Major advances in the understanding of the aetiopathogenesis and genetics of inflammatory bowel disease (IBD) have been accompanied by an increase in the therapeutic armamentarium, including immunosuppressants and anticytokine drugs. Whereas patients are in many cases highly motivated to use prescribed drugs in those chronic disorders, they would be even more willing to change lifestyle and dietary habits so they could actively influence the course of their disease. Therefore, one of the most common questions physicians treating patients with IBD are asked is whether changing diet could positively affect the course of their disease. So far, and this has been especially true for patients with ulcerative colitis (UC), our answer had been “we do not know and there are no special recommendations”.

This may now change as Jowett and colleagues¹ in this issue of Gut present interesting and clinically novel data studying the role of dietary factors on the clinical course of UC (see page 1479). In this prospective cohort study, they investigated the effects of habitual diet on relapses of disease. Impressively, 96% of patients (n = 191) completed the study. Dietary factors such as red and processed meat, protein, and alcohol, as well as sulphur and sulphate intake were positively associated with relapses. Even though dietary factors in this study were less important than measures of prior disease activity in determining the risk of relapse,² clinically this information is extremely valuable as it may open the perspective of lifestyle modification in the treatment of UC. As discussed in detail by the authors, these effects may be related to sulphur and sulphate contents of food. Most importantly, to continue to prove this important work, in a next step an intervention study is needed before it can be concluded that sulphur and sulphate rich foods definitely increase the risk of relapse. However, caution with regard to interpretation of the data of Jowett et al is also warranted. Habitual diet was assessed only once and therefore might not a priori reflect food intake over the entire observation period, especially the period immediately preceding relapse. Furthermore, based on energy intake estimates by physical activity level (PAL), 23% of patients over- or underreported their food intake. When these patients were excluded from the analysis, only high meat intake (particularly red and processed meat) and high alcohol consumption were associated with relapse while all other associations were no longer statistically significant. Provocatively, therefore, it may well be speculated that other constituents of meat besides sulphur compounds (see below) might play a role in relapsing UC.

PRE-ILLNESS DIET AND SUBSEQUENT DEVELOPMENT OF UC

As the rising incidence of IBD in the last decades coincides with profound changes in diet pattern, various lifestyle/dietary aspects have been addressed. Available studies mainly investigated the effects of pre-illness diet and subsequent development of UC. Russel et al performed a case control study in recently diagnosed cases with UC.³ They showed a positive correlation between consumption of soft drinks and chocolate and UC. In another study, a high fat intake was associated with an increased risk for UC whereas a negative correlation with vitamin C and fruit consumption was found.⁴ A third study also showed a positive correlation with fat intake and development of UC.⁵ All of these findings however may also be an expression of modern lifestyle involving other risk factors for the development of IBD.

HYDROGEN SULPHIDE: BAD MALODOROUS GAS RESPONSIBLE FOR RELAPSES IN UC?

Mercaptides such as sodium hydrogen sulphide (one of the main malodorous compounds in human flatus) are reducing agents that help maintain anaerobic conditions in the colonic lumen. They are produced in the human large intestine by bacterial reduction of dietary inorganic sulphate and sulphite and by fermentation of sulphur amino acids. The acute toxicity of hydrogen sulphide appears to result from inhibition of cytochrome oxidase leading to mucosal damage, loss of barrier function, and histological changes resembling UC. Hence the colonic mucosa has developed a very effective means of detoxifying hydrogen sulphide.⁶

Mainly exogenous sources contribute to the colonic pool of sulphur, such as red meat, cheese, milk, fish, nuts, and eggs, and as preservatives found in commercial breads, beers, many alcoholic drinks, sausages, and dried fruits. Faecal sulphide levels increase after consumption of increasing amounts of meat,^7,8 providing evidence that meat is an important substrate for sulphide generation by bacteria in the human large intestine.

It has been proposed that sulphide toxicity may be important in the pathogenesis of UC.^9,10 The initial evidence in this regard was demonstration that experimental exposure of colonic tissue to sulphide causes inhibition of butyrate use (see below), a defect similar to that observed in mucosal biopsies obtained from UC patients.¹¹ UC patients have significantly higher luminal concentrations of hydrogen sulphide than controls, and disease activity correlates with sulphide production rates.¹² Hydrogen sulphide induces hyperproliferation of colonic mucosa and this effect is antagonised by butyrate.¹³ Treatment with 5-aminosalicylates and bismuth subsalicylates has been shown to reduce hydrogen sulphide production in the colonic lumen.^12,14 Apart from the direct toxicity of hydrogen sulphide, it has been speculated that thiols may react with sulfhydryl containing compounds to form persulfides, which may alter protein function as well as antigenicity, which could theoretical lead to a chronic immune mediated process, as known in UC.⁶ In summary, there is evidence in the literature that hydrogen sulphide may play a role in UC and on the other hand certain foods such as meat cause an increase in colonic levels of hydrogen sulphide.

FAECAL BUTYRATE: KEY METABOLITE IN UC

Short chain fatty acids, including butyrate, proprionate, and lactate, are generated in the colon as result of bacterial fermentation of dietary fibre by luminal bacteria such as Bifidobacterium, Eubacterium, and Lactobacillus species. Roediger et al demonstrated significant inhibition of butyrate but not glucose oxidation by hydrogen sulphide in the ascending colon, splenic flexure, and in the rectosigmoid region.¹⁵ A direct anti-inflammatory effect for butyrate, the most extensively studied of the short chain fatty acids, may be attributable to its inhibition of nuclear factor κB, thus preventing the transcription of proinflammatory cytokines.¹⁶ In this study, butyrate also attenuated dextran sulphate sodium (DSS) induced colitis. Furthermore, butyrate has been demonstrated to reduce colonic permeability by enhancing peroxisome proliferator activated receptor γ (PPAR-γ) activation.¹⁷ This is of special interest as PPAR-γ ligands show antineoplastic and anti-inflammatory effects in experimental colitis.¹⁸

Patients with active extensive UC have decreased colonic butyrate oxidation. As remission of disease is associated with normalisation of butyrate oxidation, UC mucosa is not intrinsically altered in butyrate oxidation.¹⁹ Butyrate enemas have been shown to be of benefit in the management of distal UC.^20,21

So, how to increase faecal butyrate levels? In animal and human studies, ingestion of resistant fibre has resulted in an increase in the population of Bifidobacillus and Lactobacillus in the colon and an increase in faecal butyrate concentrations. Administration of oat bran over three months to UC patients in remission (corresponding to 20 g dietary fibre) has recently been shown to result in increased faecal butyrate levels and in this pilot study no relapses were observed.²² Alternative strategies of delivering short chain fatty acids to the inflamed colon are by providing a substrate, a “prebiotic”, for short chain fatty acid production by colonic bacteria, or directly delivering probiotics to the intestinal lumen.

PREBIOTICS IN UC: EFFECTIVE VIA BUTYRATE INDUCTION?

Prebiotics are defined as non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of bacterial species already present in the gut. A germinated barley foodstuff (GBF) which contains hemicellulose rich fibre and glutamine rich protein has been shown to attenuate inflammation in DSS, trinitrobenzene sulphonic acid (TNBS), and HLA-B27 transgenic animal models of colitis.²³ In DSS colitis, GBF suppressed significantly serum interleukin 6 levels and mucosal STAT-3 expression. These effects may be caused by increased faecal butyrate production.²⁴ GBF has been demonstrated to improve disease activity in a small pilot study in patients with active UC.²⁵ In a controlled small study investigating 18 patients with active UC, patients were treated with baseline anti-inflammatory treatment with or without GBF. GBF therapy resulted in a significantly better outcome and was associated with increased faecal concentrations of Bifidobacterium and Eubacterium limosum.²⁶ Another important study in the area of prebiotic and dietary fibre has been performed by a Spanish collaborative group.²⁷ In this large study, Plantago ovata seeds (dietary fibre 20 g/day) was compared with mesalamine in the maintenance of remission in patients with UC (n = 105). Treatment failure rate was 40% in the Plantago ovata seed group, 35% in the mesalamine group, and 30% in the Plantaga ovata plus mesalamine group. A significant increase in faecal butyrate levels was observed after Plantago ovata seed administration. The same preparation was also shown to ameliorate colonic damage in HLA-B27 transgenic rats and this effect was also associated with increased production in short chain fatty acids.²⁸ Therefore, most of prebiotic products might exert their beneficial effects via modulating short chain fatty acid metabolism.

FISH OIL SUPPLEMENTATION/ESSENTIAL FATTY ACIDS: NOT EFFECTIVE IN THE TREATMENT AND MAINTENANCE OF REMISSION IN UC

Prostaglandin E₂ and leukotriene B4 are metabolites of arachidonic acid via the cyclooxygenase pathway and the lipoxygenase pathway, respectively. Increased levels of prostaglandin E₂ and leukotriene B4 are found in active UC. Diets containing high levels of n-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid are known to modify leukotriene production. Dietary fish oil supplementation has improved patients with other inflammatory disorders, such as rheumatoid arthritis. Five placebo controlled double blind studies have addressed this question in UC.^29–33 Despite reduced levels of leukotriene B4, some histopathological improvement, and a tendency towards a steroid sparing effect, no overall convincing clinical benefit of dietary fish oil supplementation for 4–12 months was seen in the treatment of patients with active UC. Most of these trials involved treatment of active disease whereas one study³¹ failed to demonstrate any benefit in maintenance therapy. A recent randomised controlled trial again failed to demonstrate any efficacy of essential fatty acid supplementation in the maintenance of remission in UC.³⁴ Therefore, despite some modest effects of n-3 polyunsaturated fatty acids in the treatment of active mild to moderate disease, essential fatty acids combination therapies have no benefit in maintaining remission in UC.

ANTIOXIDANTS AND OXIDATIVE STRESS

Oxidative stress is believed to play a key role in the pathogenesis of IBD as intestinal inflammation is accompanied by excessive production of reactive oxygen species and nitrogen metabolites. D’Odorico et al showed increased free radical peripheral leucocyte DNA damage and decreased plasma antioxidant defences in both UC and Crohn’s disease patients.^35,36 N-3 fatty acids have been shown to increase antioxidant concentrations, although as mentioned, n-3 polyunsaturated fatty acids are not effective in the therapy of UC. Dietary iron supplementation increases lipid peroxidation, decreases antioxidant vitamins, and enhances DSS induced colitis in rats.³⁷ Studies investigating the effects of oral iron administration in humans are lacking, as well as clinical studies assessing the effects of antioxidants in patients with UC.

CONCLUSION

In summary, this provocative and clinically important report by Jowett et al reopens the topic of diet and relapsing UC.¹ The findings are well taken and may offer a new perspective for potential intervention by practical lifestyle modifications, and as such are eagerly awaited by our patients. Despite this excitement, interventional studies are now needed, setting the scene for specific dietary recommendations and for further defining the role of sulphur/sulphate which may even lead to novel therapies.