Postprandial Chylomicron Output and Transport Through Intestinal Lymphatics Are Not Impaired in Active Crohn's Disease.
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ABSTRACT:
SUBMITTER: Huang LH
PROVIDER: S-EPMC7680355 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The mechanisms by which alterations in intestinal bile acid (BA) metabolism improve systemic glucose tolerance and hepatic metabolic homeostasis are incompletely understood. We examined metabolic adaptations in mice with conditional intestinal deletion of the abetalipoproteinemia (ABL) gene microsomal triglyceride transfer protein (Mttp-IKO), which blocks chylomicron assembly and impairs intestinal lipid transport. Mttp-IKO mice exhibit improved hepatic glucose metabolism and augmented insulin signaling, without weight loss. These adaptations included decreased BA excretion, increased pool size, altered BA composition, and increased fibroblast growth factor 15 production. Mttp-IKO mice absorb fructose normally but are protected against dietary fructose-induced hepatic steatosis, without weight loss or changes in energy expenditure. In addition, Mttp-IKO mice exhibit altered cecal microbial communities, both at baseline and following fructose feeding, including increased abundance of Bacteroides and Lactobacillus genera. Transplantation of cecal microbiota from chow-fed Mttp-IKO mice into antibiotic-treated wild-type recipients conferred transmissible protection against fructose-induced hepatic steatosis in association with a bloom in Akkermansia and increased Clostridium XIVa genera, whose abundance was positively correlated with fecal coprostanol and total neutral sterol excretion in recipient mice. However, antibiotic-treated Mttp-IKO mice were still protected against fructose-induced hepatic steatosis, suggesting that changes in microbiota are not required for this phenotype. Nevertheless, we found increased abundance of fecal Akkermansia from two adult ABL subjects with MTTP mutations compared to their heterozygous parents and within the range noted in six healthy control subjects. Furthermore, Akkermansia abundance across all subjects was positively correlated with fecal coprostanol excretion. Conclusion: The findings collectively suggest multiple adaptive pathways of metabolic regulation following blocked chylomicron assembly, including shifts in BA signaling and altered microbial composition that confer a transmissible phenotype.
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Project description:Chylomicron metabolism is critical for determining plasma levels of triacylglycerols (TAGs) and cholesterol, both of which are risk factors for CVD. The rates of chylomicron secretion and remnant clearance are controlled by intracellular and extracellular factors, including apoC-III. We have previously shown that human apoC-III overexpression in mice (apoC-IIITg mice) decreases the rate of chylomicron secretion into lymph, as well as the TAG composition in chylomicrons. We now find that this decrease in chylomicron secretion is not due to the intracellular effects of apoC-III, but instead that primary murine enteroids are capable of taking up TAG from TAG-rich lipoproteins (TRLs) on their basolateral surface; and via Seahorse analyses, we find that mitochondrial respiration is induced by basolateral TRLs. Furthermore, TAG uptake into the enterocyte is inhibited when excess apoC-III is present on TRLs. In vivo, we find that dietary TAG is diverted from the cytosolic lipid droplets and driven toward mitochondrial FA oxidation when plasma apoC-III is high (or when basolateral substrates are absent). We propose that this pathway of basolateral lipid substrate transport (BLST) plays a physiologically relevant role in the maintenance of dietary lipid absorption and chylomicron secretion. Further, when apoC-III is in excess, it inhibits BLST and chylomicron secretion.
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Project description:The microbiota in the lumen of patients with Crohn's disease (CD) is characterized by reduced diversity, particularly Firmicutes and Bacteroidetes. It is unknown whether the introduction of the intestinal microbiota from healthy individuals could correct this dysbiosis and reverse mucosal inflammation. We investigated the response to fecal microbial transplantation (FMT) from healthy individuals to subjects with active CD.We performed a prospective open-label study (uncontrolled) of FMT from healthy donors to subjects with active CD. A single FMT was performed by colonoscopy. Recipients' microbial diversity, mucosal T-cell phenotypes, and clinical and inflammatory parameters were measured over 12 weeks, and safety over 26 weeks.Nineteen subjects were treated with FMT and completed the study follow-up. Fifty-eight percent (11/19) demonstrated a clinical response (Harvey-Bradshaw Index decrease >3) following FMT. Fifteen subjects had sufficient pre/postfecal samples for analysis. A significant increase in microbial diversity occurred after FMT (P = 0.02). This was greater in clinical responders than nonresponders. Patients who experienced a clinical response demonstrated a significant shift in fecal microbial composition toward their donor's profile as assessed by the Bray-Curtis index at 4 weeks (P = 0.003). An increase in regulatory T cells (CD4CD25CD127lo) was also noted in recipients' lamina propria following FMT. No serious adverse events were noted over the 26-week study period.In this open-label study, FMT led to an expansion in microbial bacterial diversity in patients with active CD. FMT was overall safe, although the clinical response was variable. Determining donor microbial factors that influence clinical response is needed before randomized clinical trials of FMT in CD.
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Project description:Mucus constitutes a protective layer which coats the gastrointestinal tract, controlling interactions of both commensal and pathogenic microbes with underlying tissues. Changes to the mucus barrier, for example due to altered mucin expression or external stimuli, may impact interactions with microbes and thus potentially contribute to altered gut homeostasis, onset of inflammation, or pathogen invasion. Food-associated stimuli, including lipids, have been shown to change mucus barrier properties and reduce transport of model drug carriers through mucus. Here, we explore the impact of lipids, specifically triglycerides in a model intestinal medium mimicking a fed state, on Escherichia coli (E. coli) transport through mucus by directly imaging swimming patterns and analyzing associated changes in mucus structure. Lipids in model fed state intestinal contents reduced E. coli speed and track linearity within mucus. These changes may be due in part to changes in molecular interactions within the mucus network as well as crowding of the mucus network by lipid emulsion droplets, which visibly stay intact in the mucus gel. In addition, observed physical interactions between bacteria and lipid structures may impact microbial speed and trajectories. As lipids are normal food components and thus represent safe, mild stimuli, these results support exploration of lipid-based strategies to alter the mucus barrier to control interactions with microbes and potentially prevent microbial invasion of underlying epithelium.
| S-EPMC6303031 | biostudies-literature
Project description:BackgroundThe glycoprotein (gp) 96 links the adaptive with the innate immune system. It is a chaperone with a binding domain for peptides generated by proteasomal degradation. During cellular stress, peptide loaded gp96 can be released and presented to T cells by antigen presenting cells (APCs).MethodsmRNAs from in vitro differentiated macrophages (iv mac) and normal intestinal macrophages (IMACs) were compared by subtractive hybridisation and Affymetrix GeneChip analysis. Differentiation induced expression of gp96 was investigated in the multicellular spheroid (MCS) model. In vivo gp96 protein expression was detected by double labelling immunohistochemistry of human colon and in the CD4+ CD62L+ T cell transfer mouse model.ResultsFive of 76 clones obtained by subtractive hybridisation revealed >99% sequence homology to gp96. Affymetrix GeneChip analysis confirmed induction of gp96 in IMACs. Gp96 mRNA was detected in IMACs from normal and intestinal bowel disease mucosa. Induction of gp96 protein was observed after seven days in the MCS model of IMAC differentiation. Immunohistochemistry confirmed the presence of gp96 protein in IMACs in normal mucosa as well as in mucosa from patients with ulcerative colitis and diverticulitis. In mucosa from Crohn's disease (CD) patients, gp96 protein was not detectable. In the CD4+ CD62L+ T cell transfer mouse model, gp96 was verifiable in non-activated IMACs.ConclusionGp96 is induced during differentiation of normal IMACs but is not detected in IMACs in CD mucosa. As gp96 has been described as having a role in tolerance induction, this may be relevant for loss of tolerance against luminal bacteria found in CD patients.
| S-EPMC1774602 | biostudies-literature
Project description:BackgroundPostprandial rise of plasma essential amino acids (EAAs) determines the anabolic effect of dietary protein. Disturbed gastrointestinal function could impair the anabolic response in critically ill patients. Aim was to investigate the postprandial EAA response in critically ill patients and its relation to small-intestinal function.MethodsTwenty-one mechanically ventilated patients and 9 healthy controls received a bolus containing 100 ml of a formula feed (Ensure) and 2 g of 3-O-Methyl-d-glucose (3-OMG) via postpyloric feeding tube. Fasting and postprandial plasma concentrations of EAAs, 3-OMG, total bile salts, and the gut-released hormone fibroblast growth factor 19 (FGF19) were measured over a 4-hour period. Changes over time and between groups were assessed with linear mixed-effects analysis. Early (0-60 minutes) and total postprandial responses are summarized as the incremental area under the curve (iAUC).ResultsAt baseline, fasting EAA levels were similar in both groups: 1181 (1055-1276) vs 1150 (1065-1334) μmol·L-1, P = .87. The early postprandial rise in EAA was not apparent in critically ill patients compared with healthy controls (iAUC60 , -4858 [-6859 to 2886] vs 5406 [3099-16,853] µmol·L-1 ·60 minutes; P = .039). Impaired EAA response did not correlate with impaired 3-OMG response (Spearman ρ 0.32, P = .09). There was a limited increase in total bile salts but no relevant FGF19 response in either group.ConclusionPostprandial rise of EAA is blunted in critically ill patients and unrelated to glucose absorption measured with 3-OMG. Future studies should aim to delineate governing mechanisms of macronutrient malabsorption.
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Project description:Intestinal handling of dietary triglycerides has important implications for health and disease. Following digestion in the intestinal lumen, absorption, and re-esterification of fatty acids and monoacylglycerols in intestinal enterocytes, triglycerides are packaged into lipoprotein particles (chylomicrons) for secretion or into cytoplasmic lipid droplets for transient or more prolonged storage. Despite the recognition of prolonged retention of triglycerides in the post-absorptive phase and subsequent release from the intestine in chylomicron particles, the underlying regulatory mechanisms remain poorly understood. Chylomicron secretion involves multiple steps, including intracellular assembly and post-assembly transport through cellular organelles, the lamina propria, and the mesenteric lymphatics before being released into the circulation. Contrary to the long-held view that the intestinal lymphatic vasculature acts mainly as a passive conduit, it is increasingly recognized to play an active and regulatory role in the rate of chylomicron release into the circulation. Here, we review the latest advances in understanding the role of lymphatics in intestinal lipid handling and chylomicron secretion. We highlight emerging evidence that oral glucose and the gut hormone glucagon-like peptide-2 mobilize retained enteral lipid by differing mechanisms to promote the secretion of chylomicrons via glucose possibly by mobilizing cytoplasmic lipid droplets and via glucagon-like peptide-2 possibly by targeting post-enterocyte secretory mechanisms. We discuss other potential regulatory factors that are the focus of ongoing and future research. Regulation of lymphatic pumping and function is emerging as an area of great interest in our understanding of the integrated absorption of dietary fat and chylomicron secretion and potential implications for whole-body metabolic health.
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Project description:Although impaired intestinal sodium transport has been described for decades as a ubiquitous feature of inflammatory bowel disease (IBD), whether and how it plays a pivotal role in the ailment has remained uncertain. Our identification of dominant mutations in receptor guanylyl cyclase 2C as a cause of IBD-associated familial diarrhea syndrome brought a shift in the way we envision impaired sodium transport. Is this just a passive collateral effect resulting from intestinal inflammation, or is it a crucial regulator of IBD pathogenesis? This review summarizes the mutational spectrum and underlying mechanisms of monogenic IBD associated with congenital sodium diarrhea. We constructed a model proposing that impaired sodium transport is an upstream pathogenic factor in IBD. The review also synthesized emerging insights from microbiome and animal studies to suggest how sodium malabsorption can serve as a unifying mediator of downstream pathophysiology. Further investigations into the mechanisms underlying salt and water transport in the intestine will provide newer approaches for understanding the ion-microbiome-immune cross-talk that serves as a driver of IBD. Model systems, such as patient-derived enteroids or induced pluripotent stem cell models, are warranted to unravel the role of individual genes regulating sodium transport and to develop more effective epithelial rescue and repair therapies.
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Project description:Lipids are the most energy-dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron-mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high-fat diet-induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.
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