Gut microbiota in Crohn’s disease pathogenesis

Abstract

Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.

Key Words: Crohn's disease; Fecal microbiota transplantation; Gut microbiota; Inflammatory bowel disease; Mesenteric adipose tissue

Core Tip: Inflammatory bowel diseases include Crohn's disease (CD) and ulcerative colitis, characterized by inflammation in different areas. In CD, gut bacteria can invade mesenteric fat, leading to complications. Fecal microbiota transplantation is explored to restore gut balance, but its effectiveness in CD is still uncertain, with ongoing questions about symptom duration and treatment frequency. There is a critical need for long-term solutions, as emphasized by recent research.

TO THE EDITOR

Depending on the location and extent of inflammation, inflammatory bowel disease (IBD) is differentiated into Crohn’s disease (CD) or ulcerative colitis (UC). In CD, inflammation is continuous and can affect any part of the digestive system, from the mouth to the anus. In UC, however, inflammation occurs in localized patches and is confined to the colon and/or rectum[1,2]. Creeping fat, or fat wrapping, is a mesenteric adipose tissue (MAT) reaction to inflammation associated with CD. However, the exact mechanism of its formation is an ongoing area of research[1,3,4].

Creeping fat arising from the MAT is increasingly recognized as a significant contributor to CD pathogenesis. However, its relationship with the gut microbiota is unclear. Although some studies have hypothesized that increased intestinal permeability causes bacteria to translocate from the gut to the MAT, direct evidence is lacking[5,6]. This gap in the literature is evident in studies such as that of Wu et al[1], in which 16S rRNA sequencing of MAT and intestinal tissue was not performed. Addressing this limitation of current research could provide critical insights into the possible microbial origins of creeping fat and its inflammatory properties. This can best be achieved by research that utilizes advanced microbiome analyses and histological investigations to clarify these interactions.

In CD, bacteria from the gut can infiltrate the mesenteric fat, causing it to expand. This enlargement, known as creeping fat, restricts the spread of bacteria throughout the body[5]. The barrier function of creeping also prevents a widespread inflammatory response. However, the protective effects this provides are offset by the tissue fibrosis it induces. The composition of gut bacteria in patients with CD varies depending on whether the disease affects the colon or the ileum. Studies have detected various bacteria in the creeping fat[1,3,5] and this is believed to originate from the gut microbiota. In CD, these gut bacteria move from the intestinal mucosa into the MAT, causing the growth of creeping fat[4,6,7].

Fecal microbiota transplantation (FMT) is an FDA-approved treatment in which feces from a healthy donor are transferred to a recipient to restore the balance of the gut microbiota[2]. FMT is frequently employed in patients with IBD to modulate the dysbiotic gut, reduce inflammation, and promote mucosal repair[2,8,9]. This range of beneficial effects makes FMT a promising treatment for IBD. Nevertheless, professional medical guidelines are yet to acknowledge FMT as an IBD treatment so its use is currently restricted to clinical trials[9].

Still, FMT is gaining increasing recognition for its potential to restore gut homeostasis in CD by modulating the gut microbiota[10]. Histopathological evaluations have shown that FMT reduces intestinal inflammation by inducing the expression of interleukin-10 and transforming growth factor-beta cytokines and inhibiting the pro-inflammatory function of T-helper-17 cells[11]. This alleviates lipopolysaccharide-induced intestinal epithelial injury[12] and promotes mucosal healing by reconstructing the gut microbiota[13]. It has also been found to decrease fibrosis and restore the crypt architecture of affected tissues[14]. These effects lead to increased microbial diversity and a shift toward anti-inflammatory bacterial profiles. Thus, FMT is a viable therapeutic option for treating both microbial imbalance and the associated histopathological alterations in CD. Further research is needed to elucidate the precise cellular and molecular pathways through which FMT causes these histological changes.

The guidelines of the American Gastroenterological Association consider the results of only one randomized clinical trial in their assessment of the efficacy of FMT on active IBD. As this did not provide convincing evidence in favor of the treatment, they do not recommend the use of FMT in patients with active CD[15]. Likewise, the European Crohn’s and Colitis Organization regards FMT for CD as an experimental treatment because of the limited and inconsistent evidence surrounding its efficacy and safety. Their guidelines stress that FMT should only be considered in severe, refractory cases of CD in which conventional therapies have proven ineffective[16]. In their consensus report, the British Society of Gastroenterology concludes that FMT is more advantageous for patients with UC than those with CD, but supports further studies of FMT for patients with CD[17]. Thus, additional research on this topic is greatly needed. Wu et al[1] agree that further research is required before the widespread implementation of FMT treatment for CD. Their study uses 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish an experimental model of colitis that mirrors some aspects of human CD in C57BL/6 mice[18]. Samples of fecal microbiota were taken from both patients with CD and healthy donors for transplant into recipient mice, which included an experimental CD mouse model group and a control group. They found that the CD symptoms in the TNBS-induced mice improved following FMT of fecal samples from healthy donors. When FMT was performed using samples from patients diagnosed with CD, the mice’s symptoms worsened. Since creeping fat harbors microorganisms, the microorganisms in the transplanted feces must infiltrate this tissue to facilitate the balancing of the intestinal microbiota. Studies have found a decreased presence of certain beneficial anti-inflammatory microorganisms in the gut microbiota of patients with CD, including Firmicutes, Bacteroidetes, Akkermansia muciniphila, and Faecalibacterium prausnitzii (F. prausnitzii), and an increase in pro-inflammatory microorganisms such as Actinobacteria and Proteobacteria[8,19,20]. FMT has emerged as a promising means of restoring microbial diversity and reestablishing balance in the gut microbiota of patients with IBD[10]. This restoration optimizes the barrier function of the intestines and reduces inflammation, as the transplanted microbiota promote the growth of beneficial species[13,21]. Notably, F. prausnitzii has been shown to produce butyrate[21], a short-chain fatty acid critical to the maintenance of gut integrity[22,23] and the control of immune activation[23].

Recent studies have shown that FMT provides significant clinical benefits for patients with IBDs, including CD. Clinical trials have shown FMT to optimize clinical and endoscopic remission rates while increasing gut microbiota diversity, a hallmark of gut health[24,25]. Furthermore, FMT reduces inflammatory markers such as C-reactive protein[26] and improves mucosal healing[11]. In patients with refractive CD, such as infliximab-resistant cases, FMT has produced sustained clinical responses, reduced relapse rates, and prolonged remission[24,27]. These findings show FMT to be a promising adjunctive therapy. However, the long-term effects and pathophysiological mechanisms require further exploration.

CONCLUSION

The use of FMT for IBD treatment is a controversial issue. The available experimental evidence remains insufficient to definitively endorse FMT as a therapeutic approach. While the findings of the current study suggest that FMT provides symptomatic relief, its curative effects are still uncertain. Furthermore, the duration of any symptom improvements, the possibility of lifelong symptom relief, and the requirements regarding repeat FMT treatments are undetermined. Given the escalating incidence of IBDs, including CD, treatment approaches that yield long-term improvements are urgently needed. The work conducted by Wu et al[1] shows FMT to have considerable therapeutic potential and provides an excellent springboard and template for future research.