CD4+T cells are crucial factors in IBD development. CD4+T cells can differentiate toward a range of distinct phenotypes such as T helper(h)1, Th17, and several types of T-regulatory cells (Tregs). Increased Th1/Th17 cell differentiation and reduced Tregs differentiation result in enhanced susceptibility to IBD, due to increased production of pro-inflammatory cytokines (IL-6, IL-1β, IL-17, and TNF-α) and decreased expression of immune regulatory factors (IL-10, retinoic acid, and IDO) (17). A study has demonstrated that Bacteroides uniformis alleviates colitis by inhibiting IL-17 signaling pathway activity and Th17 cell differentiation (18). Another study has shown that C. butyricum diminishes pro-inflammatory cytokines like IL-1β, IL-6 and TNF-α by downregulating nuclear factor kappa-B (NF-κB) signaling pathway (19). Compelling evidence demonstrates that specific bacteria can directly skew the Th17/Treg balance by modulating certain signaling pathways, which aligns with the pivotal role of T cell dysregulation in the pathogenesis of IBD.

Macrophages are essential for the development of IBD, among which M1 and M2 play critical roles in the damage and repair of intestinal homeostasis. M1 macrophages can secrete pro-inflammatory cytokines such as IL-1β, IL-6, IL-12α, IL-23, and TNF-α, while M2 macrophages can secrete anti-inflammatory cytokines IL-10. A. muciniphila can secrete the threonyl-tRNA synthetase (AmTARS), which triggers M2 macrophage polarization and orchestrates the production of IL-10 (20). Campylobacter concisus can produce indole-containing metabolites which induce the release of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 and increase the recruitment and activation of macrophages (21). These studies indicate the key role of gut microbiota in the polarization and activation of macrophages. The opposing effects in immune regulation of the above two bacteria illustrate that the microbial influence on immunity is strain-specific. Overall, targeting macrophage polarization remains a major therapeutic frontier, in which using certain microbial products to drive M2 macrophage polarization is especially a highly precise and promising approach.

ILCs are mainly located in mucosal tissues, which are essential in the maintenance of barrier functions and in the initiation of an appropriate immune response upon pathogenic infection. The family of ILCs are classified into three groups: ILC1s producing IFN-γ, ILC2s producing IL-5 and IL-13, and ILC3s producing IL-22 and/or IL-17 (22).

Signals from commensal gut bacteria can promote good expression of cytokines in the intestine and significantly affect the function of ILCs. The development of ILC1s is dependent on commensal microorganisms, while the development of ILC2s does not require microbiota (23).

Colonic ILC3s are found to express Ffar2, a microbial metabolite-sensing receptor, whose agonism promotes ILC3 expansion and function. Deletion of Ffar2 in ILC3s leads to impaired gut epithelial function, which is associated with the development of IBD (24). In another study, glucagon-like peptide-1 receptor agonists (GLP-1RAs) enhance ILC3s cytokines-producing to alleviate DSS-induced colitis, and the regulatory effect requires the involvement of the gut microbiota (25). These results demonstrate the close interactions between gut microbiota and ILCs. Emphasis is laid on the crucial role of gut microbiota metabolites and their receptors in the precise regulation of ILC3s functions and intestinal immunity. However, more specific molecular mechanisms need to be identified.

Neutrophils are implicated in the development of IBD as first responder of immune cells. Neutrophils in large numbers infiltrate in the inflamed mucosa and accumulate in the epithelia, causing damage of mucosal architecture and releasing neutrophil extracellular traps (NETs) (26).

Li et al. (27) investigated how microbiota-derived metabolites such as butyrate regulate functions of neutrophils in the pathogenesis of IBD. In vitro studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients (27). Consistently, in murine studies, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced colitis through inhibition of neutrophil-associated immune responses (27). Dong et al. reported that Clostridioides difficile aggravated DSS-induced colitis by shaping the gut microbiota and promoting neutrophil recruitment. The isolated neutrophils from C. difficile-infected mice with colitis showed a robust migratory ability and had enhanced expression of cytokines and chemokines (28). Another study reported that Fusobacterium nucleatum induced neutrophil chemotaxis and decreased the integrity of intestinal epithelial cells (IEC), which was dependent on IEC-derived IL-8 secretion and mediated by the TLR2/ERK signaling pathway (29). These preclinical studies illustrate bidirectional regulation of microbial factors on neutrophil. Microbial metabolites like butyrate can suppress neutrophil recruitment and NET, while certain microbiota can exacerbate inflammation via neutrophil chemotaxis, which may both serve as novel therapeutic potential in the treatment of IBD.

The above results exemplify the effect of gut microbiota in modulating host immune pathways, reinforcing the close association between gut microbiota and immune system. Among these mechanisms, the interactions with CD4+T cells and macrophages represent highly critical and immediately targetable pathways, as they play a pivotal role in the immune dysregulation in IBD. Meanwhile, the microbial metabolite-sensing receptor of ILC3 remains a rather promising mechanistic insight for future precise therapies. As for neutrophil interactions, their modulation may perform broader anti-inflammatory functions, rather than core modifying effects on the pathogenesis of IBD.

CDED is an exclusion diet scheme featuring in eliminating ingredients that may contain potential triggering factors for CD, which is often used alongside partial enteral nutrition (PEN) (52). A trial on adults with mild-to-moderate CD demonstrated that both CDED plus PEN and CDED alone were effective for induction and maintenance of remission and might lead to endoscopic remission (53). Levine et al. (54) reported that CDED plus PEN produced changes in the fecal microbiome and induced sustained remission in a significantly higher proportion of patients than exclusive enteral nutrition (EEN). Verburgt et al. investigated the effect of CDED plus PEN on correcting compositional or functional dysbiosis in 54 pediatric CD patients. A significant increase in Firmicutes, particularly Clostridiales, and a significant decrease in Proteobacteria, particularly Gammaproteobacteria were observed. However, 12 weeks of diet was not enough to achieve complete correction of dysbiosis (55). Though these above results indicate the significant therapeutic effect of CDED by modulating gut microbiota, the individual adaptability and adherence to the dietary plans remain severe challenges in clinical implementation of the treatment.

Ketogenic diet (KD) is a dietary therapy characterized by high-fat and low-carbohydrate, which mediates the rise of circulating ketone bodies and exerts a potential anti-inflammatory effect (56). Kong et al. investigated the effect of KD on gut microbiota. Compared with low-carbohydrate diet (LCD), KD led to a reproducible increase in Akkermansia and a decrease in Escherichia/Shigella (57). A case report also confirmed clinical improvement and higher quality of life in IBD patients with KD (58). However, another study demonstrated the opposite result that KD substantially worsened colitis in mice and led to increase in pathogenic taxa such as Proteobacteria, Enterobacteriaceae, Helicobacter and Escherichia-Shigella, and decrease in potential beneficial taxa such as Erysipelotrichaceae (59). Inconsistency of results may indicate the effect of variation in species, individuals, dietary formulas, and intervention durations. Further research on larger scale should be conducted.

The Mediterranean diet (MD) is characterized by a high consumption of vegetables, fruits, cereals, nuts, legumes, unsaturated fat such as olive oil, a medium intake of fish, dairy products, wine, and a low consumption of saturated fat, meat, and sweets (60), which has been confirmed to be associated with the reduction of inflammatory markers (61). Evidences suggest that MD is able to modulate the gut microbiota and increase its diversity.

A study reported that compared with a Western food model, the microbiota in MD would produce more SCFAs (62). This result corresponds with another study conducted by Muralidharan et al. The study suggested the role of MD changes on the host might be via SCFA producing bacteria, with a decrease in Butyricicoccus, Haemophilus, Ruminiclostridium 5, and Eubacterium hallii (63). In addition, olive oil, a crucial component of MD, has been reported to provide a considerable anti-inflammatory effect in IBD. A study indicated that the consumption of extra virgin olive oil was related to the increase of the genus Clostridium XIVa responsible for SCFA production (64). In another study, L. plantarum SC-5 combined with olive oil extract tyrosol demonstrated a decrease in Proteus and an increase in Lactobacillus, Bifidobacterium, and Akkermansia, thereby ameliorating the colonic inflammation in mice (65). These results highlight MD as a promising dietary intervention which induces IBD remission in a gut microbiota-dependent manner.

Furthermore, several studies (66–68) on diversified dietary patterns have been conducted, providing potentially innovative strategies for IBD management. A study concentrated on the long-term soy dietary fiber diet. On chronic UC mice, high-purity soy isolate dietary fiber played an important role in the maintenance of intestinal bacterial flora by inhibiting the degradation of L. intestinalis and promoting the proliferation of Oscillospira, which provided novel ideas for the treatment of the disease (66). Ye et al. investigated the effects of a reduced sulfur (RS) diet on the gut microbiome (GM) composition in individuals with remitted or active UC. The RS diet increased beneficial microbes while decreasing pathobionts, thereby reducing inflammation (67). Another study reported dietary interventions with oats or oat bran modulated the composition of gut microbiota and increased the content of SCFAs (68). These studies elucidate the ability of specific diet pattern to alter microbial communities and ameliorate inflammatory outcomes, which highlights dietary intervention as an effective and modifiable approach in IBD treatment.

Though microbiota-targeting dietary therapies like CDED, KD and MD demonstrate considerable promise in IBD remission, severe challenge lies in long-term adherence and practicality, which impacts their real-world implementation. Most clinical trials merely show short-term efficacy in modulating gut microbiota and ameliorating inflammation, and placebo effects are inevitable. Additionally, dietary responses tend to be influenced by individual baseline microbiome along with cultural and socioeconomic factors, which pose a challenge to establishing universal protocols.

Excessive colonic bile acids (BA) influx in IBD results in bile acid malabsorption (BAM) and bile acid diarrhea (BAD), affecting about 30% of CD patients with ileal involvement (71).

A clinical trial found that IBD patients especially CD patients with BAM were intended to have more obvious improvement in clinical response (66.67%) and remission (52.38%) after FMT treatment, with alleviation in abdominal pain and diarrhea (72).

Exclusive enteral nutrition (EEN) is an effective therapy for remission induction in pediatric CD, with a disadvantage of high relapse rates after return to a regular diet (73). Hoelz et al. tested the feasibility of autologous FMT after EEN in pediatric CD patients. Insufficient amount of fecal material, inadequate stool consistency and low microbial diversity indicated that autologous FMT via capsules containing EEN-conditioned microbiota was unlikely to be a suitable therapeutic approach in pediatric CD (74).

Data on FMT for CD are more limited than UC. With mixed results in published literatures, currently, FMT has not been viewed as a standard therapy for CD. More researches should be conducted to assess FMT's efficacy in CD treatment.

FMT has been confirmed by several studies to be effective in relieving or curing active UC (75). Crothers et al. conducted a study on daily, oral FMT for long-term maintenance therapy in UC. Two subjects that received encapsulated oral FMT (cFMT) achieved clinical remission vs. none in the placebo group, which was associated with sustained donor-induced shifts in fecal microbial composition (76). To identify the long-term impacts of cFMT on the colonic microbiome, larger trials should be done. Raich et al. investigated bacterial taxonomic and functional changes following oral lyophilized donor FMT in patients with UC. The GM of patients treated with oral lyophilized FMT significantly increased in species-genome bin richness compared with patients receiving placebo (77).

However, a study identified that when a low richness GM was transferred to a recipient with a high richness GM, the donor GM failed to successfully colonize, which exacerbated DSS-induced colitis (78). This effect may partly explain why there are instances in which FMT has been ineffective or even exacerbated IBD in patients. Meanwhile, this result illustrates that the success of FMT highly depends on compatibility of donor and recipient microbiota and the efficiency of colonization after transplantation. In addition, low richness of donor GM is a crucial risk factor causing failure of transplantation and aggravation of disease.

The adverse events in FMT remain an essential challenge. In a systematic review, the total incidence rate of adverse events in FMT was 28.5% (79), most of which were mild or moderate and self-limiting. A meta-analysis reported serious adverse events related to FMT developed in less than 1% of patients, including sepsis, aspiration pneumonia, and bowel perforation (80), which underscore the importance of rigorous donor screening and standardized administration. Most FMT-related deaths were reported in patients receiving FMT via the upper gastrointestinal route, and all reported FMT-related serious adverse events were in patients with mucosal barrier injury (81). To bring FMT into mainstream clinical practice, standardized procedures, careful donor screening to reduce risks, and strategies to handle the rare but serious complications that can arise are in urgent need.

FMT represents a potent and complicated microbiota-targeting intervention. Its efficacy in IBD remission highly depends on donor-recipient compatibility and successful engraftment, which are still unpredictable and uncontrollable factors. Serious safety risks and the lack of standardized administration remain major hurdles to FMT's real clinical implementation. Fully understood mechanisms, predictable positive and negative effects, and established safety protocols are indispensable for FMT to evolve into a mature clinical regimen.