The more the merrier: Faecalibacterium prausnitzii in Crohn's disease

Crohn's disease (CD) is thought to result from an inappropriate, ongoing immune response that occurs in genetically susceptible individuals as a result of a complex interaction between luminal bacteria, environmental factors, and the mucosal immune system. Three theories of microbial etiopathogenesis have been proposed:1 (i) a dysbiosis (an imbalance between potentially “beneficial” and potentially “harmful” bacteria); (ii) the presence of an unidentified pathogen; and (iii) excessive bacterial translocation. Over the past 10 years, culture-independent techniques have been used to investigate microbes and microbial communities in CD. The application of high throughput sequencing techniques and other approaches has demonstrated that no specific pathogen is associated with 100% of CD tissues, a particular disease location, or sites of bacterial translocation such as the mesenteric lymph nodes (O'Brien CL et al., unpubl. data, 2013). In contrast, in support of the dysbiosis hypothesis, there are many studies that show decreased levels of Firmicutes and Faecalibacterium prausnitzii, and an increase in Bacteroidetes and Enterobacteriaceae, particularly in patients who have ileal involvement.2 Faecalibacterium (formerly Fusobacterium) prausnitzii belongs to the Clostridium leptum subgroup (cluster IV) of the phylum Firmicutes and is one of the most abundant bacteria in the human gut ecosystem.3 It is thought to be a marker of a healthy gut: F. prausnitzii, along with Roseburia and Eubacterium spp., and other fermentative organisms supply the short-chain fatty acid, butyrate, to the colonic epithelium that it uses as an energy source. Butyrate is important for its role in reducing oxidative stress and protecting against carcinogenesis,4 as well as its anti-inflammatory properties.2 Decreased levels of F. prausnitzii are also associated with a higher risk of postoperative recurrence in patients with ileal CD.2 So it seems that the more F. prausnitzii, the merrier the gut ecosystem. The study by Fujimoto et al.5 examined levels of F. prausnitzii in 47 Japanese CD patients (only four of whom had active disease) and 20 healthy subjects using quantitative real-time PCR. They showed significantly lower levels of F. prausnitzii in CD patients. In contrast, B. wadsworthia was chosen because it is sulfite-reducing and plays a role in the development of spontaneous colitis in interleukin 10-deficient mice,6 occurred at a similar frequency in CD patients and controls, suggesting that it has no role in the pathogenesis of CD. The CD group was separated into patients with high and low levels of F. prausnitzii. Comparison of clinical markers revealed that most inflammatory parameters were significantly worse in the low F. prausnitzii group indicating that F. prausnitzii levels correlated inversely with disease activity. The microbiota composition was also compared between 10 healthy controls versus 10 randomly selected low F. prausnitzii CD patients using terminal restriction fragment length polymorphism. Analysis confirmed the presence of low levels of F. prausnitzii in CD patients and highlighted other groups of microorganisms, notably Lactobacilli, which also differed significantly in abundance. Finally, they confirmed other studies showing that the diversity of the microbial population was lower in the CD group. The gut microbiome is complex and varies significantly according to geographical location, diet, and medications (especially antibiotic usage).7 The genetic background of Japanese patients suffering from CD differs from European and North American patients.8, 9 Nevertheless, Fujimoto et al. observe that there are changes common to the intestinal microbiome of both populations—a decrease in the abundance of F. prausnitzii and decreased microbial diversity. By showing that the abundance of F. prausnitzii was decreased in CD patients compared with controls and that F. prausnitzii is also decreased in patients who have CD but are in remission, Fujimoto et al. suggest that the depletion of this bacterium is a cause, not consequence, of the disease process. It is unknown whether or not individuals that develop CD have decreased levels of F. prausnitzii before the onset of disease, but there is no evidence that levels of F. prausnitzii are decreased in unaffected family members.10, 11 In Fujimoto et al.'s study, the abundance was also shown to vary according to disease activity, raising the possibility that it was the result of the inflammatory changes in the intestinal microenvironment or that the inflammatory disease process depletes the bacterium, and its low abundance in those in remission reflects the time it takes to recover. This occurs, for example, for many species of bacteria following antibiotic treatment,12 and there is some evidence suggesting that levels of F. prausnitzii recover during remission.13, 14 There are other observations that provide evidence against a causative role in CD—clinical improvement in CD patients (unexpectedly) correlated with a significant decrease in the abundance of F. prausnitzii15—and decreases in F. prausnitzii relative to controls are also seen in other intestinal disorders, for example infectious colitis,14 ulcerative colitis, and celiac disease.13 Treatment with infliximab and high-dose cortisol has been associated with increased levels of F. prausnitzii, further implicating an aberrant immune response in the depletion of this bacterium.13 Notwithstanding the differing interpretations of these observations, Fujimoto et al. show that there are common bacteriological changes across differing geographical, dietary, and genetic backgrounds. These important observations will lead to attempts to manipulate the microbiome using probiotics or prebiotics to restore the “ecological balance” in the intestinal lumen. F. prausnitzii may be beneficial to gut health and is consistently found to be present at lower levels in CD patients in different populations. In contrast, in their study, Bifidobacteria and Lactobacilli were more abundant in CD patients; these organisms are traditionally thought to be beneficial and have been marketed as probiotics for gut health. Will increasing already high levels improve the clinical state? The choice of therapeutic agent remains problematic, but the demonstration of common microbial “themes” supports the quest for therapies to correct a consistent “imbalance” in the intestinal microbial environment.