The disordered function and the number of adaptive immune cells, especially T lymphocytes, are crucial to IBD etiology [91,92,93,94] (Figure 2). A regulatory role of HFD in adaptive immune cells was also demonstrated in HFD-fed DSS-induced colitis mice; increased non-CD1d-restricted NKT cells and decreased Tregs were observed in the colon. This is paralleled by the fact that a higher ratio of effector T cells/regulatory T cells will contribute to the inflammatory state in the intestine [95]. Moreover, HFD can disrupt the steady state of intraepithelial lymphocytes (IELs), reducing homeostatic proliferation in intraepithelial T lymphocytes and the expression of CD103 and CCR9 on these cells to worsen the outcome of DSS-induced colitis in mice [96]. Similarly, HFD-fed mice substantially increased Th17 polarization [97] and CD3+ T cell infiltration in the gut [98], resulting in colitis aggravation. HFD-produced peroxidized lipids, such as 13-HPODE, could stimulate the secretion of pro-inflammatory granzymes by resident NK cells, thereby contributing to intestinal inflammation [99]. Previous studies of IBD suggest the involvement of innate lymphoid cells (ILCs) [100]. There was an increase in IL-17-producing type 3 innate lymphoid cells (ILC3s) in the offspring of mice that were fed a high-fat diet, leading to high susceptibility to inflammation [101]. In another animal study, significantly increased expression of caspase-3 was found in type 1 innate lymphoid cells (ILC1) and ILC3 in the mice fed with HFD as compared to the control group, possibly resulting in pro-apoptotic mechanisms [102]. In terms of B cells, in the plasma and spleen of C57BL/6 mice, the HFD induced evident decreases in the number of B cells, accompanied by oxidative stress and increased oxidative damage [103]. Gurzell et al. [104] found that docosahexaenoic acid (DHA), a type of n-3 polyunsaturated fatty acid that is low in Western diets, enhances B cell activation, thereby boosting the humoral immunity of mice, which may up-regulate the resolution phase of inflammation.

Furthermore, an increased presence of colonic macrophages has been shown in HFD-induced obese mice [105]. Still, they are deficient in forkhead box O3 (FOXO3) in macrophages [105], which mediates the proapoptotic or anti-inflammatory effects of macrophages [106]. Neutrophils, generally regarded as keys to inflammation, play a crucial role in intestinal inflammation in IBD [107]. Neutrophil migration is enhanced by an HFD due to the elevated expression of associated cytokines [108], such as monocyte chemoattractant protein-1 (MCP-1) [109] and chemokine (C-X-C motif) ligands 1 (CXCL1) and 2 (CXCL2), in the intestine of mice [110]. Yoshida et al. [111] found that the secretion of growth-regulated oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) could be increased by long-chain fatty acids in rat IECs.

In a mice model of Crohn’s disease-like ileitis, DCs recruited into the intestinal lamina propria also appear because of the enhanced levels of chemokine (C-C motif) ligand (CCL) 20 and intercellular cell adhesion molecule 1 (ICAM1) induced by the HFD [112]. Moreover, increased maturity markers of DCs were found in a DSS-induced colitis model that was fed an HFD, which exacerbated intestinal inflammation [71,113].

All these data illustrate that an HFD could influence intestinal immune cells and the humoral immune response to induce intestinal inflammation, disrupt tissue structure, and exacerbate IBD conditions. More emphasis should be placed on the fact that some studies have concentrated on the changes in these cytokines and immune cells under an HFD but have not explored the alterations in intestinal microorganisms. Whether these immunity-related changes are just the results of this dietary model, the results of intestinal microorganisms, or both, is still obscure. Therefore, it is necessary to conduct these studies in germ-free mice, which may better elaborate on the direct effect of diet on intestinal immunity and help explain how environmental factors can increase susceptibility to IBD.

Polyunsaturated fatty acids (PUFAs) are a type of fatty acid that contains more than two double bonds. PUFAs contain two principal families: n-6 (or omega-6) and n-3 (or omega-3). Eicosapentaenoic acid (EPA) and DHA are precursors of n-3 PUFAs and are classified as essential lipid mediators. The typical Western-style diet has a high n-6/n-3 ratio of approximately 10–15:1 [114]. The increase in dietary n-6/n-3 PUFAs was positively correlated with the increased incidence of IBD [115] (Figure 2). John et al. [116] suggested that increasing the consumption of n-3 PUFAs may help prevent UC. In addition, prospective research has revealed that increasing the proportion of n-3/n-6 PUFA ingestion can help to maintain IBD remission [117].

Beguin et al. [118] showed that 150 mM of DHA could increase ZO-1 intensity in vitro. A lower intensity of occludin, when incubated with n-6 PUFAs, was also found in this research. Previous research has shown that TLR-2 gene expression in TNBS-induced colitis may be promoted by n-3 PUFAs [119]. The effect of n-3 PUFAs on neutrophils in the inflammatory process has also been investigated in TNBS mice in vivo; DHA and EPA could inhibit PMN transepithelial migration by reducing VCAM-1 and ICAM-1 [119]. Studies have revealed that the serum level of leukotriene B4 (LTB4) secreted by neutrophils in UC patients could be reduced by n-3 PUFAs and that the extravascular tissue damage caused by excessively activated neutrophils could also be avoided [120]. Current studies in mice show that n-3 polyunsaturated fatty acids could reduce the antigen-presenting function of DCs by inhibiting the expression of CD69 and CTLA-4 on T lymphocytes [121,122]. The metabolites of linoleic acid (LA, n-6 PUFAs) and arachidonic acid (AA, n-6) can produce thromboxane B2 (TXB2) and 4-series leukotrienes (LTS) through the cyclooxygenase (COX) pathway [123]. Additionally, n-6 PUFAs could also promote the production of PGE2 in vitro, thereby increasing the production of costimulatory molecules, including OX40 and CD70 in both DCs and T cells; this could induce T-cell proliferation and cause proinflammatory effects [124,125]. Moreover, the role of n-3 PUFAs in distinct types of enteritis models seems to differ. In the chronic model of intestinal inflammation, higher levels of suppressive cytokines are expressed by Th17 cells in the colon of mice than in the spleen. At the same time, there was no difference in the acute model [126,127]. Therefore, the relationship between PUFAs and T cells, especially Th17 cells in IBD, requires further study.

SCFAs are the products of anaerobic fermentation of dietary fiber, primarily containing acetate, propionate, and butyrate [8,128]. Nowadays, the beneficial roles of SCFAs on intestinal barrier integrity and immune cell functions in IBD have been highlighted by increasing evidence. Zheng et al. [129] revealed that claudin-2 formation is negatively regulated by butyrate via upregulating IL-10RA expression to protect gut barrier function, which was related to the signal transducing activator of transcription 3 (STAT3)-Histone Deacetylase inhibition (HDACi) pathway. Moreover, Hatayama et al. [130], who treated the human colon cancer cell line with butyrate and confirmed that SCFAs stimulates MUC2 production both in protein and mRNA levels, revealed that SCFAs increase MUC2 production.

The mechanism of butyrate stimulating AMP production has been investigated by Zhao et al. [131]. They used mammalian target of rapamycin (mTOR) siRNA and STAT3 siRNA to knockdown mTOR and STAT3, respectively, in intestinal epithelial cell (IEC) models and found that the mRNA and protein expressions of RegIIIγ and β-defensins were prominently impaired in these IECs, thus indicating that butyrate could active mTOR and STAT3 to promote AMP synthesis and confer resistance to colitis. The STAT3 and mTOR pathways have also been demonstrated to promote Th1 cells producing IL-10 by using butyrate to deal with the T cells from IBD patients and the DSS model, therefore limiting colitis [132]. Noteworthy, the role of SCFAs on T cells is related to the cytokine milieu. In the case of SCFA treatment, effector T cells, including Th1 and Th17 cells, are generated from naive T cells under a steady inflammatory condition, whereas in the active immune responses, the productions are regulatory T cells, such as IL-10+ T cells and FoxP3+ T cells [133]. Meanwhile, DC differentiation has also been reflected to be associated with mTOR and SATA3 pathways [134]. Butyrate, as a HDAC3 inhibitor, increases the antimicrobial functions of intestinal macrophages through a reduction in mTOR kinase activity [135] and downregulates macrophages secreting proinflammatory mediators [136]. The effect of SCFAs on neutrophils in the inflammatory process has also been investigated both in rats vivo and in vitro. On the one hand, SCFAs can promote neutrophils recruited into inflammatory sites by increasing L-selectin expression and chemokine release [137]. On the other hand, pro-inflammatory cytokines, TNF-α, and NO, produced by lipopolysaccharide (LPS)-stimulated neutrophils, are inhibited by SCFA treatment [138]. In view of the fact that mTOR is crucial in regulating the differentiation and function of innate and adaptive immune cells for intestinal immunity and that STAT3 has prominent aspects in the expressions of cytokines and chemokines, great insights must be explored about the interrelations between immune homeostasis and SCFAs in IBD.

It is well acknowledged that IBD is linked to compositional and metabolic alterations in intestinal microbiota. Fecal microbiota transplantation has been reported as a potential treatment of IBD [139,140]. Microbial communities can speedily and flexibly convert their components and functional repertoires following modern dietary challenges. Examples of this conversion could be supported by studies showing that a high HFD intake would increase the abundance rates of AIEC and Clostridioides difficile, decrease the abundance rates of Akkermansia muciniphila, and reduce the abundance rates of both Firmicutes and Bacteroidetes [141]. The clinical trial devised by Fritsch et al. [142] revealed that UC patients treated with a low-fat, high-fiber diet experienced a reduction in inflammation and an increase in the abundance of Bacteroidetes. Several studies have shown that these gut microbiotas and their metabolites are strongly correlated with IBD by potentially affecting intestinal immunity (Figure 2).