Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases

Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases Daniela Parada Venegas Marjorie K. De la Fuente Glauben Landskron Marı́a Julieta González Rodrigo Quera Gerard Dijkstra Hermie J. M. Harmsen Klaas Nico Faber Marcela A. Hermoso

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Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases 2019 Frontiers in Immunology 10.3389/fimmu.2019.00277 venegas2019-short-chain-fatty-acids-scfas-medi venegas2019-short-chain-fatty-acids-scfas-medi.txt, the project's staged copy f77b523c058d014ee68faec30ccdda9856aa538f cc-by biology

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them the short-chain fatty acids bacteria make from dietary fibre - acetate, propionate and butyrate - and what they do to the intestinal epithelium and immune cells in inflammatory bowel disease Quotation withheld because this record is not cleared for redistribution. whether the reduced SCFA levels seen in IBD are a mechanism of the disease and a possible therapy, or a consequence of it Quotation withheld because this record is not cleared for redistribution. an overview of SCFA production, transport and receptor signalling in the gut, which states that fecal SCFA quantification measures a steady state and not production, and that whether dysbiosis causes IBD is unresolved Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. a bacterial metabolite acting as fuel, as a barrier signal and as an immunomodulator at once, whose measured concentration is the small fraction the mucosa did not absorb Quotation withheld because this record is not cleared for redistribution. review review Quotation withheld because this record is not cleared for redistribution. 90 to 95 per cent of the SCFAs produced in the colonic lumen are taken up by the mucosa before anything is collected. A fecal SCFA concentration is therefore the small remainder, and a difference between patients and controls could be a difference in production, in absorption, or in transit - the number cannot distinguish them the measurement is what absorption left behind Quotation withheld because this record is not cleared for redistribution. germ-free conditions make IL-10-deficient chronic colitis less severe and acute chemically-induced colitis worse. Any statement of the form 'the microbiota protects against colitis' is therefore incomplete without naming the model, and two papers reporting opposite results may both be right an intervention whose sign is a property of the model Quotation withheld because this record is not cleared for redistribution. probiotics showed no significant effect in Crohn's disease - and the review notes in the next sentence that the probiotics evaluated in those studies were not butyrate-producing bacteria. The hypothesis being tested was about butyrate and the intervention did not contain any a null result whose treatment lacked the active ingredient Quotation withheld because this record is not cleared for redistribution. Bacteroidetes make acetate and propionate; Firmicutes make butyrate. A shift in phylum ratio is therefore automatically a shift in which metabolite the colon receives, which is why a compositional 16S result can be read as a functional claim and why that reading is only as good as the division a division of labour that makes composition into chemistry Quotation withheld because this record is not cleared for redistribution. butyrate absorbed and oxidised by the epithelium consumes local oxygen. Deplete the anaerobes with antibiotics, butyrate falls, the mucosa stops consuming oxygen, and the colon becomes hospitable to aerobes such as Salmonella - a chain in which the metabolite acts by changing the physical environment rather than by signalling oxygen as the intermediate Quotation withheld because this record is not cleared for redistribution. fecal and tissue SCFA quantification gives steady state levels and may not accurately reflect bacterial production, since 90-95% is absorbed by the mucosa Quotation withheld because this record is not cleared for redistribution. the fecal measurement is used as an approximation of gut levels, justified by association with resistant-starch diets rather than by direct comparison Quotation withheld because this record is not cleared for redistribution. it remains unclear whether dysbiosis is a cause or a consequence of IBD Quotation withheld because this record is not cleared for redistribution. the molecular mechanism by which SCFAs suppress pro-inflammatory mediators has not been completely determined in human or mouse mononuclear cell models Quotation withheld because this record is not cleared for redistribution. the mechanisms involved in IBD pathophysiology are still not resolved, nor how butyrate regulates inflammation and transcription in colonic mucosa Quotation withheld because this record is not cleared for redistribution. well-controlled randomised placebo-controlled trials are still needed before prebiotic supplementation can be said to produce clinical improvement Quotation withheld because this record is not cleared for redistribution. faecal microbiome transplantation has generated inconsistent results and is placed outside the scope of the review Quotation withheld because this record is not cleared for redistribution. SCFA concentration is not one number - proximal colon runs 70-140 mM against 20-70 mM distally, and both depend on fibre intake Quotation withheld because this record is not cleared for redistribution. resistant-starch feeding trials in pigs, carried into human gut physiology as a model for dietary regulation of SCFA transporters Quotation withheld because this record is not cleared for redistribution. the Codex Alimentarius definition of dietary fibre, a food-regulation standard used here to fix what counts as the substrate Quotation withheld because this record is not cleared for redistribution. SLC5A8 (SMCT1) mRNA measured alongside SLC16A1 (MCT1) in the same pigs on the same resistant-starch and digestible-starch diets eliminates: a general effect of diet on monocarboxylate transport - SMCT1 does not move, so the MCT1 response is specific to that transporter · outcome: held Quotation withheld because this record is not cleared for redistribution. germ-free conditions applied in two different colitis models - chronic IL-10-deficient and acute chemically-induced eliminates: a single-model answer standing for the microbiota's role - running both shows the sign reverses, which one model alone would have hidden · outcome: partial Quotation withheld because this record is not cleared for redistribution. SCFA levels measured in liver and blood as well as intestine eliminates: the assumption that SCFA action is systemic - levels elsewhere are much lower, placing signalling and uptake at the mucosa, while their detectability still supports systemic function · outcome: held Quotation withheld because this record is not cleared for redistribution. SCFA-producing bacteria and SCFA levels both measured in IBD patients, rather than inferring the metabolite from the taxon eliminates: a taxonomic shift being reported as a metabolic one - here both the producers and the product are shown to be reduced · outcome: held Quotation withheld because this record is not cleared for redistribution. probiotic trials in Crohn's disease, reported as showing no significant effect on inducing or maintaining remission eliminates: nothing about butyrate, and the review says so in the next sentence - the probiotics tested were not butyrate-producing bacteria, so the null result does not test the mechanism it appears to test · outcome: failed Quotation withheld because this record is not cleared for redistribution. well-controlled randomised placebo-controlled trials of prebiotic supplementation, named as needed and not yet done eliminates: placebo response and spontaneous remission in IBD - the randomised placebo-controlled trials that would rule them out are named as needed and not yet done · outcome (stated by the tagger, no quotation): absent-declared-unreported Quotation withheld because this record is not cleared for redistribution. faecal microbiome transplantation, named as producing inconsistent results and excluded from the review's scope eliminates: the possibility that the SCFA effects are reproduced by wholesale microbiota transfer - excluded from the review's scope rather than resolved · outcome (stated by the tagger, no quotation): absent-stated-about-other Quotation withheld because this record is not cleared for redistribution. SCFAs SCFAs Quotation withheld because this record is not cleared for redistribution. steady state levels steady state levels Quotation withheld because this record is not cleared for redistribution. bacterial production bacterial production Quotation withheld because this record is not cleared for redistribution. butyrate butyrate Quotation withheld because this record is not cleared for redistribution. Bacteroidetes Bacteroidetes Quotation withheld because this record is not cleared for redistribution. Firmicutes Firmicutes Quotation withheld because this record is not cleared for redistribution. germfree germfree Quotation withheld because this record is not cleared for redistribution. IL-10 deficient mice IL-10 deficient mice Quotation withheld because this record is not cleared for redistribution. chemically-induced colitis chemically-induced colitis Quotation withheld because this record is not cleared for redistribution. dysbiosis dysbiosis Quotation withheld because this record is not cleared for redistribution. IBD IBD Quotation withheld because this record is not cleared for redistribution. MCT1 MCT1 Quotation withheld because this record is not cleared for redistribution. SMCT1 SMCT1 Quotation withheld because this record is not cleared for redistribution. IECs IECs Quotation withheld because this record is not cleared for redistribution. antibiotics antibiotics Quotation withheld because this record is not cleared for redistribution. Salmonella typhimurium Salmonella typhimurium Quotation withheld because this record is not cleared for redistribution. probiotic probiotic Quotation withheld because this record is not cleared for redistribution. SCFA level - AS MEASURED IN FECES: a steady state, and 5 to 10 per cent of what was produced, because the mucosa absorbs 90-95% of the colonic lumen's SCFAs before anything is collected Quotation withheld because this record is not cleared for redistribution. SCFA level - AS INTENDED: the rate of bacterial production, which the authors say the fecal measurement may not accurately reflect and which is inferred from its association with resistant-starch diets Quotation withheld because this record is not cleared for redistribution. removing the microbiota - IN IL-10-DEFICIENT MICE: protective, giving less severe chronic bowel inflammation under germ-free conditions Quotation withheld because this record is not cleared for redistribution. removing the microbiota - IN CHEMICALLY-INDUCED COLITIS: harmful, with the acute disease exacerbated in germ-free mice against animals with a normal microbiome Quotation withheld because this record is not cleared for redistribution. SCFAs acting on the epithelium - IN HEALTH: fuel and proliferation for colonocytes Quotation withheld because this record is not cleared for redistribution. SCFAs acting on the epithelium - IN CANCER: suppression of proliferation and induction of apoptosis, the opposite sign in the same tissue Quotation withheld because this record is not cleared for redistribution. SCFA concentration - AS A SINGLE NUMBER: misleading, because proximal colon runs 70-140 mM and distal colon 20-70 mM and both vary with fibre intake Quotation withheld because this record is not cleared for redistribution. qualifies → the literature's use of fecal SCFA concentration as a measure of bacterial production, since 90-95% is absorbed before collection Quotation withheld because this record is not cleared for redistribution. qualifies → the causal reading of dysbiosis in IBD - the review states it remains unclear whether dysbiosis is cause or consequence Quotation withheld because this record is not cleared for redistribution. critiques → the probiotic trials in Crohn's disease, whose null result is reported alongside the observation that the probiotics tested were not butyrate producers Quotation withheld because this record is not cleared for redistribution. builds-on → germ-free and gnotobiotic colitis models, while reporting that they answer in opposite directions Quotation withheld because this record is not cleared for redistribution. extends → the metabolic account of SCFAs as colonocyte fuel, by adding transporter regulation and GPCR signalling as immunomodulatory routes Quotation withheld because this record is not cleared for redistribution. steady state levels —distinct-from→ bacterial production steady state levels bacterial production differs in: whether the number is a rate of production or the residue left after absorption · the relation itself is separately evidenced · strength of the relation: 0.95 · differs in (stated by the tagger, no quotation): whether the number is a rate of production or the residue left after absorption · the relation stated: quantifying SCFAs returns a standing concentration after the mucosa has absorbed 90-95% of what the lumen contained, which is not the production rate the field means Quotation withheld because this record is not cleared for redistribution. IL-10 deficient mice —distinct-from→ chemically-induced colitis IL-10 deficient mice chemically-induced colitis differs in: which direction removing the microbiota moves the disease · the relation itself is separately evidenced · strength of the relation: 0.95 · differs in (stated by the tagger, no quotation): which direction removing the microbiota moves the disease · the relation stated: germ-free conditions reduce inflammation in the chronic IL-10-deficient model and worsen acute chemically-induced colitis - one intervention, two signs Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span says the effect 'may go either way' in the two models; distinct-from is loose. Quotation withheld because this record is not cleared for redistribution. Bacteroidetes —distinct-from→ Firmicutes Bacteroidetes Firmicutes differs in: which short-chain fatty acid the organism produces · the relation itself is separately evidenced · strength of the relation: 0.95 · differs in (stated by the tagger, no quotation): which short-chain fatty acid the organism produces · the relation stated: the two dominant phyla make different SCFAs - acetate and propionate against butyrate - so the metabolite profile is a readout of which phylum is present Quotation withheld because this record is not cleared for redistribution. MCT1 —distinct-from→ SMCT1 MCT1 SMCT1 differs in: whether dietary substrate regulates the transporter's expression · the relation itself is separately evidenced · strength of the relation: 0.95 · differs in (stated by the tagger, no quotation): whether dietary substrate regulates the transporter's expression · the relation stated: resistant starch raises SLC16A1 mRNA (MCT1) in pig cecal and colonic mucosa while SLC5A8 (SMCT1) is unaffected by the same diets Quotation withheld because this record is not cleared for redistribution. antibiotics —causes→ butyrate antibiotics butyrate direction on the measure: reduces · the relation itself is separately evidenced · strength of the relation: 0.95 · direction on the measure (stated by the tagger, no quotation): reduces · the relation stated: depleting anaerobic bacteria with antibiotics lowers butyrate, which makes the colon aerobic and lets Salmonella typhimurium expand Audit 2026-09-28: DOUBTFUL - read against its span and kept, but antibiotics deplete anaerobes, which is associated with lower butyrate; causes is indirect. Quotation withheld because this record is not cleared for redistribution. fecal SCFA quantification gives steady state levels and may not reflect bacterial production, because 90-95% of lumen SCFAs are absorbed by the mucosa fecal SCFA quantification gives steady state levels and may not reflect bacterial production, because 90-95% of lumen SCFAs are absorbed by the mucosa Quotation withheld because this record is not cleared for redistribution. germ-free conditions make IL-10-deficient colitis less severe and chemically-induced colitis worse - the same intervention with opposite signs germ-free conditions make IL-10-deficient colitis less severe and chemically-induced colitis worse - the same intervention with opposite signs Quotation withheld because this record is not cleared for redistribution. it remains unclear whether dysbiosis is a cause or a consequence of IBD it remains unclear whether dysbiosis is a cause or a consequence of IBD Quotation withheld because this record is not cleared for redistribution. Bacteroidetes mainly produce acetate and propionate while Firmicutes mostly produce butyrate in the human gut Bacteroidetes mainly produce acetate and propionate while Firmicutes mostly produce butyrate in the human gut Quotation withheld because this record is not cleared for redistribution. resistant starch raises MCT1 (SLC16A1) mRNA while SMCT1 (SLC5A8) is unaffected, making the regulation transporter-specific resistant starch raises MCT1 (SLC16A1) mRNA while SMCT1 (SLC5A8) is unaffected, making the regulation transporter-specific Quotation withheld because this record is not cleared for redistribution. antibiotic depletion of anaerobes lowers butyrate, promotes an aerobic environment and expands Salmonella typhimurium antibiotic depletion of anaerobes lowers butyrate, promotes an aerobic environment and expands Salmonella typhimurium Quotation withheld because this record is not cleared for redistribution. probiotics showed no significant effect in Crohn's disease, and the probiotics evaluated were not butyrate-producing bacteria probiotics showed no significant effect in Crohn's disease, and the probiotics evaluated were not butyrate-producing bacteria Quotation withheld because this record is not cleared for redistribution. SCFAs suppress cancer cell proliferation and induce apoptosis, the opposite of their effect on healthy intestinal epithelial cells SCFAs suppress cancer cell proliferation and induce apoptosis, the opposite of their effect on healthy intestinal epithelial cells Quotation withheld because this record is not cleared for redistribution. IBD patients show both reduced SCFA-producing bacteria and reduced SCFA levels compared with healthy controls IBD patients show both reduced SCFA-producing bacteria and reduced SCFA levels compared with healthy controls Quotation withheld because this record is not cleared for redistribution. what SCFA quantification returns - a standing concentration measured after the mucosa has absorbed 90-95% of what the lumen produced, and not the production rate steady state levels Quotation withheld because this record is not cleared for redistribution. live microorganisms that when administered in adequate amounts confer a health benefit on the host - and in the Crohn's trials, ones that were not butyrate producers probiotic Quotation withheld because this record is not cleared for redistribution. to 95 per cent of colonic-lumen SCFAs are absorbed by the mucosa before any measurement is taken 90 Quotation withheld because this record is not cleared for redistribution. butyrate butyrate Quotation withheld because this record is not cleared for redistribution. dysbiosis dysbiosis Quotation withheld because this record is not cleared for redistribution.

The full text of this article is not redistributable, so it is not included here. The evidence sentences are withheld with it; the tag layer and its grounding status remain. The article itself is at https://doi.org/10.3389/fimmu.2019.00277.