Dysbiosis in inflammatory bowel diseases

Inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis and pouchitis) are considered to be due to an inappropriate immune response to the intestinal microbiota. Genome-wide association studies have identified genes contributing to susceptibility to Crohn's disease and ulcerative colitis. Many of these susceptibility loci play a role in immune responses to microbial signalling and processing⁽ Reference Xavier and Podolsky ^{11 )} as well as epithelial barrier integrity⁽ Reference Barrett, Lee and Lees ^{12 ,} Reference Anderson, Boucher and Lees ^{13 )}. Germ-free animal models of colitis indicate that the microbiota drives inflammation in genetically susceptible hosts⁽ Reference Sartor ^{14 )}. Knockout mouse models of colitis have also shown a transferrable colitogenic microbiota to wild-type mice⁽ Reference Biswas and Kobayashi ^{8 )}. Clinical evidence also points towards the microbiota-driving inflammation. Faecal diversion ameliorates inflammation in Crohn's disease while reintroduction of the ileal contents to the diverted bowel induces inflammation⁽ Reference D'Haens, Geboes and Peeters ^{15 )}. Pouchitis only occurs following closure of the ileostomy when the pouch is exposed to significantly higher concentrations of bacteria.

A number of theories exist regarding the role of the microbiota in IBD. These range from abnormalities of single organisms to a dysbiosis of the overall composition and diversity of the microbiota, to functional shifts in the microbiota. Mycobacterium avium ssp. paratuberculosis has long been associated with Crohn's disease; however, a blinded study showed no difference in the rate of culture recovery by two independent laboratories⁽ Reference Sartor ^{14 ,} Reference Sartor, Blumberg and Braun ^{16 )} and clinical trials failed to show sustained response in Crohn's disease patients treated with combination antituberculous therapy⁽ Reference Selby, Pavli and Crotty ^{17 )}. Other investigators have demonstrated an increased persistence of adherent/invasive Escherichia coli in ileal Crohn's disease⁽ Reference Darfeuille-Michaud, Boudeau and Bulois ^{18 )}. Others suggest a reduction in protective species of bacteria such as Faecalibacterium prausnitzii ⁽ Reference Sokol, Seksik and Furet ^{19 )}. Molecular analyses suggest that the overall composition and diversity of the micriobiota is altered in IBD. More recent studies have assessed the functional metabolic outcomes of disease associated dysbiosis. These demonstrate alterations in bacterial carbohydrate metabolism, bacterial–host interactions, as well as human host-secreted enzymes. However, it remains uncertain as to whether any of these changes are primary or secondary events⁽ Reference Erickson, Cantarel and Lamendella ^{20 )}.

Moderating neonatal risk

A neonate is born with an immature microbiota which receives early modulation during birth and with feeding. The mode of delivery determines the makeup of the early microbiota, with Caesarean section delivered babies colonised with skin flora, and vaginally delivered babies colonised with bacteria from the birth canal⁽ Reference Dominguez-Bello, Costello and Contreras ^{21 )}. There is some evidence that Caesarean section is a risk factor for developing IBD⁽ Reference Bager, Simonsen and Nielsen ^{22 )}. Similarly, breast milk and formula feed will lead to establishment of differing microbiota profiles⁽ Reference Cabrera-Rubio, Collado and Laitinen ^{23 )}. There are conflicting data regarding whether breast-feeding is protective against IBD⁽ Reference Khalili, Ananthakrishnan and Higuchi ^{24 ,} Reference Spooren, Pierik and Zeegers ^{25 )}.

Diet and nutrition

Nutrition is vital in the management of adult and paediatric IBD, and modulates the microbiota, but its role in the development of the disease is still to be clarified⁽ Reference Spooren, Pierik and Zeegers ^{25 )}. Patients are prone to malnutrition for a number of reasons: intestinal malabsorption, post-surgical short gut length, strictured bowel lumen and food avoidance behaviour due to meal-related symptoms. Thus patients are routinely monitored from a nutritional viewpoint, and receive supplementary nutrition when required. Nutritional status determines key outcomes including surgical recovery rates. In the paediatric population, diet may be the only treatment required. Elemental and polymeric diets may be successful in not only healing the intestinal mucosa but also in achieving and maintaining remission in IBD⁽ Reference Navas López, Blasco Alonso and Sierra Salinas ^{26 ,} Reference Akobeng and Thomas ^{27 )}. In the adult population, a low-fibre diet is often employed to prevent obstruction of a narrowed lumen. The association between specific dietary components and IBD has been researched, but the data are frequently conflicting. Butyrate, a SCFA, is derived from microbial fermentation of dietary starches. It is the major energy source for colonocytes and both butyrate and butyrate producing bacteria have been shown to be deficient in the inflamed colon⁽ Reference Thibault, Blachier and Darcy-Vrillon ^{28 –} Reference Marchesi, Holmes and Khan ^{30 )}. Butyrate enemas, although not in common clinical use, have been used as a therapy in IBD, highlighting the importance of the microbiota⁽ Reference Vieira, Leonel and Sad ^{31 )}. Other studied nutrients include n 3 and n 6 fatty acids⁽ Reference Farrukh and Mayberry ^{32 ,} Reference Yates, Calder and Ed Rainger ^{33 )} and vitamin D⁽ Reference Mouli and Ananthakrishnan ^{34 )}.

Probiotics

Probiotics are generally considered to be safe, and do have some proven clinical therapeutic uses in IBD. They reduce the risk of disease onset⁽ Reference Gionchetti, Rizzello and Helwig ^{38 )} and maintain disease remission⁽ Reference Mimura, Rizzello and Helwig ^{39 )} in pouchitis. E. coli Nissle 1917 has similar efficacy to 5-aminosalicylic acid therapy in the maintenance of remission in ulcerative colitis⁽ Reference Kruis, Schütz and Fric ^{40 )} and some studies suggest VSL#3 to be effective in the treatment of active mild-to-moderate ulcerative colitis⁽ Reference Sood, Midha and Makharia ^{41 )}. There is little evidence for the use of probiotics in Crohn's disease, however, possibly due to the smaller microbial load in the small bowel as compared with the colon⁽ Reference Bourreille, Cadiot and Le Dreau ^{42 –} Reference Van Gossum, Dewit and Louis ^{45 )}. One confounding factor of the probiotic approach is the comparatively low number and diversity of bacterial species available in a typical commercial probiotic in comparison with the gut microbiota. The commercially available products usually contain at least three orders of magnitude fewer bacteria than the microbiome which they are attempting to modify; for example a patient would need to take 1000 VSL#3 capsules to ingest a microbial load equivalent to the gut microbiota⁽ Reference Sekirov, Russell and Antunes ^{2 )}. Furthermore, probiotic bacterial strains may not be able to compete against the complex interactions of an established and adapted indigenous gut microbial community. The diversity of probiotic products on offer renders most meta-analyses irrelevant, as each trial should only be compared with trials studying the same species or combination of species.

Prebiotics

Prebiotics are non-digestible dietary components which promote the growth of beneficial gut micro-organisms. Fructo-oligosaccharides have been postulated to have a beneficial effect in active Crohn's disease, but initial trial success⁽ Reference Lindsay, Whelan and Stagg ^{46 )} has not been reproduced in larger subsequent studies⁽ Reference Benjamin, Hedin and Koutsoumpas ^{47 ,} Reference Joossens, De Preter and Ballet ^{48 )}.

Faecal microbiota transplantation

The concept of transplantation of the whole gut microbiota has been described in ruminants for some time⁽ Reference Rager, George and House ^{49 )}. Use as therapy in human subjects was first reported by Eisemen et al. in 1958 in the treatment of fulminant pseudomembranous enterocolitis⁽ Reference Eiseman, Silen and Bascom ^{50 )}. Over the subsequent decades, there have been an increasing number of case reports and case series of the potential therapeutic uses of faecal transplantation not only for Clostridium difficile infection⁽ Reference Van Nood, Vrieze and Nieuwdorp ^{51 )} but also for constipation, irritable bowel syndrome and IBD⁽ Reference Borody and Khoruts ^{52 )}. There also seems to be potential for faecal transplantation in the treatment of diseases beyond the gut such as metabolic syndrome⁽ Reference Vrieze, Van Nood and Holleman ^{53 ,} Reference Kassam, Lee, Yuan and Hunt ^{54 )}. The first randomised controlled trial of faecal transplantation for recurrent C. difficile demonstrated 94 % remission at 10 weeks following duodenal infusion of donor faeces⁽ Reference Wong, de Souza and Kendall ^{29 )}. Studies have shown a significant and durable change in the microbiota following faecal transplantation⁽ Reference Grehan, Borody and Leis ^{55 )}. In a mouse model of pseudomembranous colitis)⁽ Reference Lawley, Clare and Walker ^{56 )} suppression of C. difficile following faecal transplantation was associated with a change of the recipients’ microbiota to a composition similar to that of the healthy input bacterial community and this was closely linked to a rapid increase in species diversity⁽ Reference Lawley, Clare and Walker ^{56 )}. There are case reports of the use of faecal microbiota transplantation in IBD, but currently there are no published randomised controlled data for faecal microbiota transplantation in IBD.

Faecal transplantation, a therapy used for more than half a century, could hold great promise as a future treatment in the many diseases where dysbiosis of the gut microbiota contributes to disease. While it appears that in the short-term this therapy is safe, there remains concern regarding the long-term health risks that may be posed by faecal transplantation.