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PubMed1985

The influence of incubation time and medium composition on fatty acid production by some Bacteroides species.

Thirteen strains (eleven species) of Bacteroides have been examined for the production of short chain fatty acids (SCFAs). Two media, cooked meat glucose (CMG) and peptone yeast glucose (PYG) were examined quantitatively by gas liquid chromatography (glc) after anaerobic incubation at 37 degrees C for up to 7 days. Growth and medium pH were monitored in PYG for two species. The SCFA profile was established after 12 h and the amount of acids produced was greater in CMG than in PYG; both CMG and PYG contained SCFAs prior to inoculation. Maximum acid production and lowering of pH appear to coincide with the stationary phase of growth. Results are discussed in terms of a standardized approach to the identification of anaerobic bacteria.

Bacteroides↗

PubMed1980

Absorption of short-chain fatty acids by the colon.

Short-chain fatty acids (SCFAs) constitute the major solute fraction of normal stool water and are responsible for the diarrhea associated with carbohydrate (CHO) malabsorption. Although SCFA absorption from the human small bowel has been reported previously, the fate of SCFAs in the colon--their major site of production--was investigated in the present study. The colon of normal volunteers was perfused with neutral, isotonic solutions containing SCFA, 0-90 mM. Propionate was studied in detail with limited observations on acetate and n-butyrate. SCFA absorption was concentration-dependent; back diffusion of metabolic products, ketone bodies, was quantitatively insignificant. The transport process was accompanied by increased Na, K, and water absorption, by luminal alkalinization due to bicarbonate accumulation, and by a fall in lumen PCO2. The results are consistent with the existence of two mechanisms for colonic SCFA absorption: first, nonionic diffusion of protonated SCFA involving consumption of luminal CO2; this process accounts for about 60% of total SCFA absorption; and second, cellular uptake by ionic diffusion of the Na or K salt of the SCFA.

Adult↗

PubMed1994

Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines.

The architecture of normal colonic mucosa suggest that terminally differentiated epithelial cells near the top of the crypt are extruded into the colonic lumen. Morphological studies have identified apoptotic cells among the differentiated phenotypes near the crypt-lumen interface, suggesting a link between pathways of differentiation, apoptosis, and cellular shedding. We studied these processes in HT29 and SW620 cells and found that compared to adherent cells, those cells which were shed during standard, uninduced culture conditions exhibited nonrandom DNA fragmentation characteristic of apoptosis. Moreover, these apoptotic cells, which accumulate in the media, exhibited a more differentiated phenotype. Because short-chain fatty acids (SCFAs) are natural effectors of colonic cell differentiation in vivo, we investigated the specificity of three 4-carbon atom SCFAs on potentiating differentiation and apoptosis, and thus accumulation of shed cells in the conditioned media, in these colonic carcinoma cell lines. Whereas the unbranched SCFA butyrate induced a more differentiated phenotype and enhanced apoptosis, two derivatives of butyrate, branched isobutyric acid and a nonmetabolizable fluorine-substituted analogue, heptafluorobutyric acid, were ineffective in inducing either differentiation or apoptosis. Thus, potentiated differentiation and apoptosis in colonic carcinoma cells were linked to SCFA structure and, most likely, utilization.

Apoptosis↗

PubMedDate not supplied

Effect of short-chain fatty acids on the growth of Salmonella typhimurium in an in vitro system.

Previous studies have revealed a reduction of cecal Salmonella carriage from feeding either carbohydrate or short-chain fatty acids (SCFAs). This in vitro study presents a profile of the relative SCFA content of the ceca when chicks are fed an unmedicated diet with 2.5% carbohydrate. Subsequent incorporation of these acids into culture medium was used to demonstrate their antagonistic activity toward in vitro growth of Salmonella typhimurium. Commonly found concentrations of SCFAs based upon the above findings reduced in vitro Salmonella growth by at least 50%, and 10 x concentrations inhibited growth more than 80%. An explanation of the mechanism(s) involved in growth reduction is offered.

Animals↗

PubMed1993

Dietary fiber and gastrointestinal disease.

Fiber is an important physiologic component of the diet. Dietary fiber contains soluble and insoluble substrates. Soluble fiber components are fermented by colonic microflora, with the resultant production of SCFAs and gas. SCFAs are important fuels, not only for colonic mucosa, but also for the small intestine through secondary metabolism to glutamine and ketone bodies. The clinical importance of dietary fiber and its metabolic products on gastrointestinal and nongastrointestinal functions have yet to be fully realized.

Dietary Fiber↗

PubMed2005

Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts.

Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G1 block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G1 arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21CIP are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27KIP1 is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21CIP, p27KIP1 induction did not occur at the transcriptional level; instead, the stability of the p27KIP1 protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27KIP1 similarly. p27KIP1 was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27KIP1 is required for the observed G1 blockade, as p27KIP1-deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27KIP1 in mediating G1 arrest in response to these drugs.

Animals↗

PubMed2005

Effects of dietary fiber on inflammatory bowel disease.

The chronic idiopathic inflammatory bowel diseases (IBDs), namely Crohn's disease and ulcerative colitis, appear to be derived from an inappropriate reaction towards a luminal agent, most probably driven by the intestinal microflora, which upregulates the synthesis and release of different pro-inflammatory mediators, thus contributing to tissue damage that characterizes these intestinal conditions. Several studies have reported that IBD is associated with impairment in short-chain fatty acid (SCFA) production, mainly acetate, propionate, and butyrate. They are produced in the large bowel by anaerobic bacterial fermentation of undigested dietary carbohydrates and fiber polysaccharides, with butyrate being considered as the major fuel source for colonocytes. These SCFAs have been proposed to play a key role in the maintenance of colonic homeostasis. Therefore, it is reasonable to consider therapeutic approaches that increase colonic SCFA production, as it can be achieved by administration of dietary fiber to IBD patients. Unfortunately, there is quite limited documentation of efficacy of dietary fiber in properly designed trials. This review discusses the rationale, available evidence for the use of dietary fiber and its mechanisms of action in the treatment and prevention of IBDs.

Animals↗

PubMed1977

Absorption of short-chain fatty acids from the human ileum.

Acetate, propionate, and n-butyrate are the major short-chain fatty acid (SCFA) anions in the gastrointestinal tract of animal and man, accounting for 90% of total SCFA in stool water. Their absorption from the human ileum was investigated in 8 volunteer subjects by the triple-lumen perfusion technique. Each test solution contained one of the SCFAs at a concentration of 0-100 mM; sodium, potassium, and bicarbonate concentrations were kept constant, as were pH and osmolality. Absorption of each SCFA was found to be rate-limited with an apparent K'm between 22 and 27 mM and a calculated Vmax between 0.54 and 0.82 mmol/hr cm. Water, sodium, and chloride transport were not affected by substantial rates of SCFA absorption. Rather, significant stimulation of calculated bicarbonate secretion and a rise in intraluminal pH were consistently observed. The results are compatible with either of two mechanisms for SCFA absorption: an anion exchange between bicarbonate (or hydroxyl) and SCFA ions, or protonation of the SCFA anion at the mucosal surface followed by simple diffusion of nonionized SCFA into the absorbing cell.

Acetates↗

PubMed1984

Sodium absorption with bacterial fatty acids and bile salts in the proximal and distal colon as a guide to colonic resection.

Rates of sodium absorption in the presence of bacterial fatty acids and bile salts are unknown along the length of the colon. Such information may guide resection of colon with a view to leaving colon most optimal for ion absorption. Absorption of sodium and permeability of the colonic mucosa to 51Cr EDTA was measured in the proximal (PC) and distal colon (DC) instilled with NaCl (120 mM), n-butyrate (40 mM) and chenodeoxycholic acid (1 or 2 mM) in varying combinations. Sodium absorption in the PC was 123.6 +/- 19 (nmoles/min/cm2)(n = 7) with saline alone and was doubled (P less than .001) when 40 mM n-butyrate replaced chloride anions. Sodium absorption in the DC with saline alone was 106.9 +/- 18 without significant alteration by addition of n-butyrate. CDC (1 mM) diminished sodium absorption in the PC and DC. Diminished sodium absorption induced by bile salts was significantly reversed by n-butyrate in the PC but not DC. Permeability of 51Cr EDTA was greatest with 2 mM CDC in the distal colon. Mucosal function--sodium absorption with SCFAs, permeability changes, and protection by bacterial fatty acids from sodium losses due to bile salts--was superior in the PC compared with DC. Our results suggest that it may be preferable to preserve the proximal rather than distal colon in operations of the colon to secure optimal absorption of sodium.

Animals↗

PubMed1997

Effects of selenium on colonic fermentation in the rat.

Studies were conducted to determine the effects of dietary selenium (Se) on the hindgut microbial activity in rats. Selenium was fed as L-selenomethionine (SeMet) at either 0 or 2 ppm Se in the presence or absence of wheat bran (WB, 10%), a known substrate for the enteric microflora. Wheat bran feeding caused the greatest fermentation, measured by the production of short-chain fatty acids (SCFAs) along the entire intestinal tract and feces; however, its effects were suppressed by SeMet in the proximal large bowel, cecum, and colon. Selenium significantly enhanced fermentation in the colon and rectum, but not in the cecum or feces. Selenium was found in association with the bacterial cell fractions of gut contents and feces: 40-46% of the total Se was associated with colonic microbes and 58% in fecal microbes. Increased acetate and reduced butyrate production were driven by the addition of Se regardless of whether WB was fed.

Animals↗

PubMed2003

Germinated barley foodstuff, a prebiotic product, ameliorates inflammation of colitis through modulation of the enteric environment.

BACKGROUND: Germinated barley foodstuff (GBF), which contains glutamine-rich protein and hemicellulose-rich fiber, exhibits therapeutic effects in ulcerative colitis; however, its mechanism is still under investigation. The aim of this study was to evaluate the anti-inflammatory effects of GBF on colitis in terms of the epithelial inflammatory response. METHODS: Mice with dextran sulfate sodium-induced colitis were used. The effects of GBF on the colitis were evaluated by measuring the body weight; disease activity; mucosal damage (histology, mucosal inflammatory parameters, nuclear factor kappa B [NFkB] activation, and signal transducer and activator of transcription 3 [STAT3]); serum interleukin 6 (IL-6) level; cecal short-chain fatty acids (SCFAs); and bile acid contents. RESULTS: GBF significantly prevented disease activity and body weight loss after induction of colitis. Serum IL-6 level and mucosal STAT3 expression were also significantly attenuated, with a conspicuous reduction of mucosal damage; NFkB activity showed the same tendency. Cecal butyrate content was significantly higher and, interestingly, GBF mice had lower bile acid concentrations than the control group. CONCLUSIONS: GBF has the potential to reduce the epithelial inflammatory response by depressing STAT-3 expression and inhibiting NFkB binding activity. These effects may be brought about by an increase of butyrate production and adsorption of bile acids.

Animals↗

PubMed1992

Gas-liquid chromatographic analysis of volatile short chain fatty acids in fecal samples as pentafluorobenzyl esters.

A protocol was developed for the analysis of volatile short chain fatty acids in microsamples of feces, short chain fatty acid (SCFA) extraction was from fecal samples using ethanol incorporating n-hexanoic acid as an internal standard. The SCFAs were converted to pentafluorobenzyl esters with alpha-2,3,4,5,6-pentafluorotoluene and analyzed on a gas-liquid chromatograph equipped with an electron capture detector. One hundred milligrams of sample was routinely used but analysis could be carried out on 20 mg of sample.

Animals↗

PubMed2026

Defined human Clostridia consortia reverse colitis via dual effects of tryptophan metabolites on microbiota and immunity.

Microbial dysbiosis and disrupted mucosal immune homeostasis are integrally involved in the pathogenesis of inflammatory bowel diseases (IBDs). Live biotherapeutic products (LBPs) offer a potential therapeutic strategy to restore beneficial microbes and mitigate disease. We investigated the therapeutic efficacy of 2 LBPs, human Clostridia consortia 17-mix and 11-mix, by treating established colitis in murine models. Both LBPs exhibited therapeutic effects in T cell-mediated chronic colitis models induced by human microbiota and in pathobiont-driven gnotobiotic colitis models established with combinations of IBD-relevant human-derived strains. Metagenomic and metabolomic analyses elucidated mechanisms that go beyond established functions driven by short-chain fatty acids (SCFAs) and interleukin (IL)-10-producing regulatory T cells. Notably, LBPs exerted therapeutic effects by directly inhibiting resident pathobionts and through IL-10-independent activation of host anti-inflammatory aryl hydrocarbon receptor (AhR) pathways by bacterial tryptophan metabolites. These results elucidate SCFA- and IL-10-independent protective mechanisms exerted by defined resident bacterial strains that are depleted in IBD dysbiosis.

Animals↗

PubMed2006

Dietary pectin stimulates protein metabolism in the digestive tract.

OBJECTIVE: The aim of this study was to determine if protein metabolism was altered in small and large intestines by feeding pectin, a soluble fiber known to stimulate cecal production of short-chain fatty acids (SCFAs) and to have a trophic effect in these tissues. METHODS: Twenty-four weanling male Sprague-Dawley rats were fed ad libitum for 14 d with a balanced control diet or an isoproteic, isocaloric pectin (citrus) diet (80 g/kg). SCFA production, intestinal histomorphometry, and protein synthesis were determined in the proximal and distal parts of the small intestine, the cecum, and the colon. Protein synthesis rates were determined by measuring the (13)C valine incorporation rate in tissue proteins. RESULTS: Pectin feeding slightly decreased food intake and growth rate. It increased the acetate, propionate, and butyrate pools in the cecum. Pectin feeding resulted in heavier intestinal tissues corresponding to higher villus height in the small intestine and crypt depth in the small and large intestines compared with feeding of the control diet. Compared with the control group, the rats fed the pectin diet had significantly higher protein synthesis rates in all the parts of their intestines. CONCLUSION: Supplementation of pectin, as a soluble fiber, in the diets, stimulated SCFA production, had a trophic effect on the different parts of the intestines, and greatly stimulated protein synthesis in those tissues.

Animals↗

PubMed2006

Expression of CD147 and monocarboxylate transporters MCT1, MCT2 and MCT4 in porcine small intestine and colon.

Lactate, formed mainly in the stomach and small intestines, and short-chain fatty acids (SCFAs) formed in the colon, are ionised and require transporter proteins such as monocarboxylate transporters (MCTs) for absorption. The amounts of MCT1, MCT2, MCT4 and CD147, an ancillary protein for MCT1 and MCT4, were measured by immunoblotting the small intestine and colon of 40 pigs (Landrace, Yorkshire and LandracexYorkshire). MCT1 and MCT4 were found in both small intestine and colon, but MCT2 only in the small intestine. In both small intestine and colon, Yorkshire pigs had more CD147 than Landrace pigs, while no interbreed differences were found in MCT isoforms. Since CD147 is essential for the activity of MCT1 and MCT4, the breed difference suggests that MCT activity is higher in Yorkshire than in Landrace pigs. The absence of MCT2 in the colon suggests that it is mainly a lactate transporter, while MCT1 and MCT4 facilitate the transport of both lactate and SCFA.

Amino Acid Sequence↗

PubMed2003

Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids.

Short-chain fatty acids (SCFAs) have long been known to exert cellular effects on blood leukocytes. Acetate, propionate, and butyrate represent the most capable SCFA, inducing calcium mobilization which subsequently regulates leukocyte function in the immune system. We have cloned the previously described putative orphan G-protein coupled receptor, GPR43, and have functionally identified SCFA as the activating ligands. Acetate and propionate were found to be the two most potent ligands, although butyrate, formate, and valerate (in this order of potency) also were able to induce receptor activation. Both the human and mouse receptor homologues were found to share the same pattern of ligand activation. This finding, together with a high degree of amino acid sequence similarity between the mouse and human homologues, indicates an evolutionary conserved function. Upon ligand stimulation, the receptor mobilized intracellular calcium in both a recombinant system as well as in human granulocytes. We found the human gene to be predominantly expressed in peripheral blood leukocytes and, to a lesser extent, in spleen. We suggest the designation FFA(2)R to this second receptor activated by free fatty acids. The first-described FFAR, now named FFA(1)R, is activated by medium- to long-chain free fatty acids.

Amino Acid Sequence↗

PubMed2002

The antimicrobial properties of milkfat after partial hydrolysis by calf pregastric lipase.

Studies on the kinetic characteristics of calf pregastric lipase (EC 3.1.1.3) have shown that it preferentially releases short chain fatty acids (SCFAs) from bovine milkfat. The released fatty acids form mixed micelle structures. The aim of this investigation has been to test whether hydrolysed milkfat is antimicrobial, and how the state of the emulsion alters the bactericidal or bacteriostatic effects. Partial hydrolysis of milkfat by pregastric lipase was carried out in two types of emulsion systems, containing either Triton X-100 or casein/lecithin, plus milkfat in citrate/phosphate buffer (pH 5.0-6.0). The concentrations and compositions of fatty acids were determined by gas chromatography. The minimum percentages of hydrolysed milkfat which affected growth and survival of selected Gram-positive and Gram-negative bacteria were measured. The bacterial experiments were repeated using pure fatty acids at similar concentrations. Lauric acid (C12:0) was found to be the most potent bactericidal fatty acid against Enterococcae (Gram-positive), and caprylic acid (C8:0) was the most potent against coliforms (Gram-negative). Use of Triton X-100 for milkfat emulsification provided a more compatible medium for studying bacterial growth in the hydrolysed milkfat than did use of casein/lecithin. The results also show that the antimicrobial effects of individual fatty acids released from hydrolysed milkfat were at least additive and suggest that hydrolysis of milkfat may be a significant factor in controlling growth of organisms imbibed with food in pre-weaned animals. The amount of pregastric catalyzed triglyceride hydrolysis in the digestive tract is sufficient to produce an antibacterial concentration of fatty acids and monoglycerides.

Animals↗

PubMed1988

Fecal lactate and ulcerative colitis.

Impaired metabolism of short-chain fatty acids, as well as a modified fecal ionogram, have been reported in ulcerative colitis. Fecal water samples from 62 patients with ulcerative colitis were analyzed in the present investigation to evaluate changes in SCFAs and lactic acid in relation to activity and severity of disease. Short-chain fatty acid levels were high in quiescent and mild disease (162.6 +/- 63.6 and 147.8 +/- 63.2 mM/L, respectively), but significantly decreased in the severe form (64.7 +/- 46.9 mM/L). Lactate showed a progressive increase from mild colitis (3.0 +/- 1.8 mM/L) to severe colitis (21.4 +/- 18.6 mM/L). It thus appears that mild colitis displayed a fecal pattern characterized by normal pH and bicarbonate, slightly impaired electrolyte handling, high short-chain fatty acid values, and only moderately increased lactate. Severe colitis, on the other hand, was characterized by low fecal pH, bicarbonate, and potassium, high sodium and chloride, low short-chain fatty acid levels, and very high lactate levels. A critical lowering of intraluminal pH, which shifts bacterial metabolism from short-chain fatty acid to lactate production, may be responsible for the intraluminal pooling of lactate.

Colitis, Ulcerative↗