SCFAs – A Treatment for Gastrointestinal Inflammation?

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As each month goes by the dynamic and intersecting relationships between our gastrointestinal organisms and the food we consume continues to open all sorts of opportunities for comprehension and treatments. Faced as the western and many non-western cultures are with the expansion of non-communicable diseases and inflammatory disorders, the idea of simply suppressing a abnormal response to a common trigger is losing some of its appeal – there is no doubt that pharmaceuticals have tremendous clinical benefits, but faced with the decision to use a drug every day for life, or to make lifestyle changes – many people are opting for the lifestyle option.

For many reasons, economic, political, cultural and health, the desire to take some control over body responses is instinctively appealing, and co-opting our bacterial bedfellows to contribute to this is gathering a strong following. However, there are as yet many unknowns and inevitably numerous false starts – so this short post looks at some of the potential implications of fibre, mucins, bacteria and our immune system, to explore how we can combine numerous choices to provide the best option for tolerance – or health.

The initial proposals that a deviation towards a T helper Cell :TH1 or TH2 dominant phenotype in explaining many of the inflammatory conditions seen in humans, has quite naturally evolved, as more is learnt about the complex systems involved in maintaining immunological health.

The emergence of the adaptive immune system in humans set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterise adaptive immunity have afforded us the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence.

These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonise the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for approaches to modulate immune networks to treat and prevent disease.

Short Chain Fatty Acids

In a recent mouse study, the increase of fats in the diet amplified asthma and body weight and the standard diet but with added fibre decreased it. In part the aggravation is attributed to activation of the inflammasome,[1]and the reduction attributed to the increase in regulatory dendritic cells DCR. But how does dietary fibre affect disease severity and the activation state of DCs in the lung?

An analysis of the gut and lung microbial communities from mice fed diets of varying fibre content showed that high fibre intake increased the proportion of Bacteroidaceae and Bifidobacteriaceae in the microbiota, whereas a low-fibre diet led to a microbiota that was dominated by Firmicutes.

Bacteroidaceae ferment fibre into short-chain fatty acids (SCFAs), including propionate, and an increase in SCFA levels in the caecum and serum was observed in mice on the high-fibre diet.[2]

One of the other mechanisms proposed to beneficially influence the generation of Treg cells, essential for the control of adverse inflammation in the gut has also been linked to the metabolic end products derived from microbial fermentation of fibre. The vital metabolic function afforded by commensal microorganisms, and their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. In mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells essential for immunological tolerance.

In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Results from this paper suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms – another reason to ensure adequate suitable fibre is included in the diet.[3]

Whilst many of these exploratory research studies are using mouse models, there is much to take away for our recommendations – the first is that Butyrate and Propionate have distinct immunological roles to play in the cross talk between the bacteria and our immune system, on the whole it appears to be advantageous to the management of inflammation.[4]

Butyrate has long been appreciated for its beneficial effects on the human gut, including trophic and anti-inflammatory effects on epithelial cells. The butyrate transporter is down regulated in the colonic mucosa of patients with inflammatory bowel diseases (IBD).[5] In addition, butyrate-producing bacteria are decreased in the intestinal microbiota at the gut mucosa and in the faecal samples of patients with IBD compared to control patients.

These facts suggest that butyrate insufficiency may be involved in the pathogenesis of IBD. In support of this idea, butyrate enema, alone or as a cocktail of SCFAs, has been shown to ameliorate colonic inflammation in patient with IBD. Oral supplementation of Butyrate and suitable SCFA favouring fibres such as stewed apples may also confer additional inflammation control.

Speed of Dietary Impact

Whilst microbial composition is important the foods we select have significant implications in terms of the compositional analysis. For many years it was thought that dietary influences would take many months of change to exert alterations in bacterial communities, but a recent paper, suggest that this may not be the case. They show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. This demonstrates that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles and explaining some of the varied responses to food selection and ingestion in terms of health or illness outcomes.[6]

References


[1] Kim, H. Y. et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nature Med. 20, 54–61 (2014) View Abstract

[2] Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nature Med. (2014). View Abstract

[3] Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013 Dec 19;504(7480):451-5. View Abstract

[4] Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013 Dec 19;504(7480):451-5 View Abstract

[5] Thibault R, De Coppet P, Daly K, Bourreille A, Cuff M, Bonnet C, Mosnier JF, Galmiche JP, Shirazi-Beechey S, Segain JP. Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology. 2007 Dec;133(6):1916-27 View Abstract

[6] David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014 Jan 23;505(7484):559-63. View Abstract

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