Bratisl Lek Listy 2007; 108 (8): 354358
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
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,
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,
CRC is more common in some families and in certain condi-
tions like ulcerative colitis, history of polyps, or in women with
thehistory of ovarian or uterine cancer. Many factors have been
found to be associated with CRC, such aslow 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 asignificant 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 acarcinogenic event and
appearance of tumours is aproblem. 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
areasonable 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
Hijova E, Chmelarova A. Short chain fatty acids and colonic health
abiomarker is critical to its application as aresearch 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 atissue 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 arange 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 atarget 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 avariety SCFA metabolites by bacterial fermentation in the colonic lumen. (Macfarlane and Gibson, 1996).
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,
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 ava-
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
, and H
) and heat (Topping and
Clifton, 2001). Various population data show that SCFA pro-
duction is in order of acetate > propionate > butyrate in amolar
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,
(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
, phenols, and amines (Roberfroid, 2005). The primary
effect of SCFAs on colonic function is theresult 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. Alarge
microflora population is present in the human colon at 10
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 acrucial 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 ahigher delivery of SCFA
distally, especially butyrate, may have arole in preventing these
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
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
amajor substrate for the maintenance of energy producing path-
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
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-
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
to form succinate, which is subsequently decarboxylated (the
dicarboxylic acid pathway); 2) from lactate and acrylate (the
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.
Anumber 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
amolecular 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 SCFAsplay 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 aneed 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.