Many of these studies help focus attention on the role of gut microbes in the pathogenesis of IBD, especially the presence of pathobionts, and how EEN might dampen such adverse effects and reduce pathobionts. Observed changes in microbiota with EEN are diverse and depend on study design and technical consideration (see:
Table 2). Nonetheless, some taxonomic alterations are reproducible [
38,
75]. These changes can be rapid, occurring even within one week of initiating EEN therapy [
76]. Indeed, dramatic effects are observed, some of which are counterintuitive to our understanding of the impact of microbiota on CD pathogenesis. For example, EEN appears to reduce microbial diversity, lower SCFA concentrations (including butyrate), and reduce
Faecalibacterium prausnitzii, which is usually considered beneficial in IBD [
77]. In another study, responders to EEN showed lower bacterial richness than nonresponders [
78]. Quince et al. showed a decrease in Shannon diversity with EEN, but this returned to pretreatment levels two months after EEN was stopped, as did decreases in
Bifidobacterium, Ruminococcus, and Faecalibacterium [
79]. It is hypothesized that some of these decreases in specific taxa and diversity are simply due to the lack of fibre in EEN [
80,
81]. Furthermore, a baseline reduction in dysbiosis-associated taxa could potentially be a marker of better response to EEN, where patients who respond to therapy may subsequently have paradoxical increases in pathobiont taxa.
Several studies have attempted to correlate response to EEN with changes in microbes. How the baseline microbes respond to such a drastic diet change could determine the likelihood of therapy response [
84]. Patients who demonstrated decreases in
Bacteroides and
Prevotella species with EEN treatment improved clinically, and these changes in microbiota persisted for several months after completing EEN [
81]. While bacterial composition has been shown to be predictive in several studies, it is critical to differentiate it from microbial function (measured using metagenomics), which highlights potential mechanisms of action [
85]. A recent study using stool metabolomics showed that amino acids, primary bile salts, trimethylamine, and cadaverine are reduced with EEN in children with Crohn’s disease, likely mediated by microbes, and it is believed that this reduction best predicts response to EEN [
86,
87].
It remains unclear whether microbial shifts observed with EEN are responsible for the effectiveness of therapy or are a consequence of successful therapy and resolution of inflammation. One recent study showed an improvement in microbial diversity with both EEN and steroids, associated with response to therapy, suggesting that at least some of the microbial changes may simply be due to reduced inflammation [
86]. Collectively, these studies do suggest that EEN does act through compositional and functional microbial changes, but much remains to be understood in this growing field of research.