The immune system comprises innate and adaptive branches, linked by dendritic cells (DCs) as a critical connection. The adaptive immune response is mainly mediated by lymphocyte receptors that recognize specific protein antigens, whereas the innate immune response is predominantly activated through pattern recognition receptors (PRRs) that are commonly expressed on innate immune cells. The PRRs involved in the innate immune response mainly contain transmembrane proteins, e.g., Toll-like receptors (TLRs), C-type lectin receptors, and cytoplasmic proteins, e.g., NOD-like receptors (NLRs), retinoic acid-inducible gene-I-like receptors (39, 43, 44).

IECs not only selectively facilitate the uptake of nutrients but also serve as a physical and biochemical barrier that segregates the luminal microbial communities from the mucosal immune system, protecting the host from unnecessary immune responses to luminal contents or microbiota (64). In this section, we outline the bidirectional influence between A. muciniphila and IECs within IBD.

TLRs are present not only on the surface of immune cells but also on the surface of IECs. Shi et al. revealed that the live and pasteurized A. muciniphila, upon recognizing TLR2 in Caco-2 IECs, induced the activation of AMP-activated protein kinase (AMPK), which facilitated the assembly of tight junction proteins and contributed to the maintenance of the intestinal barrier integrity. Moreover, both live and pasteurized A. muciniphila inhibited NF-κB activation through the TLR2-mediated pathway and resulted in the alleviation of inflammatory disorders (65).

Other proteins present on the IECs have also shown associations with the abundance of A. muciniphila in IBD. The natural killer group 2 member D (NKG2D) receptor is a type of stimulatory immune receptor expressed on natural killer (NK) cells, γδ T cells, CD56⁺ T cells, CD8⁺ T cells, activated CD4⁺ T cells, etc. (66–69). The increased expression of NKG2D and NKG2D ligands is related to IBD pathogenesis through modulating T and innate immunity cell activity (66, 70–72). Several monoclonal antibodies targeting NKG2D have been tested and shown to have a positive effect in improving IBD (73–75). However, limited research has revealed the relationship between gut microbiota and NKG2D/NKG2D ligands in IBD. Hansen et al. discovered that the gut microbiota has an effect on the expression of NKG2D ligands on the small IECs. In particular, the abundance of A. muciniphila, whether increased by treating mice with vancomycin or decreased by treating mice with dietary xylooligosaccharides, was negatively correlated with the expression of NKG2D ligands (76). Indoleamine 2,3-dioxygenase 1 (IDO1) is the initial enzyme responsible for metabolizing tryptophan (Trp) in the Kynurenine (Kyn) pathway. The research of Alvarado et al. found that the IDO1-TG mice (transgenic mice characterized by the overexpression of fluorescence-tagged IDO1 in the IECs) exhibited a 3.0-fold higher abundance of A. muciniphila in comparison to wild-type mice. They demonstrated that overexpression of IDO1 in IECs promoted the differentiation of secretory cells and increased mucus production, leading to enhanced levels of mucin-associated microbiota (A. muciniphila and Mucispirillum schaedleri), ultimately resulting in the amelioration of colitis severity (77). It is more likely that A. muciniphila could be regulated by IDO1 on IECs, thereby effectively alleviating intestinal inflammation in IBD.

Autophagy is an important catabolic recycling pathway that degrades cytoplasmic materials by the lysosome to maintain cellular homeostasis. The interplay between autophagy and the gut microbiota plays a vital role in IBD (78). Currently, emerging evidence suggests that variations in autophagy-related genes of IECs could influence the abundance of A. muciniphila, thereby playing a significant role in IBD. Naama et al. constructed the constitutive activation of autophagy mice through mutating the phenylalanine residue at position 121 of the autophagy-initiating protein Beclin 1 to alanine (Becn1^F121A mice). The results indicated that continuous activation of autophagy protected the intestine from colitis, characterized by alleviating endoplasmic reticulum (ER) stress in goblet cells, thereby facilitating mucus secretion and altering the gut microbiome, specifically increasing A. muciniphila (79). Yang et al. discovered that the intestinal epithelium-specific autophagy-related 5 knockout (Atg5^-/-) mice with a disruption of autophagic flux in the IECs dramatically decreased the abundance of A. muciniphila and Lachnospiraceae family compared with that of wild-type mice. Differential gene expression analysis revealed that two key IBD-related transcription factors, RORC and TBX21, were upregulated in Atg5^-/- mice (80).

Conversely, A. muciniphila can also modulate the autophagy of IECs. Yu et al. discovered that the supplementation of A. muciniphila regulated the intestinal microbiota and metabolites, activated the NLRP6 inflammasome, promoted autophagy of IECs, and maintained the normal secretory function of Paneth cells and goblet cells (57, 58). Wang et al. discovered that the outer membrane vesicles (OMVs) of A. muciniphila not only could restore the disturbed gut microbiota homeostasis by selectively promoting the proliferation of beneficial bacteria, but also could enter the Peyer’s patches and the IECs to elicit the immune regulation and stimulate goblet cells to produce mucus for repairing the mucus barrier (62).

In the study of Duan et al., they assessed the regulatory relationship between fucose, gut bacteria, and ISCs. The research revealed that the administration of fucose promoted the proliferation of ISCs. However, ISCs were not directly impacted by fucose. They indicated that fucose administration-promoted ISCs-mediated intestinal epithelial development was gut microbiota-dependent, as confirmed by the administration of an antibiotic cocktail to the mice to eliminate their gut microbiota. Ultimately, they elucidated that fucose supplementation significantly increased the A. muciniphila and A. muciniphila-related propanoate metabolism. This process enhanced the stemness and function of ISCs via the Wnt signaling pathway (81). Kang et al. further confirmed that the secreted protein Amuc_1409 of A. muciniphila could promote the proliferation, regeneration, and epithelial development of ISCs by interacting with E-cadherin. This interaction leads to the dissociation of the E-cadherin/β-catenin complex, ultimately activating the Wnt/β-catenin signaling pathway (82).

Trp is an indispensable aromatic amino acid. Humans primarily acquire it from common natural foods. The metabolic activity of Trp takes place within the host cells and intestinal microbiota, mainly relying on the following three Trp metabolic pathways (83). Approximately 95% of Trp in the human body could be converted into kynurenic acid, quinolinic acid, nicotinic acid, and other compounds through the catalytic action of specific enzymes, which is known as the kynurenine (Kyn) pathway (84). Trp also could be transformed into indoles and indole derivatives. This process is known as the indole pathway. Additionally, through the catalysis of Trp hydroxylase and decarboxylase, Trp could be converted into 5-hydroxytryptamine (5-HT, also known as serotonin), and this is the 5-HT pathway (83). Many of the Trp metabolites, e.g., Kyn and indole, have been reported to be able to bind and activate the aryl hydrocarbon receptor (AhR). This entire process is termed the Trp-AhR pathway (85). Supplementation with Trp or several microbial Trp metabolites has been demonstrated to protect against colitis in mice through the activation of AhR, followed by the regulation of intestinal barrier, immune response, gut microbiota homeostasis, and other factors (86, 87). Recent studies have uncovered a mutual regulatory interplay between A. muciniphila and Trp metabolism in IBD.

The synthesis of 5-HT from Trp primarily involves two stages. Initially, Trp is transformed into 5-hydroxytryptophan (5-HTP) through the catalysis of Trp hydroxylase with indole ring hydroxylation. And then, 5-HT is produced undergoing the decarboxylation of 5-HTP, which takes place by Trp decarboxylase (83, 88). 5-HT was predominantly generated by enterochromaffin cells which are a subset of enteroendocrine cells in the gastrointestinal tract. The intestine holds approximately 95% of the total 5-HT levels in the body (89, 90). The research conducted by Yaghoubfar et al. demonstrated that A. muciniphila and its extracellular vesicles notably boosted 5-HT levels in colon tissue, increased the expression of serotonin transporter (SERT), and decreased the level of 5-HT in serum. Additionally, the OMVs of A. muciniphila had more biological effects on increasing the serotonin level in colon compared to the bacterium itself. Interestingly, the oral administration of A. muciniphila or its OMVs to male C57BL/6J mice without colitis for 4 weeks caused no adverse effect on inflammation, as there were no indications of inflammatory cell infiltration in the mucosal, epithelial, lamina propria, or submucosal layers (91). Several studies have shown that SCFAs, the metabolites of gut microbiota, play a crucial role in the production of 5-HT in the colon by promoting the expression of Trp hydroxylase 1 on enterochromaffin cells which is the rate-limiting enzyme for mucosal 5-HT synthesis (90, 92). A. muciniphila can metabolize mucin from the intestine with the production of SCFAs. Hence, the regulatory mechanism of A. muciniphila-SCFAs in Trp metabolism upon the 5-HT pathway remains to be elucidated in the future, especially concerning the amelioration of IBD.

In individuals with UC, there was a noted decrease in serum Trp levels and an activation of the Kyn pathway (93). Gu et al. comprehensively examined the impact of A. muciniphila on three Trp metabolic pathways in both UC patients and colitis mice through fecal metagenomics, untargeted serum metabolomics, and colonic transcriptomics. They confirmed that in UC patients or colitis mice, the Trp metabolism was activated with significantly decreased levels of Trp and related metabolites, such as Kyn, in the serum. Through treatment with live A. muciniphila, pasteurized A. muciniphila, or Amuc_1100, Trp metabolism was normalized by gut microbiota, exhibiting the restoration of Trp levels and a reduction in Kyn degradation. In addition, the expression of AhR targeted genes (CYP1A1, IL-10, and IL-22) was enhanced in colon of colitis mice through treatment with pasteurized A. muciniphila or Amuc_1100. But live A. muciniphila, pasteurized A. muciniphila, or Amuc_1100 failed to restore the decreased metabolites in the serotonin pathway during the colitis process. This indicated that from the perspective of regulating Trp metabolism, A. muciniphila, pasteurized A. muciniphila, or Amuc_1100 predominantly alleviated colitis in mice by inhibiting the Kyn pathway, activating the indole pathway, and enhancing AhR signaling. AhR, widely expressed in intestinal immune and epithelial cells, promotes the secretion of IL-10 and IL-22—L-22tionl that respectively prevent pro-inflammatory responses and protect against tissue damage by regulating antimicrobial peptides and microbiota (36). Although these studies suggested that A. muciniphila can simultaneously influence multiple pathways of tryptophan (Trp) metabolism in alleviating IBD, the in-depth mechanism of how A. muciniphila influences Trp metabolism in different pathways remains unclear. In addition, the influence of A. muciniphila on the state of the serotonin pathway with/without intestinal colitis remains inconclusive.

The SCFAs, mainly acetate, propionate, and butyrate, are one of the metabolites through fermenting unabsorbed dietary fibers, non-starch polysaccharides, undigested proteins, as well as some peptides by gut microbiota. SCFAs play a pivotal role in host homeostasis, e.g., strengthening the gut barrier, regulating energy metabolism, and exerting immunomodulatory functions (94, 95). IBD patients exhibit a reduction in the levels of dominant SCFAs-producing microorganisms both in the intestinal mucosa and feces. Additionally, the concentrations of SCFAs in IBD patients seem to be lower compared with healthy individuals (96). A. muciniphila is a bacterium that is recognized for its ability to produce SCFAs, primarily acetate and propionate, by degrading mucin with its abundant enzymes. Recently, numerous studies have investigated the connection between A. muciniphila, SCFAs, and IBD.

A. muciniphila supplementation resulted in changes to the SCFAs profile. Bian et al. demonstrated that A. muciniphila exhibited protective effects on DSS-induced colitis mice. The pre-treatment of A. muciniphila to colitis mice not only stabilized the colon mucosal barrier, regulated inflammatory cytokines (e.g., TNF-α, IL-6) and chemokines MIP-1, but also alleviated dysbiosis of the gut microbiome. Remarkably, the A. muciniphila pre-treatment in the DSS-induced colitis mice resulted in a marked increase in SCFAs, including acetate, propionate, iso butyrate, and butyrate (30).

Although studies have shown that elevating the levels of A. muciniphila is beneficial for alleviating intestinal inflammation in mice, Zhai et al. discovered that there are strain-specific differences in improving intestinal colitis. They noticed that both A. muciniphila strains (strain ATCC BAA-835 and strain 139) contributed to the recovery of chronic colitis and promoted normalization of the gut microbiota in mice, but the ATCC BAA-835 strain exhibited a more significant effect. They further identified that the Treg cell differentiation and the production of SCFAs are the primary distinguishing factors in the effectiveness of the two strains. Only strain ATCC BAA-835 increased the overall concentration of SCFAs in the cecum with a significant upregulation of the G-protein coupled receptors 43 (GPR43) in colon and the number of Foxp3⁺ Treg cells in the mesenteric lymph nodes of mice. The possible mechanism underlying the beneficial effects of A. muciniphila in colitis is the upregulation of SCFAs. These SCFAs activate GPR43 and further regulate immune responses by increasing the number of colonic Foxp3⁺ Treg cells and inhibiting the expression of pro-inflammatory mediators (97).

Besides the A. muciniphila supplement directly, some other measures can alter the composition and abundance of A. muciniphila as well as the SCFAs level. Huang et al. found that the colon inflammation in DSS-induced mice could be significantly mitigated via lithium carbonate administration which is predominantly utilized in clinical settings as the antimanic and antidepressant drug. Notably, the administration of lithium carbonate not only changed the structure and composition of gut microbiota, especially resulting in an increased abundance of A. muciniphila, but also significantly transformed SCFAs profiles with a pronounced upregulation of acetate and propionate. They corroborated that A. muciniphila and its metabolic SCFAs, especially acetate and propionate, played a pivotal role in the improvement of colitis in lithium carbonate treatment. The SCFAs-sensing GPR43 was activated, which upregulated the population of Treg cells (CD25⁺Foxp3⁺CD4⁺) in colonic lamina propria and initiated anti-inflammatory responses (98). Duan et al. revealed that fucose treatment led to changes in the composition and functions of gut bacteria, with significant increases observed in A. muciniphila and its related propanoate metabolism. The acetate and propionate are the main SCFAs involved in propanoate metabolism of A. muciniphila. The increase in A. muciniphila and propanoate metabolism-related SCFAs triggered the activation of the Wnt signaling pathway, ultimately enhancing ISCs’ function and preserving the intestinal epithelium development (81). Luan et al. found that the ethanol extract of R. sterilis S. D. Shi fruits has the potential to ameliorate inflammation in DSS-induced mice. This effect was primarily characterized by the promotion of mucin expression, the inhibition of inflammatory mediator expression, the regulation of gut microbiota composition (notably the suppression of Escherichia-Shigella and the increase of A. muciniphila), and the enhancement of SCFAs production, particularly acetate (99).

Lee et al. carried out a study in which they pre-treated DSS-induced colitis mice with SCFAs, either sodium butyrate or a mixture of acetate, butyrate, and propionate, and then investigated the impact of SCFAs administration on intestinal inflammation and microbiota composition. During the experimental period, the mice were orally given SCFAs in their drinking water for 3 weeks, and in the third week, the mice were induced to have colitis through drinking water containing 2.0% DSS. The results determined that the oral administration of SCFAs did not yield a significant alleviation of colon inflammation. Supplementing with SCFAs affected T cell differentiation, resulting in enhanced expression of CD4⁺Foxp3⁺ regulatory T cells, which play a role in preventing excessive immune responses. Paradoxically, this supplementation also promoted the population of IL-17-producing T cells, exacerbating colon inflammation. In addition, the structure of gut microbial community was also altered in the SCFAs-treated group, which showed an elevated relative abundance of protective A. muciniphila and aggressive Escherichia fergusonii resulting in a neutral effect on colon inflammation in the DSS-induced colitis model. Taken together, these findings suggest that supplementing SCFAs alone has a neutral effect on colon inflammation (100).

Primary BAs, e.g., cholic acid (CA) and chenodeoxycholic acid (CDCA), are small molecules that are produced in the liver from cholesterol. In hepatocytes, primary BAs are conjugated with either glycine or taurine, and conjugated BAs are subsequently released into the intestine. Approximately 95% of intestinal BAs are reabsorbed from the intestinal lumen and transported back to the liver through the portal vein. While the residual 5% are transported into colon, where they are either converted into unconjugated or secondary BAs (e.g., ursodeoxycholic acid (UDCA), lithocholic acid (LCA), deoxycholic acid (DCA)), or excreted in feces. The outcome depends on a variety of enzymes present in the colonic microbiota, e.g., bile salt hydrolase (BSH) and bile acid-inducible enzymes (BAI) (101–104). Abnormal synthesis or metabolism of BAs is related to the occurrence of diseases. Studies have revealed that patients with IBD and colitis animal models both exhibited abnormal BAs metabolism. And regulating BAs metabolism, such as targeting BAs receptors, has been employed as a therapeutic approach for IBD or colorectal cancer (105–110). The mutual interactions between gut microbiota and BAs metabolism in IBD have drawn significant attention from researchers. A portion of probiotics, e.g., Bifidobacterium, Lactobacillus, have exhibited the positive effects on regulating the gut microbiota-BAs axis (103). Recently, researchers have provided evidence of the regulatory relationship between A. muciniphila and BAs metabolism in IBD.

Supplementing with secondary BAs has been shown to increase the levels of A. muciniphila in feces and protect against colitis in mice. According to a study by Bossche et al., the UDCA and its taurine conjugates (tauroursodeoxycholic acid, TUDCA) or glycine conjugates (glycoursodeoxycholic acid, GUDCA) equally lowered the severity of DSS-induced colitis mice. They identified that colitis mice administered with UDCA, TUDCA, or GUDCA normalized the Firmicutes/Bacteroidetes ratio and increased the abundance of Clostridium cluster XIVa and A. muciniphila, which are recognized to be significantly reduced in IBD patients (111).

Dong et al. demonstrated that the polyphenol dihydromyricetin (DHM) not only ameliorates colitis by restoring microbial balance, notably enriching Lactobacillus and A. muciniphila, but also increases the levels of CDCA and LCA in a gut microbiota-dependent manner. These BAs subsequently activate their respective receptors, with LCA serving as the natural ligand for the G protein bile acid receptor (TGR5) and CDCA acting as the natural agonist for the nuclear receptor farnesoid X receptor (FXR). The activation of TGR5 and FXR plays a vital role in maintaining intestinal homeostasis through two key mechanisms. FXR activation protects against colitis by inhibiting pro-inflammatory cytokine production and preserving goblet cells, whereas TGR5 signaling promotes epithelial repair by enhancing the proliferation of ISCs. Together, they coordinately uphold intestinal integrity and regulate immune responses (112). Zhai et al. indicated that supplementation with Eucommia ulmoides leaf extracts (ELE) alleviated colitis, with a significant increase in the abundance of Akkermansiaceae and Ruminococcaceae. They discovered that ELE resulted in a marked increase in the concentrations of DCA and TUDCA in the serum, which are positively associated with the presence of Akkermansiaceae and unidentified_Ruminococccaceae. In addition, the expression of TGR5, which significantly maintains the barrier function of IECs, was also upregulated in the colons. and the improvement in colitis was mediated through the gut microbiota-BAs-TGR5 axis (113). These suggest that further efforts are required to clarify the exact regulatory mechanisms of A. muciniphila-BAs, potentially offering a viable strategy to address IBD.

Polysaccharides and other substances have been found to improve intestinal inflammation, along with the increase or decrease in the abundance of A. muciniphila. Nevertheless, the specificity between these substances and A. muciniphila, as well as the full molecular mechanisms, remains to be fully researched and clarified (114–120).