The gut microbiota refers to the vast numbers of bacteria and other organisms, such as viruses and fungi, that reside within our gastrointestinal tract. Changes in the microbiota is associated with allergies, metabolic disorders, and even autism!
What is the gut microbiota?
The gut microbiota refers to the vast numbers of bacteria and other organisms, such as viruses and fungi, that reside within our gastrointestinal tract. Collectively, there are approximately 1014 microorganisms, which is 10-fold higher than the number of human cells!
The relationship between dietary intake and the type of bacteria within us is a very active area of research. It has been shown that changes in the protein, lipid and dietary fibre content of the diet rapidly and reproducibly alters the types of bacteria present (1). This is important because disturbances in the types of bacteria within us is associated with allergies, autoimmune diseases, metabolic disorders, and even autism. Altering the composition of the gut microbiota through dietary manipulation may therefore have a clinical benefit. However, a major challenge in the field concerns how best to discriminate between changes that are the cause of a disease, and those that are a mere consequence of the disease process itself or of the pharmacological treatment of it.
What are short-chain fatty acids?
The trillions of microorganisms that live within us are highly diverse in terms of their metabolism. They produce a treasure trove of enzymes that can metabolise the dietary components, and even pharmaceutical drugs, that we ingest. The carbohydrates that escape digestion and absorption in the small intestine, which are referred to as dietary fibre, are fermented by these microorganisms. This leads to the production of by-products called short-chain fatty acids. These molecules are fatty acids with fewer than 6 carbon atoms, most notably acetate (2 carbons), propionate (3 carbons), and butyrate (4 carbons).
If the host diet is deficient in dietary fibre, these starved microorganisms will instead consume the mucus that lines our gastrointestinal tract (which does not produce short-chain fatty acids as a by-product). This is problematic as the function of mucus is to reduce intestinal inflammation by acting as a physical barrier that prevents microbes from getting too close to the human cells that line the gastrointestinal tract.
Short-chain fatty acids as a fuel source
Butyrate is the preferred energy source for the cells that line the colon, which are called colonocytes. Fermentation of resistant starch is thought to contribute significantly to butyrate production in the colon and is dominated by Ruminococcus bromii (2). However, propionate and acetate are largely absorbed across the gut lumen to be utilised as a fuel outside of the gastrointestinal tract. Propionate is transported to the liver to be oxidised (for use as a fuel source) or used in gluconeogenesis (production of glucose), whereas acetate is used for lipogenesis (fat deposition) and cholesterogenesis (production of cholesterol) or oxidised by muscle cells.
However, short-chain fatty acids play important functions in host health beyond the mere recovery of energy from undigested food. As we will see, short-chain fatty acids influence the host by regulating the immune system, gut barrier integrity, and appetite.
Short-chain fatty acids regulate the integrity of the gut epithelium
Butyrate plays a central role in maintaining the integrity of the gastrointestinal tract. It does this by inducing the production of the tight junction proteins called claudin-1 and ZO-1 which fill in the small gaps between colonocytes (3). If these tight junctions are disrupted, material can pass from the gastrointestinal tract into the underlying blood vessels and transported to the liver via the hepatic portal system. When bacteria and/or their components, such as the cell wall constituent lipopolysaccharide, pass into the bloodstream, an immune response is triggered to protect the body against invasion by potentially pathogenic microorganisms. An additional function of butyrate is to stimulate the production of mucus, which as mentioned earlier acts as a physical barrier to prevent microbes from getting close to the colonocytes (4).
Short-chain fatty acids regulate the immune system
Butyrate also plays a critical role in the regulation of the immune response. One way it achieves this is by promoting the decision of an immune cell to become a T regulatory cell, which function to switch off immune responses. It does this by diffusing into cells and blocking the activity of histone deacetylases which alters the whole transcriptional profile of the cell toward an anti-inflammatory phenotype.
Obesity and the anorexigenic gut hormones peptide YY and GLP-1
Acetate, butyrate and propionate all stimulate the enteroendocrine L-cells (via FFAR2) present within the colon to release the anorexigenic gut hormones peptide YY and GLP-1, which induce satiety. This explains how short-chain fatty acids protect against obesity, by reducing appetite and therefore energy intake. Indeed, targeted propionate delivery induces appetite regulation, reduced food intake and prevents weight gain in humans (5). Other mechanisms also contribute. For example, there is also evidence that short-chain fatty acids regulate appetite via direct gut-brain communication via the nervous system, referred to as the gut-brain axis, albeit will not be discussed here. A further mechanism is the stimulation of leptin secretion from adipocytes by acetate.
(1) David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B. E., Ling, A. V., Devlin, A. S., Varma, Y., Fischbach, M. A., Biddinger, S. B., Dutton, R. J. & Turnbaugh, P. J. (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature. 505 (7484), 559-563.
(2) Louis, P., Young, P., Holtrop, G. & Flint, H. J. (2010) Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene. Environmental Microbiology. 12 (2), 304-314.
(3) Wang, H. B., Wang, P. Y., Wang, X., Wan, Y. L. & Liu, Y. C. (2012) Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Digestive Diseases and Sciences. 57 (12), 3126-3135.
(4) Cornick, S., Tawiah, A. & Chadee, K. (2015) Roles and regulation of the mucus barrier in the gut. Tissue Barriers. 3 (1-2), e982426.
(5) Chambers, E. S., Viardot, A., Psichas, A., Morrison, D. J., Murphy, K. G., Zac-Varghese, S. E., MacDougall, K., Preston, T., Tedford, C., Finlayson, G. S., Blundell, J. E., Bell, J. D., Thomas, E. L., Mt-Isa, S., Ashby, D., Gibson, G. R., Kolida, S., Dhillo, W. S., Bloom, S. R., Morley, W., Clegg, S. & Frost, G. (2015) Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 64 (11), 1744-1754.