Study Title:

Fiber and Friendly Flora Reduce Inflammation

Study Abstract

The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases1, 2. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes3, and a concurrent reduction in SCFAs4. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis5, 6, 7, 8, 9. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2)10, 11, and here we show that SCFA–GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43-/-) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43-/- immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.

From press release:

Diet And Intestinal Bacteria Linked To Healthier Immune Systems

Insoluble dietary fibre, or roughage, not only keeps you regular, say Australian scientists, it also plays a vital role in the immune system, keeping certain diseases at bay.

The indigestible part of all plant-based foods pushes its way through most of the digestive tract unchanged, acting as a kind of internal broom. When it arrives in the colon, bacteria convert it to energy and compounds known as 'short chain fatty acids'. These are already known to alleviate the symptoms of colitis, an inflammatory gut condition. 1

Similarly, probiotics and prebiotics, food supplements that affect the balance of gut bacteria, reduce the symptoms of asthma and rheumatoid arthritis, also inflammatory diseases. Until now no-one has understood why.

Published October 28 in Nature, breakthrough research by a Sydney-based team makes new sense of such known facts by describing a mechanism that links diet, gut bacteria and the immune system.

PhD student Kendle Maslowski and Professor Charles Mackay from the Garvan Institute of Medical Research, in collaboration with the Co-operative Research Centre for Asthma and Airways, have demonstrated that GPR43, a molecule expressed by immune cells and previously shown to bind short chain fatty acids, functions as an anti-inflammatory receptor.

"The notion that diet might have profound effects on immune responses or inflammatory diseases has never been taken that seriously" said Professor Mackay. "We believe that changes in diet, associated with western lifestyles, contribute to the increasing incidences of asthma, Type 1 diabetes and other autoimmune diseases. Now we have a new molecular mechanism that might explain how diet is affecting our immune systems."

"We're also now beginning to understand that from the moment you're born, it's incredibly important to be colonised by the right kinds of gut bacteria," added Kendle. "The kinds of foods you eat directly determine the levels of certain bacteria in your gut."

"Changing diets are changing the kinds of gut bacteria we have, as well as their by-products, particularly short chain fatty acids. If we have low amounts of dietary fibre, then we're going to have low levels of short chain fatty acids, which we have demonstrated are very important in the immune systems of mice."

Mice that lack the GPR43 gene have increased inflammation, and poor ability to resolve inflammation, because their immune cells can't bind to short chain fatty acids.

There is plenty of evidence to suggest that bacteria and their by-products play an important role in people. An American study published in Nature in 2006 2 compared the bacteria in the guts of obese and lean people. The obese people were put on a diet, and as they lost weight their bacteria profile gradually came to match that of the lean people.

Another study 3 looked at what diets might do to short chain fatty acid levels. Obese people were put on three different diets over time -- high, medium and low fibre -- and there was a direct correlation between the level of carbohydrate, or fibre, in the diet and the level of short chain fatty acids.

The conclusions drawn from the current research provide some of the most compelling reasons yet for eating considerably more unprocessed whole foods -- fruits, vegetables, grains, nuts and seeds. 4

Dietary fibre, of course, has many known health benefits in addition to those discussed above, including reduced risk of cardiovascular disease and certain cancers 5, and various health organizations around the world recommend daily minimum levels. 6 It is certain that the majority of people in countries like Australia, the United States and Britain eat much less fibre than they need to stay healthy.

"The role of nutrition and gut intestinal bacteria in immune responses is an exciting new topic in immunology, and recent findings including our own open up new possibilities to explore causes as well as new treatments for inflammatory diseases such as asthma," said Professor Mackay.

1. In several trials, people with colitis have been given dietary fibre, resulting in beneficial anti-inflammatory effects:

Harig, J. M., Soergel, K. H., Komorowski, R. A. & Wood, C. M. Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 320, 23-28 (1989).

Kanauchi, O. et al. Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial. J. Gastroenterol. 37 (suppl. 14), 67-72 (2002).

Breuer, R. I. et al. Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Preliminary report. Dig. Dis. Sci. 36, 185-187 (1991).

Scheppach, W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebo-controlled trial. German-Austrian SCFA Study Group. Dig. Dis. Sci. 41, 2254-2259 (1996).

Vernia, P. et al. Short-chain fatty acid topical treatment in distal ulcerative colitis. Aliment. Pharmacol. Ther. 9, 309-313 (1995).

2. Ley, R. Turnbaugh, P.J. Klein, S Gordon, J.I Human gut microbes associated with obesity. Nature 444, 1022-1023 (2006).

3. Duncan, S.H Belenguer, A. Holtrop, G. Johnstone, A.M. Flint, H.J. Lobley, G.E. Reduced Dietary Intake of Carbohydrates by Obese Subjects Results in Decreased Concentrations of Butyrate and Butyrate-Producing Bacteria in Feces. Applied and Environmental Microbiology, 1073-1078 (2007)

4. There are many online sources where information can be found about foods and their levels of soluble and insoluble fibre -- the effects of the latter investigated in this research. Some foods, such as wheat bran, chick peas, dried fruits (apricots, peaches, figs and dates) and berries (raspberries and blackberries) have particularly high levels of insoluble fibre. CSIRO produces a useful fact sheet.

5. O'Keefe, S Ou, J Aufreiter, S O'Connor, D Sharma, S Sepulveda, J Fukuwatari, T Shibata, K Mawhinney, T. Products of the Colonic Microbiota Mediate the Effects of Diet on Colon Cancer Risk. J. Nutr. 2009 139: 2044-2048. First published online November 1, 2009; doi:10.3945/jn.109.104380

6. Australian Dietary Guidelines, produced by the National Health and Medical Research Council recommend a daily intake of 30-35 grams of fibre.

Study Information

Kendle M. Maslowski, Angelica T. Vieira, Aylwin Ng, Jan Kranich, Frederic Sierro, Di Yu, Heidi C. Schilter, Michael S. Rolph, Fabienne Mackay, David Artis, Ramnik J. Xavier, Mauro M. Teixeira & Charles R. Mackay.
Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43.
2009 October
1.Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.

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