Butyrate and its multifarious effects on intestinal health

Microbial fermentation of dietary fibre in the colon results in the production of short-chain fatty acids (SCFA’s), such as acetate, propionate and butyrate. The prebiotic potential of different fibre sources is frequently compared based on microbial production of SCFA’s and in particular butyrate. The positive effect of butyrate can also be achieved by direct addition of the SCFA to the diet. However, unprotected butyrate will be directly absorbed in the first part of the digestive tract before reaching the large intestine. Micro-encapsulation of butyrate results in the targeted release of butyrate over the whole digestive tract and, just as importantly, correct coating reduces the typical unpleasant smell of butyrate.

Natural production of butyrate

The intestinal microbiota plays a critical role in the establishment and maintenance of intestinal health. Fermentation of dietary fibres by commensal bacteria results in the production of SCFA’s. Approximately 95-99% of SCFA’s produced in the hindgut is quickly absorbed and delivers energy to the animal (1). Dietary fibre and their fermentation metabolites play an important role in the metabolism and health of companion animals, even in cats with their carnivorous nature (2).

Butyrate is considered the most important SCFA for intestinal epithelial cells. Especially the cells in the colon take up butyrate where it is used for the production of energy and the maintenance of colonic homeostasis (3). Numerous studies indicate the importance of butyrate for the provision of energy to epithelial cells, sodium and water absorption, influence on epithelial cell proliferation and differentiation, villi development and in improving gut defence systems. Butyrate strength the barrier function, have antimicrobial potency and positively influence immune system (4) (5).

The lumen of the colon has the highest density of microbes in the body and specific bacteria belonging to genera such as Clostridium, Eubacterium and Butyrivibrio ferment dietary fibre into butyrate at very high concentrations (4). The quantity of butyrate produced in the colonic lumen depends on the composition of the microflora and the amount of fermentable substrates available in the diet. Higher levels of butyrate can be achieved by adding fermentable fibres to the diet. However diets with too large amounts of fermentable fibres can have negative effects on faecal characteristics such as loose stools and flatulence. Intestinal infections, chronic inflammatory disorders and use of antibiotics negatively affect the colonic microflora and may result in reduced production of butyrate (5). The addition of microencapsulated butyrate to the diet is a solution to provide additional amounts of butyrate to the colon (6).

Energy source for intestinal cells

Energy supply to intestinal epithelial cells is important due to the fact that the mammalian intestinal mucosa is one of the most rapidly replicating tissues in the body. For example, studies in rodents demonstrate that the small intestinal epithelium is completely replaced every two to three days (7). Thereby, the colonic epithelium is permanently in close association with microbes and their product. There is a constant immunological challenge, which makes the barrier defence function of the epithelial layer of great importance (8). The dynamic processes of intestinal cells (proliferation, migration, differentiation and apoptosis) and defence function are markedly influenced by the type of diet and the adequacy of specific nutrients in the diet (7) (9).

In the small intestine microbial formation of butyrate is low or absent. Nevertheless, cells in the small intestine also express the transporter to bring butyrate into the cells. Claus et al. (2006) fed butyrate to healthy growing piglets and demonstrated that targeting butyrate into the small intestine improves villi development, gut morphology and function.

Further on in the digestive tract, butyrate represents the preferred energy-providing substrate for the colonic cells. Whereas most other cell types utilize glucose as their primary energy source, colonocytes have a great capacity to rapidly metabolize butyrate. After transport into the colonic cells, β-oxidation in the mitochondria results in acetyl-CoA, which goes into the citric acid cycle and proceeds in the production of adenosine triphosphate (ATP) with CO2 as a byproduct (4). Otherwise butyrate is, after acetate, a major precursor for de novo lipid synthesis. High proportion of these synthesized lipids is used for incorporation into the cell membrane (10). As such, the synthesis of many key components of the intestinal epithelial tissue depends on butyrate metabolism. Only small quantities of butyrate will reach the general peripheral blood circulation and liver (6).

At an early stage of life butyrate is an important factor in the development of the gastrointestinal tract. Newborn animals produce small quantities of butyrate, the production increases during the development of the hindgut (6). Supplementation of milk formula and starter diets with butyrate contribute to enhanced development of the intestinal mucosa and improvement of digestive processes in neonatal calfs and piglets (11) (12)

Cell growth and proliferation; the ‘butyrate paradox’

Cells in the large intestine particularly use butyrate as energy source for cell metabolism and it stimulates colonocyte proliferation and differentiation both in vivo and in vitro (7). In contrast to the trophic effect on normal healthy colonocytes, butyrate decreases proliferation and differentiation of tumor cell lines and can finally induce apoptosis; programmed cell death (6) (13) (7). Butyrate has the ability to influence the gene expression, thereby inducing early apoptosis in cancer cells. Its opposite is seen in normal cells, where butyrate activates gene expression for cell proliferation and maturation (14)

Several epidemiological studies support the protective role of dietary fibre and its breakdown product butyrate against colonic cancer. These contradictory patterns of butyrate of stimulating cell growth and differentiation of normal cells and apoptosis (early cell death) of tumor cells, represents the so called ‘butyrate paradox’ (14).

Colonic water absorption and antidiarrheal agent

The absorption of SCFA’s has a significant impact on the absorption of sodium, potassium, water and on the electrolyte balance in general. Transport mechanism of SCFA’s involves Na+ and H+ uptake in cells. Herschel et al (1981) determined that SCFA’s and Na+ were rapidly absorbed, and at the same rate, in the colonic mucosa of dogs. This results in osmotic changes and increased absorption of water from the colon to the epithelial cells (3) (14).

Clausen et al (1991) found a correlation between antibioticassociated diarrhea and reduced faecal concentrations of butyrate from microbial fermentation. The researchers suggest that the diarrhea might be a secondary effect coming from impaired colonic fermentation, resulting in the accumulation of luminal fibres and/ or reduced SCFA’s stimulated water absorption. Scarpellini et al (2007) provided fat-coated butyrate to patients with diarrhea-predominant irritated bowel syndrome. The treatment resulted in improved faecal consistency (reduction of faecal moisture) and reduced frequency of daily stools. Symptoms as abdominal pain, meteorism (bloating) and flatulence were significantly reduced after 30 days of butyrate administration.

Inflammatory status

Butyrate has a role as an anti-inflammatory agent, primarily via inhibition of nuclear factor kB (NF-kB) activation in colonic