Article
Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.
Thesis
Par sa contribution à l'ensemble des grandes fonctions de l'organisme, le microbiote intestinal possède un rôle essentiel dans la physiologie et la pathologie de son hôte. Un microbiote est caractérisé par son répertoire de gènes exprimés et, plus important encore, par les métabolites qu'il sécrète. De nombreuses études ont déterminé la composition taxonomique du microbiote, mais peu en ont caractérisé les gènes actifs, les protéines ou les métabolites, ce qui pourrait être plus pertinent. En effet, la composition taxonomique du microbiote humain varie énormément d'un individu à l'autre, tandis que sa composition génétique ou sa capacité fonctionnelle est très conservée. La capacité fonctionnelle du microbiote est redondante et capitale pour maintenir sa stabilité et sa résilience. A la notion de redondance fonctionnelle est associée l'idée que, jusqu'à un certain point, les espèces sont substituables d'un microbiote à l'autre en termes de fonctionnalité. Il est donc majeur d'identifier les métabolites du microbiote intestinal et de déterminer leur effet sur l'hôte. Les travaux présentés dans cette thèse sont focalisés sur la caractérisation de métabolites lipidiques produits par les bactéries intestinales afin d'étudier les interactions entre le microbiote intestinal et son hôte. Pour notre premier projet, nous nous sommes intéressés à une souche d'Escherichia coli, E. coli Nissle 1917 (EcN), indiquée comme probiotique dans les phases de rémission de la rectocolite hémorragique. Nous avons quantifié une augmentation de la concentration d'un acide gras ß-hydroxylé, le C18-3OH, produit par EcN par rapport à des E. coli commensales ou pathogènes. Nous avons donc testé les propriétés anti-inflammatoires de ce lipide dans un modèle murin de colite induit par le DSS. Le C18-3OH diminuait la sévérité de l'inflammation en se liant au récepteur nucléaire PPARgamma. L'utilisation d'un prébiotique (fructo-oligosaccharide) ayant une activité anti-inflammatoire, nous a permis de démontrer qu'une autre bactérie du microbiote intestinal, Holdemanella biformis, était également capable de produire de grande quantité de C18-3OH. Le microbiote joue un rôle critique dans la maturation et le développement, notamment intestinal, de son hôte. Par exemple, chez la souris, une modification du microbiote, ou dysbiose, induite par des antibiotiques lors du sevrage augmente l'intensité de l'inflammation dans un modèle de colite. Le microbiote étant extrêmement sensible à son environnement, le stress, qu'il soit subit en prénatal, post natal ou à l'âge adulte, modifie sa composition. Néanmoins, le lien de causalité entre le stress prénatal, la dysbiose du microbiote intestinal et les troubles fonctionnels digestifs n'a jamais été établi. Dans un modèle murin de stress prénatal (SP), nous avons montré que la descendance adulte mâle et femelle développait une hypersensibilité viscérale associée à une dysbiose du microbiote intestinal et une absence d'inflammation macroscopique, trois caractéristiques du syndrome de l'intestin irritable. Comme l'abondance de Ligilactobacillus murinus/animalis était inversement corrélée à l'hypersensibilité viscérale, nous avons étudié les lipides produits par cette bactérie et identifié un lipopeptide, le C14AsnGABA. L'administration intra-colique de cette molécule restaurait une normo-sensibilité viscérale chez les souris SP. Ces deux projets nous ont permis d'identifier des lipides ayant des propriétés anti- inflammatoires ou analgésiques produits par des bactéries présentes dans le microbiote intestinal. Ces molécules pourraient jouer un rôle dans l'interaction entre le microbiote et son hôte.
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Physiologically based kinetic (PBK) models are a promising tool for xenobiotic environmental risk assessment that could reduce animal testing by predicting in vivo exposure. PBK models for birds could further our understanding of species-specific sensitivities to xenobiotics, but would require species-specific parameterization. To this end, we summarize multiple major morphometric and physiological characteristics in chickens, particularly laying hens (Gallus gallus) and mallards (Anas platyrhynchos) in a meta-analysis of published data. Where such data did not exist, data are substituted from domesticated ducks (Anas platyrhynchos) and, in their absence, from chickens. The distribution of water between intracellular, extracellular, and plasma is similar in laying hens and mallards. Similarly, the lengths of the components of the small intestine (duodenum, jejunum, and ileum) are similar in chickens and mallards. Moreover, not only are the gastrointestinal absorptive areas similar in mallard and chickens but also they are similar to those in mammals when expressed on a log basis and compared to log body weight. In contrast, the following are much lower in laying hens than mallards: cardiac output (CO), hematocrit (Hct), and blood hemoglobin. There are shifts in ovary weight (increased), oviduct weight (increased), and plasma/serum concentrations of vitellogenin and triglyceride between laying hens and sexually immature females. In contrast, reproductive state does not affect the relative weights of the liver, kidneys, spleen, and gizzard.
Chapter
For the majority of drugs, the oral route is the preferred route of administration and thus, a thorough understanding of the human gastrointestinal (GI) physiology is a prerequisite for safe and effective pharmacotherapy. In this chapter, the authors give a brief summary of the transit times and hydrodynamics arising during the GI passage of oral dosage forms. They pay special attention to the comparison of the conditions arising after fasted and fed state administration of oral drug products. The authors also discuss how age, gender, diseases, certain drugs, and excipients interfere with motility and hydrodynamics. In recent years, numerous studies have been conducted with modern imaging technologies that have led to a better understanding of GI transit times as well as the hydrodynamic conditions in the stomach, small intestine, and colon.
Article
Ethnopharmacological relevance Dandelion (Taraxacum officinale Weber ex F. H. Wigg.), as a garden weed grown globally, has long been consumed as a therapeutic herb. Its folkloric uses include treatments of digestive disorders (dyspepsia, anorexia, stomach disorders, gastritis and enteritis) and associate complex ailments involving uterine, liver and lung disorders. Aim of the study The present study aims to critically assess the current state of research and summarize the potential roles of dandelion and its constituents in gastrointestinal (GI) -protective actions. A focus is placed on the reported bioactive components, pharmacological activities and modes of action (including molecular mechanisms and interactions among bioactive substances) of dandelion products/preparations and derived active constituents related to GI protection. Materials and methods The available information published prior to August 2021 was reviewed via SciFinder, Web of Science, Google Scholar, PubMed, Elsevier, Wiley On-line Library, and The Plant List. The search was based on the ethnomedical remedies, pharmacological activities, bioactive compounds of dandelion for GI protection, as well as the interactions of the components in dandelion with the gut microbiota or biological regulators, and with other ingested bioactive compounds. The key search words were “Taraxacum” and “dandelion”. Results T. coreanum Nakai, T. mongolicum and T. officinale are the most commonly used species for folkloric uses, with the whole plant, leaves and root of dandelion being used more frequently. GI-protective substances of dandelion include taraxasterol, taraxerol, caffeic acid, chicoric acid, chlorogenic acid, luteolin and its glucosides, polysaccharides, inulin, and β-sitosterol. Dandelion products and derived constituents exhibit pharmacological effects against GI disorders, mainly including dyspepsia, gastroesophageal reflux disease, gastritis, small intestinal ulcer, ulcerative colitis, liver diseases, gallstones, acute pancreatitis, and GI malignancy. The underlying molecular mechanisms may include immuno-inflammatory mechanisms, apoptosis mechanism, autophagy mechanism, and cholinergic mechanism, although interactions of dandelion's constituents with GI health-related biological entities (e.g., GI microbiota and associated biological modulators) or other ingested bioactive compounds shouldn't be ignored. Conclusion The review reveals some in vivo and in vitro studies on the potential of dandelion derived products as complementary and alternative medicines/therapeutics against GI disorders. The whole herb may alleviate some symptoms related GI immuno-inflammatory basing on the abundant anti-inflammatory and anti-oxide active substances. Dandelion root could be a nontoxic and effective anticancer alternative, owing to its abundant terpenoids and polysaccharides. However, research related to GI protective dandelion-derived products remains limited. Besides the need of identifying bioactive compounds/complexes in various dandelion species, more clinical studies are also required on the metabolism, bioavailability and safety of these substances to support their applications in food, medicine and pharmaceuticals.
Article
Extensive research is underway to discover a safe and effective vehicle to deliver the vaccines at the desired cutaneous site. These efforts majorly comprise the development of a fit-to-purpose vehicle for in-situ intracutaneous vaccine delivery for achieving the systemic cellular and humoral response to combat infectious diseases. Advancements in nanoscience, bioengineering, and skin science provided much support to vaccine adjuvant development. However, the bench-to-bench side translation of vaccines is still unsatisfactory. A skilfully designed vaccine delivery program aiming to translate the product into market use must address safety, efficacy, scaleup, reproducibility, cost of production, self-administrative potential, and regulatory concerns. This review provides deep insights into skin immunization approaches like mucosal vaccines, cellular/molecular immunological responses, and antigen-adjuvant combinations in modulating immunity. Further, the manuscript discusses distinct vaccine delivery systems used to date for engineering skin immunization, including microparticles, nanoparticles, spherical nucleic acids, STAR particles, niosomes, dendrimers, ethosomes, liposomes, and microneedles. The manuscript will interest researchers working towards developing a next-generation fit-to-purpose vehicle for intracutaneous vaccine delivery.
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Objective: The aim of this study was to determine the total size of the oral mucosa. Method: Five human adult cadaver heads were cut in the median sagittal plane, and the total area of the oral surface was determined using silicon casts. The surface of the tongue was measured with quantitative profilometry. Photographs of oral blood vessels were taken in different areas of the oral mucosa of adult test subjects using intravital microscopy, and the pictures were compared with vessel casts of the oral mucosal capillaries of a maccaca fasciculrais monkey, which was studied using a scanning electron microscope. Result: The results showed that the dorsal side of the tongue comprises a large proportion of the total oral mucosal surface. The surface area of the epithelium increases moving from anterior to posterior on the tongue, and the number of underlying blood vessels increases proportionally. Conclusion: It can be concluded that the back of the tongue plays an important role in the oral resorption of drugs. Clinical relevance: The results may be of relevance for the delivery and development of oral drug application.
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In many pharmacological and toxicological studies knowledge about the intestinal absorption, which is dependent upon the surface area of absorptive epithelia, is indispensible. Although mice are often used in such preclinical studies, very few quantitative data about their intestinal surface area are available. Especially for locally acting candidate drugs in development, this information is crucial for dose translation towards humans. Therefore, the surface area of the intestinal tract of CD-1TM IGS mice was assessed in the present study. The intestinal tracts of 12 mice were collected after euthanasia. From six animals, histological sections from the duodenum, jejunum, ileum, caecum and colon–rectum were made according to common stereological principles. Using these sections, the volumes and surface areas of each intestinal segment were estimated applying stereological counting procedures. In the other six animals, the density and surface area of the microvilli present in each intestinal segment were determined by means of scanning and transmission electron microscopy to assess the increase of the intestinal surface area attributable to the presence of microvilli. The mean total volume and surface area of the intestinal tract were 1.34 cm3 and 1.41 m2, respectively. The relative intestinal surface area (intestinal surface area divided by the body surface area) was 119. The relative intestinal surface area of mice is very similar to that of humans. The results of this study are important for the appropriate dose translation of candidate therapeutic compounds in drug development from mouse to humans.
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Anatomical and physiological parameters of the gastrointestinal (GI) tract dramatically affect the rate and extent of absorption of ingested compounds. These parameters must be considered by nutritionists, pharmacologists and toxicologists when describing or modeling absorption. Likewise, interspecies extrapolation (e.g. from rat to human) requires species-to-species comparison of these parameters. The present paper (1) describes the alimentary canal and the barrier to absorption; (2) relates the major sites of absorption; (3) compares the dimensions and surface areas of human and rat intestinal tracts; (4) discusses motility of the gut and transit times through regions of the alimentary canal; (5) explains how luminal contents are altered by physical, chemical and metabolic processes; and (6) describes the flow of blood and lymph from the GI tract to the systemic circulation, including the enterohepatic circulation. Despite strong morphological similarities between humans and rats at the microscopic level, gross anatomical differences in the relative absorptive surface areas provide a basis for concluding that the human GI tract is capable of absorbing materials faster and to a greater extent than that of the rat. Differences in the environment of the GI lumen of the two species make it possible to infer which substances are more likely to be present in a dissolved/non-ionized state for each species. Taken together, these differences may be of sufficient magnitude to alter the assessment of risks/benefits for a given compound when those risks/benefits are based on interspecies extrapolations.
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Impaired gastric accommodation may lead to dyspeptic symptoms. A non-invasive method using single photon emission computed tomography (SPECT) has been developed to measure gastric volumes. Our aims were: to assess the accuracy of SPECT with three dimensional image analysis to measure balloon volumes in vitro; to compare gastric barostat balloon volumes measured post-meal and post-distension with total gastric volumes measured simultaneously with SPECT; to present normal gastric volume data for healthy adults; and to compare SPECT data in health with symptomatic post-fundoplication patients. In vitro balloon volumes measured by SPECT were highly accurate (R(2)=0.99). When measured simultaneously by gastric barostat and SPECT, postprandial/fasting volume ratios (2.2 (0.12) (mean (SEM)) v 2.3 (0.15), respectively; p=0.6) and post-distension volume ratios (1.4 (0.1) v1.3 (0.1); p=0.2) were highly comparable. In females, postprandial gastric volumes (675 (14) v 744 (20) ml for males; p=0.004) and changes in gastric volumes (464 (14) ml v 521 (20) ml for males; p=0.01) measured by SPECT were significantly lower than in males. No effects of age or body mass index were noted. The postprandial/fasting gastric volume ratio by SPECT was lower in post-fundoplication patients (2.7 (0.2)) than in healthy controls (3.4 (0.1); p=0.003). SPECT provides a non-invasive estimate of the effect of a meal on total gastric volume that is comparable to changes in balloon volume observed with the gastric barostat. The SPECT technique is promising for investigation of gastric volumes in health and disease and the effects of pharmacological agents.
Article
Zusammenfassung Schl�uche, die den ganzen Darmkanal durchlaufen, gestatten in vivo eine L�ngenmessung des Verdauungsrohres vom Mund bis zum Anus. Die Ma�e sind sehr viel kleiner als es die Leichenanatomie bislang lehrte, weil der lebende Darm durch einen sehr starken Muskeltonus bedeutend verk�rzt ist. Durch F�llung mit Quecksilber und Verwendung sogenannter sichtbarer oder schattengebender Schl�uche kann der Verlauf des Intestinaltraktus r�ntgenologisch hergestellt werden. Die Abbildungen zeigen, da� die Lagerung der Darmschlingen nicht nur individuell verschieden ist, sondern auch bei ein- und derselben Person wechseln kann und von unseren bisherigen Anschauungen in wesentlichen Punkten abweicht.
Article
Background: Impaired gastric accommodation may lead to dyspeptic symptoms. A non-invasive method using single photon emission computed tomography (SPECT) has been developed to measure gastric volumes. Aims and methods: Our aims were: to assess the accuracy of SPECT with three dimensional image analysis to measure balloon volumes in vitro; to compare gastric barostat balloon volumes measured post-meal and post-distension with total gastric volumes measured simultaneously with SPECT; to present normal gastric volume data for healthy adults; and to compare SPECT data in health with symptomatic post-fundoplication patients. Results: In vitro balloon volumes measured by SPECT were highly accurate (R2=0.99). When measured simultaneously by gastric barostat and SPECT, postprandial/fasting volume ratios (2.2 (0.12) (mean (SEM)) v 2.3 (0.15), respectively; p=0.6) and post-distension volume ratios (1.4 (0.1) v1.3 (0.1); p=0.2) were highly comparable. In females, postprandial gastric volumes (675 (14) v 744 (20) ml for males; p=0.004) and changes in gastric volumes (464 (14) ml v 521 (20) ml for males; p=0.01) measured by SPECT were significantly lower than in males. No effects of age or body mass index were noted. The postprandial/fasting gastric volume ratio by SPECT was lower in post-fundoplication patients (2.7 (0.2)) than in healthy controls (3.4 (0.1); p=0.003). Conclusions: SPECT provides a non-invasive estimate of the effect of a meal on total gastric volume that is comparable to changes in balloon volume observed with the gastric barostat. The SPECT technique is promising for investigation of gastric volumes in health and disease and the effects of pharmacological agents.
Article
Computed tomography colonography (CTC) is an accurate tool for assessing the large intestinal anatomy. Our aims were to determine the normal distribution of in vivo colorectal anatomy and to investigate the effect of age, sex, and body mass index (BMI) on colorectal length. Asymptomatic adults who underwent primary CTC examination at a single institution over an 8-month period were evaluated. The interactive three-dimensional map was used to determine total and segmental lengths and number of acute-angle flexures. The two-dimensional multiplanar display was used to measure luminal diameters. The effects of age, sex, and BMI on colorectal lengths were examined. The study cohort consisted of 505 consecutive adults (266 women, mean age 56.6 years). Mean total colorectal length was 189.5 +/- 26.3 cm and mean number of acute-angle flexures was 10.9 +/- 2.4. Total length for older adults (> 60 years) did not significantly differ from those who were younger than 60 years ( P = 0.22), although the transverse colon was significantly longer in older adults ( P = 0.04). Women had significantly longer colons than men (193.3 cm vs. 185.4 cm, P = 0.002), whereas overweight adults (BMI > 25) had significantly shorter colons compared with those with BMI <or= 25 (187.2 cm vs. 194.5 cm, P = 0.005). Differences in total length were predominately due to differences in the transverse colon. Our results define the normal distribution of colorectal anatomy in an asymptomatic adult cohort, and may help to facilitate both colonoscopy training efforts and design of novel endoscopic devices. The transverse colon was the major determinant in length differences according to age, sex, and BMI, and was significantly longer in older adults, women, and thinner adults, respectively.
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Based on the importance of bowel length in massive bowel resection, the aim of this study is to evaluate the small bowel length in patients who had laparotomy. In this study, 100 consecutive adults (age >/= 20 years old) who underwent laparotomy were studied. Patients with peritonitis, intra-abdominal infection, bowel obstruction and ascitis were excluded. For comparison we used 30 cadavers as control group after case control matching. Under general anesthesia and after opening of abdomen, bowel length was measured by an umbilical tape from Treitz' ligament to ileocecal valve, antimesentrically. Data such as age, sex, height, weight and bowel length were measured and analyzed. Between May 2007 and December 2007, 100 patients (54 males and 46 females) aged 20-43 years were studied. The small bowel length was 459.6 +/- 78.47 cm in patients and 632.5 +/- 88.9 cm in cadavers (P < 0.01). Small bowel length was 452.2 +/- 79.36 cm in males and 468.2 +/- 80.44 cm in females (P = NS). Jejunum length was 140.2 +/- 45.4 cm in males and 138.6 +/- 40.2 cm in females (P = NS). Ileum length was 286.3 +/- 34.7 cm in males and 289.9 +/- 37.8 cm in females (P = NS). In this study, we report a measurement of the length of small bowel more accurate than the estimation given by the classical anatomic books. In our study, there was no correlation between bowel length and age, gender, height and weight.
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Intestinal disaccharidase and dipeptidase activities were measured in mucosal biopsies from the proximal jejunum in 20 patients with Crohn's disease apparently confined to the distal ileum or large bowel, 14 patients with ulcerative colitis, and 14 healthy volunteers who acted as controls. The dissecting microscopy and histological appearance of the biopsies were normal (Gd 0-1) except for two which showed grade 2 changes. tbiopsy morphometry showed a reduction of jejunal mucosal surface area and an increase in mucosal volume in patients with Chron's disease when compared with the other two groups. The mucosal enzymes studies demonstrated that patients with Crohn's disease had a significant reduction in brush-border enzymes (disaccharidase) but no change in cytoplasmic enzyme activity (dipeptidases). The enzyme levels in patients with ulcerative colitis did not differ from the healthy controls. The reduction of brush-border enzymes with normal cytoplasmic enzymes in the presence of abnormal morphometry is further evidence of the concept of Crohn's disease as a diffuse lesion of the gastrointestinal tract. It also suggests that there is either specific damage to the microvilli or some other abnormality such as impairment of enzyme synthesis.
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Jejunal biopsies of 10 normal subjects and 7 patients with coeliac disease were analysed quantitatively using the microdissection technique described by Clarke. Mucosal surface in the healthy upper jejunum was increased 8.3 +/- 1.1 times, the number of villi per mm2 intestine being 18.2 +/- 2.1. The ratio of the number of crypts per villi was 10.7 +/- 2.3. Mucosal transformation in coeliac disease was associated with a decrease in villi and crypts per mm2 intestine as well as in mucosal surface and an increase in crypt depth and number of mitotic figures per crypt. There was a highly significant linear correlation between villous height and mucosal surface per mm2 intestine (r = 0.93).
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Length, diameter and surface area of each of 6 segments of the large intestine were determined and calculated in 920 Japanese patients who underwent barium enema. Of the length and surface area measurements obtained, those of the transverse colon were the largest, followed by those of the sigmoid colon. The diameter of the ascending colon was the largest, while those of the descending colon and sigmoid colon were the smallest. There were various sex differences in size of the large intestine. Length and surface area of the entire large intestine in males were shorter and smaller respectively than those in females. Lengths of the cecum, ascending colon, transverse colon and rectum in males were shorter than those in females. Diameters of the descending colon, sigmoid colon and rectum in males were larger than those in females. Total surface areas of the ascending colon and transverse colon in males were smaller than those in females, while total surface areas of the descending colon, sigmoid colon and rectum in males were larger than those in females. Length of the entire large intestine tended to be increased with age. Length and surface area of the entire large intestine tended to be increased with an increase in physical dimensions in females.
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This review is intended to present our knowledge on both chronomorphology and chronophysiology of jejunum mainly in humans, as well as on implications of chronobiologic principles in the practice of gastroenterology.
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This review summarizes the rationale of stereology and the most recent developments for estimating the volumes, surface areas, lengths and numbers of structures from the subcellular to the whole organ level
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Most drug products are administered via the alimentary canal; prominent are the dosage forms which are swallowed, i.e., p.o. dosage forms, followed by those administered within the oral and the rectal cavities. The innermost surface of the alimentary canal is the epithelial lining which is void of keratinized superficial layers. The epithelium at both ends of the canal, i.e., oral cavity and esophagus, and anal canal is a multilayered (20-50 layers) stratified squamous epithelium, whereas that of the rest of the canal, i.e., gaster, small and large intestine and rectum is a single layer of columnar cells. The drainage is via both venous blood capillaries and lymphatic vessels. Blood drainage from the oral cavity and the lower end of the rectum is directly into systemic circulation via the vena cava. From the GI tract, however, the blood quantitatively passes through the portal vein and liver, hence is available for first-pass effect prior to entering systemic circulation. Targeting can be approached from two angles: 1) to exert the pharmacologic response at a specific site, or 2) to utilize a specific site for drug absorption. Targeting utilizes the anatomic, histologic, physiologic and biochemical features of various segments within the alimentary canal, paired with the design of special drug delivery systems or devices, and the use of special vehicle substances, such as polymers, bioadhesives, sorption promoters, or chemical modification (pro-drug) of the active moiety. Numerous examples of new types of drug delivery systems are presented. Many novel drug delivery systems discussed are still in experimental stage and evaluation, or even in the conceptual stage. However, it is anticipated that they all will contribute to further advancement in optimizing drug therapy.
Article
Mucosa biopsy specimens were obtained from 12 patients with continent ileostomy reservoirs constructed 15 to 19 years previously. Biopsies from normal ileal mucosa, taken from six other patients with no apparent bowel disease, served as controls. The specimens were processed for light and electron microscopy. The reservoir mucosae showed an increased amount of inflammatory cells, but there were no signs of dysplasia. In the goblet cells, sialomucins dominated over sulfomucins; in this respect no difference was found between reservoirs and controls. Morphometric studies showed an increase of mucus-storing goblet cells in the reservoir mucosae, both with regard to relative number and to volume density. The mitotic index was higher than normal in the reservoirs, but the relative number of the Paneth cells and the height of the villus epithelial cells were similar in the reservoirs and the controls. In the reservoirs, the surface amplification factors due to villi and to microvilli (near the villus tips) were reduced by some 29% and 20%, respectively, indicating villus hypotrophy. It is concluded that only minor morphologic changes appear in the ileal reservoir mucosa 15 to 19 years after construction. Morphometry provides a sensitive tool to demonstrate such changes in intestinal morphology.
Article
Measurements of villus height, crypt depth and mucosal thickness were made for each of duodenum, jejunum and ileum of rat small intestine from animals on both unrestricted and restricted feeding regimens. Contrary to a previous report, there was no evidence for consistent or synchronized diurnal variation in villus height at any region of small intestine on any of the feeding regimes. Likewise, no diurnal variation was seen in crypt depth or mucosal thickness. Variation in villus cell numbers, therefore, cannot account for previously reported diurnal variation in absorptive and digestive activities in rat small intestine. The present results support the hypothesis that the stimulus for exfoliation is probably cell recruitment and migration up the villi.
Article
Small-bowel length, number and thickness of folds in the jejunum and ileum, diameter of the loops, and thickness of the bowel wall were measured on double-contrast small-bowel enema radiographs, obtained from 182 patients with no jejunal or ileal morphologic abnormalities. The length of the small bowel ranged from 160 to 430 cm, with an average length of 291 cm. No correlation was observed between the number of folds and the total length. © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Article
In addition to metabolic differences, the anatomical, physiological, and biochemical differences in the gastrointestinal (G.I.) tract of the human and common laboratory animals can cause significant variation in drug absorption from the oral route. Among the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and content can modify dissolution rates, solubility, transit times, and membrane transport of drug molecules. The microbial content of the G.I. tract can significantly affect the reductive metabolism and enterohepatic circulation of drugs and colonic delivery of formulations. The transit time of dosage forms can be significantly different between species due to different dimensions and propulsive activities of the G.I. tract. The lipid/protein composition of the enterocyte membrane along the G.I. tract can alter binding and passive, active, and carrier-mediated transport of drugs. The location and number of Peyer's patches can also be important in the absorption of large molecules and particulate matter. While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for determining the mechanism of drug absorption and bioavailability values from powder or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess absorption from formulations. The understanding of physiological, anatomical, and biochemical differences between the G.I. tracts of different animal species can lead to the selection of the correct animal model to mimic the bioavailability of compounds in the human. This article reviews the anatomical, physiological, and biochemical differences between the G.I. tracts of humans and commonly used laboratory animals.
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This study examined the variations in colonic length and mesenteric attachments in 118 patients undergoing laparotomy. Measurements were taken according to a set protocol with the bowel pulled medially, or towards the pubic symphysis or the xiphisternum, mimicking the possible displacements that may occur during colonoscopy. A free sigmoid loop was not present in 20 patients (17 percent) because of adhesions. A descending mesocolon of 10 cm or more in length was recorded in ten patients (8 percent) and an ascending mesocolon 10 cm or greater in 11 (9 percent). Some 24 patients (20 percent) had mobile splenic flexures and in 34 (29 percent) the mid-transverse colon reached the symphysis pubis or lower when pulled downwards. Mean (range) total colonic length was 114.1 (68-159) cm. This study helps define anatomical variations that may affect the facility, or otherwise, of colonoscopy.
Article
In animal experiments total parenteral nutrition induces an atrophy of the small intestinal mucosa. In humans morphological data are few and controversial. Therefore, the aim of this study was to investigate the effect of parenteral nutrition on the intestinal mucosa of human adults. For this purpose samples of the proximal jejunum of a) patients with chronic pancreatitis receiving total parenteral nutrition as presurgical treatment, b) enterally nourished patients without (controls) and c) with chronic pancreatitis were compared using light and scanning electron microscopy. Statistical differences were assessed applying computer-assisted morphometry. The results demonstrated that the thickness of the jejunal mucosa decreased already in enterally nourished patients with chronic pancreatitis. However, after total parenteral nutrition the decrease (atrophy) was enhanced due to a strong reduction in villus height albeit the crypt length increased. In addition, scanning electron microscopy revealed distinctive changes in mucosal surface pattern, whereby finger-like villi were replaced by leaf-like villi and by long, winding bifurcating ridges. Cell shedding was absent. In conclusion, total parenteral nutrition in humans induces 1) an atrophy and 2) a remodelling of the intestinal mucosa (epithelium and lamina propria) with a decrease in the absorbing surface. These alterations involve both cell proliferation and cell shedding. The response of the mucosa to parenteral nutrition is immediate and the effect of the treatment in bringing about morphological alterations is more efficacious at the beginning than in the successive period. The basic disorder (chronic pancreatitis) of the patients nourished parenterally contributes to mucosal atrophy, but not to remodelling.
Article
The present treatise is primarily concerned with the structural and morphometric parameters of the cecum and large intestine of mammals. Over the past century, numerous accounts have visually presented the variation and diversity of the large intestine of mammals. This includes above all comprehensive works on the macroscopic anatomy. More recently, the microscopic anatomy of various animals at the light, electron, and scanning electron microscopy levels has been covered, especially for rodents and primates. In the past two decades, progress has been made by adding a new dimension to the previous structural studies, namely, the morphometrical analysis of the intestine of various animals and subsequent employment of this data in an analysis based on principles of scaling. The present account follows essentially this outline, but presented in a slightly different order. First, in the introductory section, the scientific aims and general prologue to this field of study are presented. Included in this section is a short, concise literature survey that deals with the major literature available on the subject of the large intestine at the macroscopical and microscopical level, as well as the most recent morphometric analyses of the intestines. The main focus of the present work is on the methodological; a new method is described to measure the intestines of animals ranging in size from the harvest mouse to the horse. This technique may also be applicable to other hollow or tube-like organs. Heretofore, previous techniques have been based on obtaining the area of the surface mucosa by measuring lengths and widths and calculating the area by multiplying the two measurements. Alternatively, some methods have taken probes and made measurements at the light microscopy level and then extrapolated these results to determine the entire area. The former method is inadequate, while the latter possesses the inherent disadvantages of all sampling techniques. The present technique has two levels: (1) obtaining the basal surface area of the entire intestine and (2) accounting for any increase in the mucosal surface area that is due to microscopically visible folds, villi, or other such structures. The former is accomplished by flattening appropriately sized pieces of intestine between two glass plates and tracing the contours onto transparent paper. The entire intestine is processed in this manner, resulting in a basal surface area, the contours having been submitted to analysis on a semi-automatic image analyzer to determine the area in square millimeters. The second-level measurements determine a factor of surface enlargement by calculating a ratio of the distance along the surface contour of the mucosa on a histological section cut perpendicular to the width of the intestine to a second distance (reference line) drawn straight beneath the mucosa but not tracing the enlargements. The measurements obtained at both levels are multiplied to give a final surface area. In addition to a detailed description of the technique complete with a flow sheet and pictorial diagram, the various aspects of proper fixation, tissue embedding, shrinkage, and determination of sampling sites (for the second level of measurement) are discussed. A pilot experiment to determine the surface enlargement due to microvilli is presented from material taken from the giant pouched rat. This was performed by measuring video sequences of microvilli taken from electron microscopy images. Cecal microvilli increase the surface area 15-fold, while in the colon the increase is approximately 19- to 20-fold. In the discussion, the choice of using three animals per group is discussed, based on simple statistical tests. Section 3 is entitled "Morphology of the Mammalian Cecum." Chronologically, it marks the onset of the entire investigation. Before having developed the method described in Sect. 2, these morphological investigations at the light, electron and scanning electron microscopy
Article
The mucosal surface area of small intestines in non-ruminant eutherian mammals increases approximately in proportion to the 0.6 power of body mass, whereas resting metabolic rate (RMR) increases approximately with the 0.74 power of body mass; the mass exponent for field metabolic rates (FMR) may exceed 0.8. These relationships imply that the average rate of absorption of metabolic substrates, expressed per unit area of mucosal surface, is greater in large animals than in small. In the present paper I collate data from the literature relating mucosal surface area, fluid absorption and glucose transport rates to body size. Glucose-stimulated fluid absorption per unit area of mucosal surface increases with body size, whereas transcellular, carrier-mediated glucose transport per unit area decreases with body size. In perfused jejunal segments of normal human subjects the rates of fluid absorption per unit area of mucosa are five to ten times greater than in laboratory rats. The absorbed fluid contains glucose in amounts that may greatly exceed the maximum transport capacity of the apical glucose transporter. It follows that the paracellular component of glucose absorption increases with body size. Scaling of intestinal dimensions and transport therefore provides new information about the relative contributions of transcellular and paracellular pathways to absorption of nutrients.
Article
The colonic epithelium has both absorptive and secretory functions. The transport is characterized by a net absorption of NaCl, short-chain fatty acids (SCFA), and water, allowing extrusion of a feces with very little water and salt content. In addition, the epithelium does secret mucus, bicarbonate, and KCl. Polarized distribution of transport proteins in both luminal and basolateral membranes enables efficient salt transport in both directions, probably even within an individual cell. Meanwhile, most of the participating transport proteins have been identified, and their function has been studied in detail. Absorption of NaCl is a rather steady process that is controlled by steroid hormones regulating the expression of epithelial Na(+) channels (ENaC), the Na(+)-K(+)-ATPase, and additional modulating factors such as the serum- and glucocorticoid-regulated kinase SGK. Acute regulation of absorption may occur by a Na(+) feedback mechanism and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl(-) secretion in the adult colon relies on luminal CFTR, which is a cAMP-regulated Cl(-) channel and a regulator of other transport proteins. As a consequence, mutations in CFTR result in both impaired Cl(-) secretion and enhanced Na(+) absorption in the colon of cystic fibrosis (CF) patients. Ca(2+)- and cAMP-activated basolateral K(+) channels support both secretion and absorption of electrolytes and work in concert with additional regulatory proteins, which determine their functional and pharmacological profile. Knowledge of the mechanisms of electrolyte transport in the colon enables the development of new strategies for the treatment of CF and secretory diarrhea. It will also lead to a better understanding of the pathophysiological events during inflammatory bowel disease and development of colonic carcinoma.
Article
Although the sigmoid colon is commonly afflicted with disease, studies on its anatomical dimensions are scarce. It is suspected that dimensions of the sigmoid colon change with age. This study documents data on the anatomical measurements of the sigmoid colon in 70 Indian subjects (51 live and 19 cadavers). Seven parameters of sigmoid colon anatomy measured included length and width of the sigmoid colon and mesocolon at specific points. Three mesocolic indices (width to length ratios) were calculated. Comparisons of measurements in the live and cadaver subjects and in the two sexes were made. The relationship of change in parameters with age was assessed. Appropriate statistical methods were used and the differences were considered significant at P < or = 0.05. The study showed wide ranging variations in the values of various measured parameters of the sigmoid colon. Seven patterns of the shape of the sigmoid loop were identified. In the commonest pattern the sigmoid mesocolon was vertically longer than wide (dolichomesocolic), the sigmoid loop having its maximum convexity located just a little proximal to the apex. Patterns where the width of the mesocolon was greater than the vertical length (brachymesocolic) were also observed. The gender analysis showed that the sigmoid mesocolon of the female was brachymesocolic (wider than long), whereas that of the male was dolichomesocolic (longer than wide). This might explain the higher incidence of sigmoid volvulus in the male. This study also showed that the measurements of the sigmoid colon and its mesocolon do not change significantly within the age range of 16-60 years in the two sexes. Also noteworthy is the observation that in the cadaver the sigmoid colon shows considerable shrinkage, particularly of its mesocolon; consequently the data from cadaver subjects, though valuable for anthropometric use, have limitations when used for clinical applications.
Article
The intestines play an important role in the absorption and secretion of nutrients. The colon is the final area for recapturing electrolytes and water prior to excretion, and in order to maintain this electrolyte homeostasis, a complex interaction between secretory and absorptive processes is necessary. Until recently it was thought that secretion and absorption were two distinct processes associated with either crypts or surface cells, respectively. Recently it was demonstrated that both the surface and crypt cells can perform secretory and absorptive functions and that, in fact, these functions can be going on simultaneously. This issue is important in the complexities associated with secretory diarrhea and also in attempting to develop treatment strategies for intestinal disorders. Here, we update the model of colonic secretion and absorption, discuss new issues of transporter activation, and identify some important new receptor pathways that are important modulators of the secretory and absorptive functions of the colon.
Article
The gut immune system has the challenge of responding to pathogens while remaining relatively unresponsive to food antigens and the commensal microflora. In the developed world, this ability appears to be breaking down, with chronic inflammatory diseases of the gut commonplace in the apparent absence of overt infections. In both mouse and man, mutations in genes that control innate immune recognition, adaptive immunity, and epithelial permeability are all associated with gut inflammation. This suggests that perturbing homeostasis between gut antigens and host immunity represents a critical determinant in the development of gut inflammation and allergy.
Article
Mucosal dendritic cells (DCs) constantly survey the luminal microenvironment which contains commensal microbiota and potentially harmful organisms regulating pathogen recognition and adaptive as well as innate defense activation. Distinct mechanisms are beginning to emerge by which intestinal antigen sampling and handling is achieved ensuring specificity and contributing to redundancy in pathogen detection. Distinct DC subsets are associated with these mechanisms and regulate specific innate or adaptive immune responses to help distinguish between commensal microbiota, pathogens and self antigens. Understanding DC biology in the mucosal immune system may contribute to the unraveling of infection routes of intestinal pathogens and may aid in developing novel vaccines and therapeutic strategies for the treatment of infectious and inflammatory diseases.
Quantitative Untersuchungen zur dreidimensionalen Struktur der Dünndarmschleimhaut bei Gesunden und Patienten mit einheimscher Sprue
  • Riecken Eo
  • M Sahlfeld
  • Lorenz
  • Meyer
Riecken EO, Sahlfeld M, Lorenz-Meyer H. Quantitative Untersuchungen zur dreidimensionalen Struktur der Dünndarmschleimhaut bei Gesunden und Patienten mit einheimscher Sprue. Dtsch med Wschr 1976;101:51–3.
Länge und Lage des Ver-dauungsrorhes beim Lebenden. Ztschr f d ges exper
  • Reis V Van
  • Schembra
  • Fw
van der Reis V, Schembra FW. Länge und Lage des Ver-dauungsrorhes beim Lebenden. Ztschr f d ges exper Med 1924;43:94–115.