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PubMed2005

Mechanisms underlying the effects of inulin-type fructans on calcium absorption in the large intestine of rats.

Inulin-type fructans (inulin, oligofructose, fructooligosaccharides) in the diet do increase intestinal calcium absorption in animals and humans, but the underlying mechanism has not been identified. We therefore assessed the effects of fermentation of inulin-type fructans on transepithelial calcium transport in rat large intestine. Transepithelial calcium fluxes in vitro (Ussing chamber), effects on gene expression, mucosal morphology, and composition of luminal contents were determined in rats fed a standard diet and/or a diet containing 10% (w/w) 1/1 inulin-oligofructose mixture (INOF). Net transepithelial calcium transport in large intestine of rats fed a standard diet was increased by high mucosal calcium concentrations, the presence of 100 mmol/L mucosal short-chain fatty acids (SCFAs), the presence of 10 g/L INOF at the mucosal side, but not by reducing mucosal pH. Tissues from rats fed INOF did not show altered calcium transport when compared to controls. However, when flux data were based on the total caecal surface area, INOF-fed rats nearly doubled absorption rate in caecum. INOF feeding altered transcript levels of several mucosal genes that can be linked to transcellular and paracellular calcium transport processes. In addition, a decreased luminal pH in caecum with markedly increased caecal pools of total, soluble, and ionized calcium resulted from INOF ingestion. Thus, inulin-type fructans increase the large intestinal calcium absorption by different mechanisms including enhanced pools of soluble and ionized calcium, an increase in the absorptive surface predominantly in caecum, the increased concentrations of SCFAs, and by direct interaction with the intestinal tissue.

Animals↗

PubMed2006

Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: involvement of NF-kappaB and ERK signaling pathways.

The overactivation of macrophages causes abnormal cell death and chronic inflammatory diseases. Therefore, the modulation of macrophage-mediated cytotoxicity is expected to become a new therapeutic strategy for various inflammatory diseases. In this study, three types of short chain fatty acids (sodium butyrate (NaB), sodium phenylbutyrate (NaPB), sodium phenylacetate (NaPA)) were found to have anti-inflammatory effects in IFN-gamma-stimulated RAW 264.7 cells. They inhibited the expression of iNOS, TNF-alpha, and IL-6 induced by IFN-gamma, while they enhanced the expression of the anti-inflammatory cytokine, IL-10. Their potency as anti-inflammatory agents was in the order of NaB>NaPB>NaPA. Further mechanistic studies revealed these three agents to repress the DNA binding and transcriptional activities of NF-kappaB, which is an important modulator of inflammation. In addition, these agents repressed the IFN-gamma-induced ERK1/2 phosphorylation without affecting the Jak/STAT activities. The potency of NF-kappaB and ERK inhibition was also in the order of NaB>NaPB>NaPA. The results suggest that the NF-kappaB and ERK signaling pathways are at least in part involved in the anti-inflammatory activities of these SCFAs. Considering that SCFAs are normally present in the body and have few side effects, they might be promising agents for the prevention and/or treatment of various inflammatory diseases.

Animals↗

PubMed2001

Pre-acidification in anaerobic sludge bed process treating brewery wastewater.

The effect of pre-acidification on anaerobic granule bed processes treating brewery wastewater was the focus of a comparison study employing two configurations, (a) a single stage upflow anaerobic sludge bed (UASB) and (b) an upflow acidification reactor in series with a methanogenic UASB. The pre-acidification reactor achieved 20 +/- 4% SCOD removal and 0.08 +/- 0.003 L of methane produced per gram of SCOD removal at a hydraulic retention time (HRT) of 0.75-4 h. Butyric acid was not detected and short chain fatty acids (SCFAs) were mainly acetic and propionic acids. The acidification ratio was about 0.42 +/- 0.02g SCFAs as COD,g of influent COD. Both systems' critical loading rate to achieve 80% COD removal was established at 34-39kgCOD/nm3 of total sludge bed volume per day. SCOD removal efficiency of 90 +/- 3% was achieved by both systems at an organic loading rate of 25 +/- 1 kg COD/m3 of total sludge bed volume per day, indicating that the installation of an acidification reactor had no effect in terms of the maximum granular activity, biomass granulation and the settleability of granules. At an organic loading rate of 67 kg COD/m3 of total sludge bed volume per day at an HRT of 1 h, the series system outperformed the single UASB by a removal of 62 compared to 57%.

Bacteria, Anaerobic↗

PubMed2003

Specific fatty acids and human colorectal cancer: an overview.

BACKGROUND: Evidence suggests that dietary fats are associated with risk of colorectal cancer. The effect of fats depends not only on the quantity, but also on their composition in specific fatty acids. Moreover, fats are peroxidizable, and peroxidation products as well as antioxidants play a role in the pathogenic process of colorectal cancer. METHODS: The published literature was reviewed for the relationship between dietary intake or concentration of specific fatty acids in adipose tissue, erythrocytes, plasma or feces in relation to colorectal cancer. RESULTS: Increased concentrations of short-chain fatty acids (SCFAs) and eicosanopentaenoic acid (EPA) seem to protect against colorectal cancer. Increased concentrations of medium-chain fatty acids (MCFAs) and arachidonic acid (AA) might be associated with increased risk. Long-chain saturated fatty acids (LCSFAs) seem unrelated to colorectal cancer, while the associations between monounsaturated fatty acids (MUFAs), trans fatty acids, polyunsaturated fatty acids (PUFAs) such as linoleic acid (LA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), omega-3/omega-6 ratio and colorectal cancer are unconvincing. CONCLUSIONS: It is suggested that the substitution of food with high MCFAs and AA content by a SCFAs- and EPA-rich diet may contribute to reduced risk of colorectal cancer.

Adipose Tissue↗

PubMed2002

Metabolic acidosis: separation methods and biological relevance of organic acids and lactic acid enantiomers.

Metabolic acidosis can result from accumulation of organic acids in the blood due to anaerobic metabolism or intestinal bacterial fermentation of undigested substrate under certain conditions. These conditions include short-bowel syndrome, grain overfeeding of ruminants and, as recently reported, severe gastroenteritis. Measuring fermentation products such as short-chain fatty acids (SCFAs) and lactic acid in various biological samples is integral to the diagnosis of bacterial overgrowth. Stereospecific measurement of D- and L-lactic acid is necessary for confirmation of the origin and nature of metabolic acidosis. In this paper, methods for the separation of SCFAs and lactic acid are reviewed. Analysis of the organic acids involved in carbohydrate metabolism has been achieved by enzymatic methods, gas chromatography, high-performance liquid chromatography and capillary electrophoresis. Sample preparation techniques developed for these analytes are also discussed.

Acidosis, Lactic↗

PubMed2002

Intestinal short-chain fatty acids alter Salmonella typhimurium invasion gene expression and virulence through BarA/SirA.

Salmonella typhimurium causes enteric and systemic disease by invading the intestinal epithelium of the distal ileum, a process requiring the invasion genes of Salmonella pathogenicity island 1 (SPI-1). BarA, a sensor kinase postulated to interact with the response regulator SirA, is required for the expression of SPI-1 invasion genes. We found, however, that a barA null mutation had little effect on virulence using the mouse model for septicaemia. This confounding result led us to seek environmental signals present in the distal ileum that might supplant the need for BarA. We found that acetate restored the expression of invasion genes in the barA mutant, but had no effect on a sirA mutant. Acetate had its effect only at a pH that allowed its accumulation within the bacterial cytoplasm and not with the deletion of ackA and pta, the two genes required to produce acetyl-phosphate. These results suggest that the rising concentration of acetate in the distal ileum provides a signal for invasion gene expression by the production of acetyl-phosphate in the bacterial cytoplasm, a pathway that bypasses barA. We also found that a Delta(ackA-pta) mutation alone had no effect on virulence but, in combination with Delta(barA), it increased the oral LD50 24-fold. Thus, the combined loss of the BarA- and acetate-dependent pathways is required to reduce virulence. Two other short-chain fatty acids (SCFA), propionate and butyrate, present in high concentrations in the caecum and colon, had effects opposite to those of acetate: neither restored invasion gene expression in the barA mutant, and both, in fact, reduced expression in the wild-type strain. Further, a combination of SCFAs found in the distal ileum restored invasion gene expression in the barA mutant, whereas colonic conditions failed to do so and also reduced expression in the wild-type strain. These results suggest that the concentration and composition of SCFAs in the distal ileum provide a signal for productive infection by Salmonella, whereas those of the large intestine inhibit invasion.

Animals↗

PubMed2004

The concentrations of short-chain fatty acids and other microflora-associated characteristics in faeces from children with newly diagnosed Type 1 diabetes and control children and their family members.

AIMS: The gut flora is quantitatively the most important source of microbial stimulation and may provide a primary signal in the maturation of the immune system. We compared the microflora-associated characteristics (MACs) in 22 children with newly diagnosed diabetes, 27 healthy controls, and their family members to see if there were differences between the children and if there was a familial pattern. METHODS: The MACs were assessed by determining the concentrations of eight short-chain fatty acids (SCFA), mucin, urobilin, b-aspartylglycine, coprastanol and faecal tryptic activity (FTA). RESULTS: There were no statistically significant differences between the concentrations of SCFA in the diabetes and control children. Members of families with a diabetic child had a higher concentration of acetic acid (P < 0.02) and lower concentrations of several other SCFAs than control families (P < 0.05-0.02). The other MACs showed no differences between the children or between the two family groups. CONCLUSION: In this pilot study we saw no differences in the MACs between children with diabetes and their controls. There were, however, some differences between the family members of diabetic children and controls that may indicate a familial pattern regarding the production of SCFAs by the gut flora. The role of the gut flora in relation to the risk of developing Type 1 diabetes needs to be analysed in larger and/or prospective studies.

Acetic Acid↗

PubMed2001

Diversion procto-colitis: response to treatment with short-chain fatty acids.

BACKGROUND/PURPOSE: Diversion procto-colitis (DPC) results from a deficiency of luminal short-chain fatty acids (SCFAs). Endoscopic and histopathologic features of the disorder are almost universally present in defunctioned bowel, but symptomatic DPC is less common. METHODS: Five children with symptomatic DPC underwent endoscopy and rectosigmoid biopsies. An endoscopic index (EI) was used to quantify disease severity. An SCFA mixture was administered into the defunctioned bowel. RESULTS: A good clinical response and improvement in the endoscopic index occurred in all children. Undiversion or rectal excision was carried out in 4 and was curative in each case. One child is awaiting a redo pull through. CONCLUSIONS: DPC should be considered in children with a defunctioned colon presenting with evidence of colitis. Histopathology provides supportive evidence and SCFAs may provide effective relief of symptoms. Stoma reversal or rectal excision is curative.

Child↗

PubMed2025

Specificities of chemosensory receptors in the human gut microbiota.

The human gut is rich in metabolites and harbors a complex microbial community, yet surprisingly little is known about the spectrum of chemical signals detected by the large variety of sensory receptors present in the gut microbiome. Here, we systematically mapped the ligand specificities of selected extracytoplasmic sensory domains from twenty members of the human gut microbiota, with a primary focus on the abundant and physiologically important class of Clostridia. Twenty-five metabolites from different chemical classes-including amino acids, nucleobase derivatives, amines, indole, and carboxylates-were identified as specific ligands for fifteen sensory domains from nine bacterial species, which represent all three major functional classes of transmembrane receptors: chemotaxis receptors, histidine kinases, and enzymatic sensors. We have further characterized the specificity and evolution of ligand binding to Cache superfamily sensors specific for lactate, dicarboxylic acids, and for uracil and short-chain fatty acids (SCFAs). Structural and biochemical analysis of the dCache sensor of uracil and SCFAs revealed that its two different ligand types bind at distinct sensory modules. Overall, combining experimental identification with computational analyses, we were able to assign ligands to approximately half of the Cache-type chemotaxis receptors found in the eleven gut commensal genomes from our set, with carboxylic acids representing the largest ligand class. Among these, the most commonly found ligand specificities were for lactate and formate, indicating a particular importance of these metabolites in the human gut microbiota and consistent with their observed growth-promoting effects on selected bacterial commensals.

Humans↗

PubMed1995

Extracellular pH regulation in microdomains of colonic crypts: effects of short-chain fatty acids.

It has been suggested that transepithelial gradients of short-chain fatty acids (SCFAs; the major anions in the colonic lumen) generate pH gradients across the colonic epithelium. Quantitative confocal microscopy was used to study extracellular pH in mouse distal colon with intact epithelial architecture, by superfusing tissue with carboxy SNARF-1 (a pH-sensitive fluorescent dye). Results demonstrate extracellular pH regulation in two separate microdomains surrounding colonic crypts: the crypt lumen and the subepithelial tissue adjacent to crypt colonocytes. Apical superfusion with (i) a poorly metabolized SCFA (isobutyrate), (ii) an avidly metabolized SCFA (n-butyrate), or (iii) a physiologic mixture of acetate/propionate/n-butyrate produced similar results: alkalinization of the crypt lumen and acidification of subepithelial tissue. Effects were (i) dependent on the presence and orientation of a transepithelial SCFA gradient, (ii) not observed with gluconate substitution, and (iii) required activation of sustained vectorial acid/base transport by SCFAs. Results suggest that the crypt lumen functions as a pH microdomain due to slow mixing with bulk superfusates and that crypts contribute significant buffering capacity to the lumen. In conclusion, physiologic SCFA gradients cause polarized extracellular pH regulation because epithelial architecture and vectorial transport synergize to establish regulated microenvironments.

Acetates↗

PubMed1997

Metabolic effects of non-absorbable carbohydrates.

Food components which are incompletely absorbed in the small intestine or not absorbed at all but are delivered to the colon have been part of the diet throughout the course of human evolution. Our great ape cousins may derive 30% or more of their dietary calories from colonic uptake of short-chain fatty acids (SCFAs) generated in the colon. The metabolic effects of dietary carbohydrate entering the colon are many and include laxation, the growth of the fecal biomass, nitrogen entrapment and SCFA generation. These SCFAs in turn may nourish mucosal cells, spare glutamine utilization, enhance hepatic gluconeogenesis and lipogenesis and possibly influence renal handling of uric acid. The health implications are significant in terms of modifying risk factors for disease and disease prevention and justify interest in the metabolic effects of non-absorbable sugars such as lactulose.

Animals↗

PubMed1997

Germ-free and conventional animal models for intestinal carbohydrate disposition.

Under conventional (CONV) conditions, the microbial flora is capable of breaking down most dietary derived carbohydrates as well as complex carbohydrates (glycolipids, glycoproteins, etc.) from the host. The major end products of these processes are short-chain fatty acids (SCFAs). In non-ruminants, most of the fermentation takes place in the large bowel. In ruminants, however, most acids are formed more proximal in the gastrointestinal (GI) tract. These microbial derived products may influence upon many host related functions, locally in the GI tract as well as elsewhere in the body. In germ-free (GF) animals, neglectable amounts of SCFAs are found in faeces. Parallel studies in GF and CONV animals given a standardized diet and ex-GF animals, receiving the same diet and mono/poly-associated with known microbial species, represent excellent models for answering such questions as (i) what can the microbes do? and (ii) what have the microbes done? These models allow detailed studies of the complex interplay between the host, his diet and his GI flora.

Animals↗

PubMed1997

Effects of short-chain fatty acids on the inflamed colonic mucosa.

Selected inflammatory conditions of the distal alimentary tract may respond to topical SCFA treatment. The rationale for using SCFA enemas is based on Roediger's (1980) observation that butyrate is the preferred fuel of colonocytes and that SCFA deficiency could lead, in the short term, to mucosal hypoplasia and, in the long term, to colitis. The absence of luminal nutrients is especially evident in the excluded rectum after complete diversion of the faecal stream. Harig et al. (1989) were the first to treat successfully diversion colitis with SCFA irrigation (acetate 60 mM, propionate 30 mM, n-butyrate 40 mM). However, subsequent studies could not reproduce the initial positive data. In distal ulcerative colitis an impaired mucosal oxidation of SCFAs has been described despite their luminal abundance. Pilot studies using either the SCFA mixture or butyrate monotherapy have yielded promising results. However, extended confirmatory studies with a larger sample size have not yet been performed. Preliminary data are also available for the use of SCFA in pouchitis and radiation proctitis. In summary, SCFA topical therapy seems to be a promising option in distinct forms of inflammatory bowel disease; however, the routine use of SCFAs cannot be recommended until their efficacy has been confirmed in larger trials.

Administration, Topical↗

PubMed1996

Dietary sucrose, glucose, fructose, and starches affect colonic functions in rats.

To study the effect of dietary sugars and starches on parameters linked to colon carcinogenesis, female Sprague-Dawley rats were fed for one month five different diets containing sucrose, glucose, fructose, cornstarch, or Hylon 7, a starch with a high amylose content. After this period, colon proliferation, assessed by [3H] thymidine incorporation in vitro, was higher (p < 0.05) in rats fed sucrose than in rats fed glucose, fructose, or cornstarch [labeling index was 7.17 +/- 0.75, 5.03 +/- 0.07, 4.55 +/- 0.72, 4.00 +/- 0.70, and 5.89 +/- 1.05 (SE) in sucrose, glucose, fructose, cornstarch, and Hylon 7 diets, respectively]. Cecal pH was lower in rats fed cornstarch and Hylon 7 than in rats fed sucrose, glucose, or fructose. Content of short-chain fatty acids (SCFAs) in the cecum was higher in rats fed Hylon 7 than in those fed glucose and fructose. In conclusion, glucose and fructose, compared with sucrose, decrease mucosal proliferation and may be considered protective factors in colon carcinogenesis, although they do not affect SCFA production and cecal pH. On the contrary, Hylon 7 does not change mucosal proliferation but increases SCFAs and lowers cecal pH, two conditions associated with a lower risk of colon cancer.

Amylose↗

PubMed2005

Comparison of different fibers for in vitro production of short chain fatty acids by intestinal microflora.

The fermentation of dietary fiber in the large intestine and the by-products of this fermentation are thought to protect against colonic diseases. As it is difficult to measure the fermentation of dietary fiber in an intact animal, in vitro techniques have been developed to compare the fermentability of various dietary fibers. The objective of this project was to compare short chain fatty acid (SCFA) production with different fibers in an in vitro fermentation model. A wide range of commercially available dietary fiber sources was compared for SCFA production. Fibers were fermented with a fecal innoculum for 0, 2, 4, 8, 12, and 24 hours. SCFAs were measured by gas chromatography. SCFA production varied among the fiber sources. Hydrolyzed guar gum and galactomannan produced the greatest amounts of total SCFAs. Butyrate production was higher with the fiber sources than the glucose control. Acetate production was less for psyllium than the other fibers. Thus, different dietary fiber sources are more readily fermented by fecal microflora. These differences most likely affect the physiological differences seen among dietary fiber sources.

Chromatography, Gas↗

PubMed1991

Fermentability of various fiber sources by human fecal bacteria in vitro.

Certain beneficial effects of fiber in the human diet may be mediated by short-chain fatty acids (SCFAs) produced during anaerobic fermentation in the colon. Two studies, both involving in vitro incubations with human fecal bacteria as inoculum, were conducted to assess fermentation of various fiber sources and to quantitate the SCFAs produced. In experiment 1, substrate fermentability based on total SCFA production ranked as follows: citrus pectin greater than soy fiber greater than sugarbeet fiber greater than pea fiber greater than oat fiber. Fermentation of soy fiber led to higher proportions of propionate and butyrate than did fermentation of other substrates. In experiment 2, fermentation of gum arabic, a mixture of arabic and guar, and apple pectin resulted in greater SCFA production than did fermentation of either oat fiber or corn bran. Fermentation of gums led to more propionate and butyrate production than did that of apple pectin. It may be possible to select fiber sources capable of supporting stipulated amounts of both total and individual SCFA production in the human colon.

Bacteria↗

PubMed1997

Colonic fermentation capacity in vitro: development during weaning in breast-fed infants is slower for complex carbohydrates than for sugars.

Fresh feces from 27 healthy infants-12 breastfed (complete, exclusive breast-feeding), 7 in early weaning (partial, high breast-feeding), and 8 in late weaning (partial, low breast-feeding)-were cultured with simple and complex carbohydrates in vitro to test the hypothesis that colonic fermentation capacity for carbohydrates increases during weaning. Infants in all three groups were able to ferment sugars, with no significant differences in median total short-chain fatty acid (SCFA) concentrations (mmol/L): preweaning, 56.4(range: 0-77.6); early weaning 68.5(range: 57.9-98.8); late weaning, 61.3(range: 28.6-120.4) for glucose. Preweaned infants were less able to ferment oligosaccharides and complex carbohydrates than were weaned infants (P < 0.05). Ability to ferment raftilose was higher in early weaning; median total SCFA concentrations (mmol/L) were as follows: preweaning 31.0 (range: 3.6-48.9), early weaning 57.1 (range: 2.5-70.6), late weaning 68.6 (range: 22.0-113.4) (P < 0.05). Ability to ferment complex carbohydrates did not develop until late weaning; median total SCFA concentrations for guar gum (mmol/L) were as follows: preweaning 6.4 (range: 0.1-57.3), early weaning 18.4 (range: 0.0-40.5), late weaning 45.4 (range: 15.6-62.1) (P < 0.05, preweaning and early weaning compared with late weaning). Development of the ability to ferment complex carbohydrate was slow. Cultures of feces from preweaned infants produced eight times more SCFAs with glucose than with complex carbohydrates, at early weaning there was a threefold difference and by late weaning the difference was only 25%, but this was still only 42% of the SCFAs produced by cultures of adult feces. These data suggest that for the complex carbohydrates tested, colonic fermentation is likely to contribute only a small proportion of daily energy needs of weaning infants.

Breast Feeding↗

PubMed2002

The colonic response to genotoxic carcinogens in the rat: regulation by dietary fibre.

The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens ("AARGC") in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no "second wave" of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.

Animals↗