Microbial mechanisms of action of exclusive enteral nutrition in Crohn's Disease: Cause or effect?

Criterion 1. Strength: strong relationship between variables. A significant decrease in bacterial diversity during treatment with EEN has been previously described within targeted and untargeted microbiome analysis studies. It is important to note that such paradoxical associations of disease improvement and induction of dysbiosis are of greater magnitude and strength among patients with a better disease response to EEN [7, 8].

Criterion 2. Experiment: change in cause = change in effect. The hypothesis of a causal relationship between microbiome changes and EEN clinical efficacy is further supported by the rebound of the gut microbiome to pre-treatment community characteristics after re-introduction of food [2, 8], and this rebound is mirrored by faecal calprotectin elevation post EEN cessation [9].

Criterion 3. Biological gradient: dose-response, more exposure leads to more outcome. Greater adherence to EEN correlates not only with better clinical outcomes, with higher volumes being significantly more efficacious, but also with stronger suppression of both microbiome composition and metabolic activity [10–12].

Criterion 4. Temporality: the cause must precede the outcome. Given the rapid inflammatory amelioration during EEN, with studies describing symptomatic and inflammation benefits within two weeks of initiation of treatment, it is important to confirm that the microbiome effect precedes the clinical benefit. In this context, studies have shown that microbial and metabolite changes are apparent within 7 days after EEN initiation [13].

Criterion 5. Consistency: the relationship is consistent in different studies/populations. Recent reviews have found that the suppressive microbial effects of EEN have been consistently described by different studies and within different populations, including paediatric and adult patients [3, 5].

Criterion 6. Coherence: the relationship is consistent with similar knowledge. In agreement with the apparent role of microbiome shifts during EEN therapy, a recent study has found that certain pre-treatment metabolic and microbial signatures are predictors of response to treatment with EEN [14].

Criterion 7. Plausibility: there is biological rationale for the relationship. The biological rationale for the discussed associations is provided by human genome studies identifying genetic variants that alter the intestinal microbiome and are associated with the development of IBD [15]. Further supportive evidence is provided by studies of animal models which have revealed that a germ-free state prevents the development of ileal disease, the pathogenesis of which resembles that of CD [16].

Criterion 8. Analogy: the relationship is synonymous with other, similar relationships. The relationship between EEN clinical benefit and microbiome suppression is synonymous with other similar relationships: (a) antibiotics which suppress the microbiome have shown some success in improving certain types of CD, (b) probiotics, prebiotics and synbiotics intended to modulate and enhance the microbiota lack efficacy in the treatment of CD, (c) faecal microbiota transplantation (FMT) is effective in conditions like C. difficile infections but has not been successful for CD and (d) food-based diets that aim to suppress gut microbial activity and diversity share similarities with EEN in targeting microbiome changes and also have similar benefits with regard to disease activity [1–4, 13]. These analogies highlight both complementary and contrasting approaches, emphasising EEN’s mechanisms of action.

Copyright of the graph © Vaios Svolos

The effectiveness of EEN in CD largely stems from its ability to manipulate the gut microbiome. By reducing inflammation and promoting mucosal healing, EEN provides a multifaceted therapeutic benefit. While further research is needed to fully elucidate the precise microbial changes and downstream effects, the central role of microbiota manipulation is increasingly clear. Current understanding attributes EEN's efficacy primarily to the suppression of gut microbiome activity. Using the Bradford-Hill criteria and analogous therapeutic comparisons, EEN’s mechanisms provide a framework to uncover additional pathways and improve the management of CD.

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