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Recently, colonic health has been linked to the maintaining overall health status and reducing the risk of diseases by changes in lifestyle. Functional foods, such as "prebiotics" and "probiotics", dietary fibers, and other dietary components that target the colon and affect its environment enhancing short fatty acid (SCFA) production have been at the forefront. The topic of this review is the key end products of colonic fermentation, the SCFA butyric, acetic, and propionic acids. SCFA are readily absorbed. Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate enters the peripheral circulation to be metabolized by peripheral tissues. Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disesase (Fig. 1, Ref. 30). Full Text (Free, PDF) www.bmj.sk.
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354
Bratisl Lek Listy 2007; 108 (8): 354358
TOPICAL REVIEW
Short chain fatty acids and colonic health
Hijova E, Chmelarova A
Institute of Experimental Medicine, Faculty of Medicine, Safarikiensis
University, Kosice, Slovakia
Address for correspondence: E. Hijova, MVD, PhD, Inst of Experi-
mental Medicine, Faculty of Medicine, LF UPJS, SNP 1, SK-040 11
Kosice, Slovakia.
Phone: +421.55.6424606, Fax: +421.55.6420253
Acknowledgements. This work was supported by the grant AV 4/0028/07.
Institute of Experimental Medicine, Faculty of Medicine, Safarikiensis University, Kosice,
Slovakia. hijova@pobox.sk
Abstract
Recently, colonic health has been linked to the maintaining overall health status and reducing the risk
of diseases by changes in lifestyle. Functional foods, such as prebiotics and probiotics, dietary
fibers, and other dietary components that target the colon and affect its environment enhancing short
fatty acid (SCFA) production have been at the forefront. The topic of this review is the key end products
of colonic fermentation, the SCFA butyric, acetic, and propionic acids. SCFA are readily absorbed.
Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate
enters the peripheral circulation to be metabolized by peripheral tissues. Specific SCFA may reduce the
risk of developing gastrointestinal disorders, cancer, and cardiovascular disesase (Fig. 1, Ref. 30). Full
Text (Free, PDF) www.bmj.sk.
Key words: colon cancer, life style, nutrition, short chain fatty acids.
Colorectal cancer (CRC) is the fourth most common cause
of cancer-related mortality in the world. Within the Europe, North
America, Australia and New Zealand, it is the second most com-
mon cancer after lung or breast and in general, the incidence and
mortality of the disease are increasing (Boyle and Langman,
2000).
CRC is more common in some families and in certain condi-
tions like ulcerative colitis, history of polyps, or in women with
thehistory of ovarian or uterine cancer. Many factors have been
found to be associated with CRC, such aslow levels of physical
activity, smoking, alcohol consumption, high body weight, his-
tory of the colon or rectum polyps, low intake of fruits and veg-
etables and high meat consumption. Evidence suggests that diet
plays asignificant role in the aetiology of CRC (Gill and Row-
land, 2002). To establish a causal relationship between the diet
and CRC risk and to identify the dietary components involved,
human intervention trials are required. These studies will be cru-
cial to the success of dietary recommendations to maximize pre-
vention of colonic disease.
Biomarkers for colorectal cancer
The issue with the human intervention studies is that cancer
is not a practical endpoint in terms of numbers, cost, study dura-
tion and ethical considerations. Particularly, the long lag phase
(up to 20 years) between exposure to acarcinogenic event and
appearance of tumours is aproblem. An alternative strategy is
the use of intermediate endpoint biomarkers of cancer, which
may be biochemical, molecular, cellular or rooted in pathologic
change (e.g. recurrence of polyps, faecal water, epithelial mark-
ers). Biomarkers have been developed from an understanding of
the sequence of events leading to colonic cancer, the biology of
normal mucosa and the factors associated with changes symp-
tomatic of progression toward cancer and the manifestation of
cancer. The advantages of biomarkers are that they represent
short-term/intermediate endpoint, which allow intervention in
areasonable time. Ethical approval is readily obtainable for
biomarker studies as they are minimally invasive, with measure-
ments occuring on an accessible material (faeces and small bi-
opsies, familial adenomatous polyposis). The ideal biomarkers
should be sensitive, reproducible and rigorously validated, al-
though this is not the case of all biomarkers in the cancer field.
Biomarkers should be causally linked, or correlated with the can-
cer and hence of a biological significance. Thus validation of
355
Hijova E, Chmelarova A. Short chain fatty acids and colonic health
abiomarker is critical to its application as aresearch tool, as an
appropriate response from the marker is required when assayed
in cancer patients or in healthy individuals on low-risk and high-
risk diets for CRC. The biomarkers available for the study of
CRC are composed of two main types: tissue, and  biochemi-
cal. Both categories possess distinct advantages.
Tissue biomarkers are analysed from atissue biopsy and as
such necessitate invasive procedures of varying complexities to
retrieve samples of rectal/colonic mucosa. The use of biopsies
increases the technical complexity of the studies, but reduces the
degree of inference required to interpret the results when com-
pared to biochemical markers. Therefore, tissue biomarkers pro-
vide the scope to examine arange of cellular aspects intimately
linked to CRC.
Biochemical markers, in contrast to the invasive techniques,
can be readily measured in blood, urine or faeces, and thus are
minimally or non invasive. Biochemical markers are composed
of two main groups, mammalian enzymes and gut microflora
associated biomarkers. The former are measures of specific en-
dogenous enzyme activity in blood, urine or biopsy specimens,
e.g. hepatic enzyme CYP1A2, glutathione S-transferase, whilst
the latter include bacterial enzyme activities, faecal metabolites,
and short chain fatty acids.
Short chain fatty acids (SCFAs)
The concept of colonic health has become atarget for the
development of functional foods such as probiotics, prebiotics,
and synbiotics and other dietary components that target the co-
lon and affect its environment, composition of the microflora, as
well as the physiology of the colon, and display distinct health
benefits (Bomba et al, 2002). Dietary carbohydrates escaping
Fig. 1. SCFA production in the colon.
The basic pathway for production of avariety SCFA metabolites by bacterial fermentation in the colonic lumen. (Macfarlane and Gibson, 1996).
356
Bratisl Lek Listy 2007; 108 (8): 354358
digestion/absorption in the small bowel and prebiotics undergo
fermentation in the colon and enhancing short chain fatty acids
(SCFAs) production. These have been associated with reduced
risk of some diseases, including the irritable bowel syndrome,
inflammatory bowel disease, cardiovascular disease, and cancer
(Roediger,1980; Jenkins et al, 1999; Floch and Hong-Curtiss,
2002).
SCFAs are organic fatty acids with 1 to 6 carbon atoms and
are the principal anions which arise from bacterial fermentation
of polysaccharide, oligosaccharide, proteins, peptide, and gly-
coprotein precursors in the colon (Miller and Wolin, 1979;
Cummings and Macfarlane, 1991). Fermentation involves ava-
riety of reactions and metabolic processes in the anaerobic mi-
crobial breakdown of organic matter, yielding metabolizable
energy for microbial growth and maintenance and other meta-
bolic end products for host use. The chief end products are SCFAs
together with gases (CO
2
, CH
4
, and H
2
) and heat (Topping and
Clifton, 2001). Various population data show that SCFA pro-
duction is in order of acetate > propionate > butyrate in amolar
ratio of approximately 60:20:20 or 3:1:1, respectively in the proxi-
mal and distal colon (Cummings, 1981; Cummings et al, 1987;
Topping and Clifton, 2001).
Carbohydrates are fermented (Fig. 1) by saccharolytic bac-
teria primarily in the proximal colon producing linear SCFAs,
CO
2
and H
2
(Macfarlane and Macfarlane, 2003), and both the
presence of carbohydrates in the colon and their fermentation
can alter the colonic physiology. Fermentation of proteins and
amino acids by proteolytic bacteria yield branched SCFAs, CO
2
,
CH
4
, H
2
, phenols, and amines (Roberfroid, 2005). The primary
effect of SCFAs on colonic function is theresult of their uptake
and metabolism by colocytes, although SCFAs are also meta-
bolic substrates for other host tissues. The production of SCFAs
is determined by many factors, including the numbers and types
of microflory present in the colon (Roberfroid, 2005), substrate
source (Cook and Sellin, 1998), and gut transit time. Alarge
microflora population is present in the human colon at 10
10
to
10
11
cfu/g wet wt (Hill, 1995), and more than 50 genera and
over 400 species of bacteria have been identified in human fe-
ces. Bacterial numbers, fermentation, and proliferation are high-
est in the proximal colon where substrate  carbohydrate avail-
ability is the greatest. Therefore, the principal site of colonic
fermentation is the cecum and proximal colon, whereas the dis-
tal colon is carbohydrate and water depleted. Specific species
such as Bifidobacterium and Lactobacillus have been associated
with an improved health, resulting in the emergence of the
probiotics, or delivery of specific bacteria to the colon and
prebiotics, or the administration of dietary component that pro-
mote the growth of specific bacteria with defined metabolic func-
tions. SCFA in general and butyrate in particular enhance the
growth of lactobacilli and bifidobacteria and play acrucial role
in the colon physiology and metabolism (Roy et al, 2006). To-
tal SCFA and regional differences in SCFA concentration are
implicated in colon diseases, especially in cancer and gastrointes-
tinal disorders, where disease often occurs distally. Therefore,
an increased SCFA production and ahigher delivery of SCFA
distally, especially butyrate, may have arole in preventing these
diseases.
Function and absorption of SCFAs
SCFAs are rapidly absorbed in the cecum and colon with
only 5 % to 10 % being excreted in the feces. This process is
associated with the enhanced sodium absorption and bicarbona-
te excretion. Two proposed mechanisms of absorption are: 1) dif-
fusion of protonated SCFAs (at least 60 %) and 2) anion ex-
change (Cook and Sellin, 1998). SCFAs uptake is associated with
the transport of water that seems to be higher in the distal than in
proximal colon.
The major SCFAs: acetate, propionate, and butyrate are ab-
sorbed at comparable rates in different regions of the colon. Once
absorbed, SCFAs are metabolized at 3 major sites in the body:
1) cells of the ceco-colonic epithelium that use butyrate as
amajor substrate for the maintenance of energy producing path-
ways;
2) liver cells that metabolize residual butyrate with propi-
onate used for gluconeogenesis; 50 % to 70 % of acetate is also
taken up by the liver;
3) muscle cells that generate energy from the oxidation of
residual acetate.
The role of SCFAs has expanded to include their role as nu-
trients for the colonic epithelium, as modulators of colonic and
intracellular pH, cell volume, and other functions associated with
ion transport, and as regulators of proliferation, differentiation,
and gene expression (Cook and Sellin, 1998). Increases in SCFAs
result in the decreases of pH, which indirectly influences the
composition of the colonic microflora, decreases solubility of
bile acids, increases absorption of minerals (indirectly), and re-
duces the ammonia absorption by the protonic dissociation of
ammonia and other amines (i.e., the formation of the less diffus-
ible NH
4
+
compared with the diffusible NH3) (Vince et al, 1978;
Jackson 1983; Jenkins et al, 1987).
Acetate, propionate, butyrate
Acetate, the principal SCFA in the colon, is readily absorbed
and transported to the liver, and therefore less metabolized in
the colon. The presence of acetyl-CoA synthetase in the cytosol
of adipose and mammary glands allow the use of acetate for li-
pogenesis once it enters the systemic circulation. In human stud-
ies, acetate is often used to monitor colonic events because it is
the main SCFA in the blood. Acetate is the primary substrate for
cholesterol synthesis. In the host, it may be absorbed and uti-
lized by peripheral tissues (Pomare et al, 1985), further, bacteria
isolated from the human intestine are capable of utilizing acetate
for the production of butyrate in the colon (Duncan et al, 2002).
Lactate and acetoacetate may form substrate for other members
of the flora and may be degraded into other SCFA.
Propionate is produced via 2 main pathways: 1) fixation of
CO
2
to form succinate, which is subsequently decarboxylated (the
dicarboxylic acid pathway); 2) from lactate and acrylate (the
357
Hijova E, Chmelarova A. Short chain fatty acids and colonic health
acrylate pathway), (Cumming, 1981). Much of the knowledge
about the nutritional fate of propionate comes from studies of
ruminants. Intestinal glucose uptake is minimal in ruminants
because of the presence of microbiota in their rumen for the di-
gestion and fementation of carbohydrates. Production of SCFA
constitutes the major source of ruminant energy (Hooper et al,
2002) where propionate is a primary precursor for gluconeoge-
nesis. Propionate metabolism in humans is less understood.
Anumber of mechanisms have been suggested to be responsible
for the observed lipid lowering effect, with an increased propi-
onate production being one of the possible mechanisms. Increased
production of propionate, through fermentation, may inhibit he-
patic cholesterol synthesis. It seems possible that one of the deter-
minants of the actions of propionate on serum lipids is the ratio of
propionate to acetate (Cheng and Lai, 2000; Wolever et al, 1996).
Butyrate is the preferred energy source of colonocytes and
has been implicated in the control of the machinery regulating
apoptosis and cellular proliferation and differentiation. 70 % to
90 % of butyrate is metabolized by the colonocyte (Zoran et al,
1997; Basson et al, 2000; Della Ragione et al, 2001). Sodium
butyrate exerts an antiproliferative activity on many cells types,
that have demonstrated preventive effects of butyrate on colon
cancer and adenoma development (Bornet et al, 2002). At
amolecular level, butyrate affects gene expression via the phos-
phorylation and acylation of histone proteins (Archer and Hodin,
1999). Butyrate is not produced by the lactic acid bacteria, how-
ever, certain probiotics may modify the ratio of SCFA in the co-
lon. This remains one of their likely mechanisms of anti-carci-
nogenic action within the colon. Butyrate also stimulates immu-
nogenicity of cancer cells.
There is a mounting evidence that SCFAsplay a key role in
colonic health and may play a key role in the prevention and
management of certain diseases. Given the potential benefits of
prebiotics and probiotics, this has added another dimension to
the study of SCFAs. Now, there is aneed for further studies ex-
amining the synergistic effects of the combination of functional
foods from different carbohydrate surces and their effects on
SCFA and health. The combination of in vitro, experimental and
clinical trials will help to guide future dietary recommendations.
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Received June 11, 2007.
Accepted July 2, 2007.
... It is a metabolite that is readily transported and absorbed in the liver and muscle through the bloodstream. 53 In the liver, acetate is taken up as a source of energy. 54 In the human gastrointestinal tract, acetate also acts as a substrate for the production of cholesterol, long-chain fatty acids, as well as co-substrates for glutamine and glutamate synthesis. ...
... 62 Thus propionate has a therapeutic effect in lowering and inhibiting hepatic cholesterol synthesis. 53,63,64 Considering the link between the population of the Bacteroides-Prevotella group and Clostridium spp., 65-67 the high production of propionate metabolites may be the result of the growth of these microbial groups. Therefore, raw SPH with approximately 18-20% of fermentable carbohydrates source 33 was found with a constant and significant highest concentration of propionate from 0 to 24 h. ...
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... Of the total SCFA produced in the colon, ≥90% is absorbed by the epithelium. The major SCFAs, acetate, propionate and butyrate account for ≥95% of the total SCFAs (molar ratios approximating 60:20:20 (Cook and Sellin, 1998;Hijova and Chmelarova, 2007)). The total concentration of SCFAs increases, depending on the diet from 70 to 140 mM in the proximal colon, to 20 to 70 mM in the distal colon (Topping and Clifton, 2001). ...
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Six healthy male volunteers underwent 2-wk metabolically controlled high-glycemic-index (GI) and low-GI diets in random order. Over the low-GI diet significant reductions were seen in serum fructosamine (7.0 +/- 1.0%, p less than 0.01), 12-h blood glucose profile (37 +/- 7%, p less than 0.01), and total serum cholesterol (15 +/- 3%, p less than 0.01). As a measure of insulin secretion, 24-h urinary C-peptide levels were 32 +/- 10% lower (p less than 0.05) after the low-GI than after the high-GI diet. Lower C-peptide levels were maintained after a standard carbohydrate challenge after the low-GI diet despite higher blood glucose levels. Differences in blood glucose were not seen after a 5-g intravenous glucose challenge. These results are of interest with respect to the effect that prolonged postprandial reductions in nutrient fluxes and insulin secretion may have on carbohydrate and lipid metabolism and renal function.
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There is now substantial evidence that some dietary polysaccharides, notably dietary fiber, escape absorption in the small bowel and are then broken down in the large intestine of man. The main end products of this colonic digestive process, which is anerobic, are short chain fatty acids (SCFA), and acetic, propionic, and butyric acids. Although these acids are known to be absorbed from the colon, their subsequent fate and significance is unknown. We have measured venous blood SCFA levels in healthy subjects after a 16-h fast, and then following oral doses of either 50 mmol SCFA, 5, 10, or 20 g doses of the fermentable carbohydrate lactulose, or 20 g of pectin. Fasting venous blood acetate was 53.8 +/- 4.4 mumol/liter (SEM) (n = 14). Fasting arterial blood acetate, taken simultaneously with venous blood in six subjects, was higher; 125.6 +/- 13.5 mumol/liter (arterial) vs. 61.1 +/- 6.9 mumol/liter (venous). Significant levels of propionate or butyrate were not detected in any blood samples. Following an oral dose of 50 mmol mixed SCFA, venous blood acetate reached a peak of 194.1 +/- 57.9 mumol/liter at 45 min and returned to fasting levels at 2 h. Blood acetate also rose in response to lactulose, peak levels occurring 2-4 h after the dose: 5 g, 98.6 +/- 23.1 mumol/liter; 10 g, 127.3 +/- 18.2 mumol/liter; and 20 g, 181.3 +/- 23.9 mumol/liter. Pectin fermentation was much slower, with blood acetate levels starting to rise after 6 h and remaining elevated at about twice fasting levels for the subsequent 18 h. However, areas under the blood acetate curves were closely related (r = 0.97; n = 5), whatever the source of acetate. These studies show that the large intestine makes an important contribution to blood acetate levels in man and that fermentation may influence metabolic processes well beyond the wall of this organ.
Chapter
The principal sources of carbon and energy for bacteria growing in the human large intestine are resistant starches, plant cell wall polysaccharides, and host mucopolysaccharides, together with various proteins, peptides, and other lower-molecular-weight carbohydrates that escape digestion and absorption in the small bowel (Cummings and Macfarlane 1991, Macfarlane and Cummings 1991). These complex polymers are degraded by a wide range of bacterial polysaccharidases, glycosidases, proteases, and peptidases to smaller oligomers and their component sugars and amino acids. Intestinal bacteria are then able to ferment these substances to short chain fatty acids (SCFAs), hydroxy and dicarboxylic organic acids, H2, CO2, and other neutral, acidic, and basic end products. Carbohydrate metabolism is quantitatively more important than amino acid fermentation in the human large intestine, particularly in the proximal colon, where substrate availability is greatest. The hydrolysis and metabolism of carbohydrates in the large intestine are influenced by a variety of physical, chemical, biological, and environmental factors, some of which are shown in Table 9.1.
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Evidence for the occurrence of microbial breakdown of carbohydrate in the human colon has been sought by measuring short chain fatty acid (SCFA) concentrations in the contents of all regions of the large intestine and in portal, hepatic and peripheral venous blood obtained at autopsy of sudden death victims within four hours of death. Total SCFA concentration (mmol/kg) was low in the terminal ileum at 13 +/- 6 but high in all regions of the colon ranging from 131 +/- 9 in the caecum to 80 +/- 11 in the descending colon. The presence of branched chain fatty acids was also noted. A significant trend from high to low concentrations was found on passing distally from caecum to descending colon. pH also changed with region from 5.6 +/- 0.2 in the caecum to 6.6 +/- 0.1 in the descending colon. pH and SCFA concentrations were inversely related. Total SCFA (mumol/l) in blood was, portal 375 +/- 70, hepatic 148 +/- 42 and peripheral 79 +/- 22. In all samples acetate was the principal anion but molar ratios of the three principal SCFA changed on going from colonic contents to portal blood to hepatic vein indicating greater uptake of butyrate by the colonic epithelium and propionate by the liver. These data indicate that substantial carbohydrate, and possibly protein, fermentation is occurring in the human large intestine, principally in the caecum and ascending colon and that the large bowel may have a greater role to play in digestion than has previously been ascribed to it.
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An in vitro fecal incubation system was used to demonstrate how lactulose influences ammonia metabolism in the colon. Lactulose and other fermentable substrates (glucose, mannitol, and sorbitol), pH and organic acid were varied independently so that their different effects could be determined. Fermentable substrate caused a fall in ammonia concentration during the period of fermentation. Acidification to pH 5.0 or less, with hydrochloric acid or a lactic-acetic acid mixture, significantly reduced ammonia generation, but unlike fermentable substrates, did not lower the existing ammonia concentration. The lactic-acetic acid mixture did not reduce ammonia generation significantly below that found with acidification by hydrochloric acid. The effect of lactulose in reducing ammonia concentration is attributed to its role as a bacterial substrate in either increasing bacterial assimilation of ammonia or reducing deamination of nitrogenous compounds. The effect of low pH in reducing generation of ammonia appears to be part of a general reduction in bacterial metabolism.