Intestinal Inflammation and Regeneration–Interdigitating Processes Controlled by Dietary Lipids in Inflammatory Bowel Disease
Abstract
:1. Background Information
1.1. Liver to the Gut Pathway
1.2. Association of Metabolic Disorder and IBD
Number of Patients and Characteristics | Results | References |
---|---|---|
153 Crohn’s disease (CD) and 229 ulcerative colitis (UC) patients, respectively | The risk of developing CD is 2.3 times higher in obese women (18 years), and there is no significant association for UC patients with obesity | [32] |
CD (n = 138) and UC (n = 394) | The risk of CD was found to be increased by 1.9 times in obese non-pregnant women, but no significant association was reported for UC | [33] |
CD (n = 75) and UC (n = 177) | According to the findings of the study, obesity alone is not enough to trigger the development of either CD or UC | [34] |
CD (n = 297) and UC (n = 284), respectively | No statistically significant association was found between obesity and either UC or CD in the studied patient populations | [35] |
377,597 men with increased BMI have an associative risk of developing CD and UC | The results of the COX regression analysis showed a positive correlation between BMI and CD in the group of 1523 patients, while an inverse correlation was observed in UC patients (n = 3323) | [36] |
A pooled analysis of cohort studies, including CD (n = 563) and UC (n = 1047) patients | The findings suggest that there is a significant association between CD and obese patients with BMI ≥ 30 kg/m2, while there is no significant relation between UC and obese patients | [17] |
Systemic studies comprising 14,947 IBD subjects | Notably, 13.6% of IBD patients with NAFLD were found to have liver fibrosis | [37] |
2. IBD Pathophysiology
2.1. Intestinal Permeability and Barrier
2.2. Inflammatory Mediators
2.3. Immune Mechanisms
2.4. Lipids and Inflammation
2.5. Intestinal Stem Cell Niche and Cell Signaling
2.6. Role of Extracellular Matrix in Intestinal Regeneration
3. Dietary Lipids and IBD Progression
3.1. The Effects of Fats on IBD
3.2. The Effects of Bile Acids on IBD
4. Therapeutic Approaches and New Candidates
- It has been shown that IL-6 was raised in mice treated with 5% DSS-induced acute colitis, while IL-6 was reduced after treatment with SM934 (artemisinin analog) and ameliorated experimental colitis [197]. The result of the tocilizumab trial on 36 patients with CD has been reported with clinical significance [198]
- In experimental models, it has been observed that deficiency of monoacylglycerol acyltransferase (MGAT) 2 provides protection against obesity. Moreover, the specific deletion of MGAT2 deters fat accumulation in the intestine [199]. In another study, monoacylglycerol lipase (MAGL) inhibition enhances the 2-arachidonoglycerol levels and results in decreased macroscopic and histological colon alterations, lowering cytokine levels [200]. MGAT2 deficiency in the intestine safeguards mice from metabolic disorders induced by high-fat feeding [201]. JTP-103237, currently in the preclinical stage, is an inhibitor of MGAT2 and impairs the absorption of luminal lipids in mice [202]. TNBS-induced murine colitis was reversed by the potent MAGL inhibitor JZL184 [200], and another MAGL inhibitor URB602 significantly repressed whole gut transient [203].
- Recent research suggests that ketogenic diets (KD) can increase the levels of circulating ketone bodies and have an anti-inflammatory effect [204]. However, the effects of this particular diet on colitis are still not well-understood. Animal studies have been conducted using KD, a low-carbohydrate diet, and a normal diet [204]. Following colitis, KD was found to protect intestinal barrier function and reduce inflammatory cytokines. Thus, KD may alleviate colitis by modifying microbiota.
- IBD frequently leads to liver injury. Milk fat globule membrane (MFGM) has been shown to mitigate colitis and liver injury [205]. Prophylactic MFGM therapy was found to be effective against colitis, improving weight loss, disease activity index, and pathological scores. Moreover, MFGM reduced levels of inflammatory mediators with an increase in IL-10 levels. MFGM thus alleviated DSS-induced injury, enhancing the mucosal barrier. It appears that MFGM may decrease oxidative stress in the liver [205].
- Signaling agents, including Wnt, EGF, Notch, and BMP ligands, promote the proliferation of Lgr5+ stem cells [206].
- Sphingosine-1-phosphate (S1P) is a signaling molecule involved in physiological processes. In IBD, the excessive infiltration of immune cells into the intestinal tissue is a significant contributor to the pathogenesis of the disease. Studies have shown that targeting S1P receptors could be a viable therapeutic strategy for IBD. Monoclonal antibodies directed to S1P have been tested in preclinical models of prostate and kidney cancer, but no studies have been conducted in IBD [207,208,209]. However, S1P receptor modulators have shown promising effects in preclinical studies [210] and are currently being evaluated in clinical trials for inflammatory disorders. These agents work downstream of S1P receptors to limit lymphocyte recruitment to inflammatory areas, reducing immune cell infiltration and mitigating inflammation in the intestine. Recently, it was reported that ozanimod has been in phase II for CD and phase III for UC treatment. Etrasimod is currently in phase II trials for UC, while amiselimod has completed phase II trials for CD [211].
- Therapeutic agents that enhance insulin sensitivity, such as GLP-1, SGLT-2, and PPAR-γ ligands, have shown benefits for IBD patients by improving insulin-sensitized supplies of fuel and building block sources [212]. However, the potential impact of obesity on IBD treatment efficacy is still not well understood. Studies on various autoimmune diseases suggest that obesity can significantly affect therapeutic efficacy, leading to suboptimal treatment outcomes due to rapid clearance and decreased trough concentrations of medications. Therefore, further investigation is needed to better understand the interplay between obesity and IBD treatment outcomes.
- Aryl hydrocarbon receptor (AhR) activation upregulates IL-22 production, which may protect the intestine from inflammation [213]. Vegetables like broccoli and cabbage can stimulate AhR, which is highly expressed in intestinal intraepithelial lymphocytes and may be involved in the protection against luminal attacks [214].
- Formula-defined feed enteral nutrition showed positive results in CD patients, with 40% relapse chances within 6 months [215].
5. Conclusions
- IBD results from the dysregulated immune system and the release of inflammatory mediators and lipotoxicity. Since inflammatory cytokines and lipotoxicity contribute to insulin resistance generation, the patients with IBD and those with metabolic disorders have common characteristics in the context of proinflammatory cytokines and oxidative stress.
- Inhibition of de novo FAS affects intestinal stem cell function and regeneration capacity, so the intake of dietary lipids should be carefully interpreted to understand epithelial tissue repair and regeneration for IBD patients (Figure 6).
- Anti-inflammatory agents and insulin-sensitizing drugs are therapeutically beneficial to patients with IBD due to the inhibition of inflammatory injury, efficient cellular fuel oxidation, and increased tissue regeneration capacity.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
IBD | Inflammatory bowel disease |
Lgr5 | Leucine-rich repeat-containing G-protein coupled receptor 5 |
IEC | Intestinal epithelial cell |
UC | Ulcerative colitis |
CD | Crohn’s disease |
NAFLD | Non-alcoholic fatty liver disease |
MAFLD | Metabolic dysfunction-associated fatty liver disease |
T2D | Type 2 diabetes |
HFD | High-fat diet |
Tslp | Thymic stromal lymphopoietin |
TNF | Tumor necrosis factor |
TRADD | Tumor necrosis factor receptor type 1-associated death domain protein |
TRAF2 | TNF receptor-associated factor 2 |
RIPK1 | Receptor-interacting serine/threonine-protein kinase 1 |
cIAP | Calf intestinal alkaline phosphatase |
IFN | Interferon |
TH17 | T helper 17 cells |
JAK | Janus kinase |
STAT | Signal transducer and activator of transcription proteins |
PI3K | Phosphoinositide 3-kinases |
AKT | Protein kinase B (PKB), also known as Akt |
mTOR | Mammalian target of rapamycin |
RAS | Renin–angiotensin system |
RAF | Rapidly accelerated fibrosarcoma |
MEK | MAPK/ERK kinase |
ERK | Extracellular signal-regulated kinases |
ADAM | A Disintegrin and metalloproteinase domain-containing protein |
SOCS3 | Suppressors of cytokine signaling 3 |
AP-1 | Activator protein 1 |
NLRP3 | NLR family pyrin domain containing 3 |
DSS | Dextran sodium sulfate |
TNBS | 2,4,6-Trinitrobenzene sulfonic acid |
RORγt | RAR-related orphan receptor gamma |
MAPK | Mitogen-activated protein kinases |
NOD | Nucleotide-binding oligomerization domain-containing protein |
TLR2 | Toll-like receptor 2 |
PMNs | Polymorphonuclear leukocyte |
ICAM1 | Intercellular adhesion molecule 1 |
S1Ps | Sphingosine-1-phosphate |
WNT | Wingless-related integration site |
EGF | Epidermal growth factor |
DLL4 | Delta like canonical notch ligand 4 |
PCs | Paneth cells |
Gli1 | Glioma-associated oncogene family zinc finger 1 |
Rspo1 | R-Spondin 1 |
Pdgfra | Platelet derived growth factor receptor alpha |
BMP | Bone morphogenetic protein |
ECM | Extracellular matrix |
YAP | Yes-associated protein |
TAZ | Transcriptional coactivator with PDZ-binding motif |
FAK | Focal adhesion kinase |
CF | Cystic fibrosis |
FAS | Fatty acid synthesis |
2-MAG | 2-Monoacyglycerol |
FFA | Free fatty acids |
PBA | Primary bile acids |
CA | Cholic acid |
CDCA | Chenodeoxycholic acid |
LCA | Lithocholic acid |
DCA | Deoxycholic acid |
SBA | Secondary bile acids |
MAGL | Monoacylglycerol lipase |
MFGM | Milk fat globule membrane |
S1P | Sphingosine-1-phosphate |
GLP-1 | Glucagon-Like Peptide 1 |
SGLT-2 | Sodium-Glucose Cotransporter 2 |
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Drugs | Mechanisms of Action | Doses | References |
---|---|---|---|
Adalimumab | Monoclonal antibody to TNF-α | Subcutaneous injection 5–10 µg/mL leads to reduced TNF-α levels | [185] |
Filgotinib | JAK1 inhibitor | 100 mg O.D. While 200 mg resulted in a primary embolism | [186,187] |
Golimumab | Monoclonal antibody to TNF-α | Initial starting with 200 mg and reduced to 100 mg after 2 weeks, and the dose is maintained by either 50 mg or 100 mg administered at intervals of 4 weeks for UC treatment | [188] |
Infliximab | Monoclonal antibody to TNF-α | Highest blood concentration via intravenous infusion 80–100 µg/mL and not less than 5 µg/in 4–6 weeks | [185] |
Mesalazine (5-ASA) | Anti-inflammatory effect on colonic epithelial cells | 0.5 g and can be increased to 1 g 5-aminosalicylic acid T.I.D. against ulcerative colitis | [189] |
Methotrexate | Inhibition of the enzymes responsible for nucleotide synthesis | 12.5–25 mg/week p.o or i.p. | [190] |
Tofacitinib | JAK1, JAK3 inhibitor | 5 or 10 mg B.I.D. for moderately to severe UC | [191,192,193] |
Vedolizumab | Anti-α4β7 integrin | 300 mg within 2 weeks | [194] |
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Kwon, S.J.; Khan, M.S.; Kim, S.G. Intestinal Inflammation and Regeneration–Interdigitating Processes Controlled by Dietary Lipids in Inflammatory Bowel Disease. Int. J. Mol. Sci. 2024, 25, 1311. https://doi.org/10.3390/ijms25021311
Kwon SJ, Khan MS, Kim SG. Intestinal Inflammation and Regeneration–Interdigitating Processes Controlled by Dietary Lipids in Inflammatory Bowel Disease. International Journal of Molecular Sciences. 2024; 25(2):1311. https://doi.org/10.3390/ijms25021311
Chicago/Turabian StyleKwon, Soon Jae, Muhammad Sohaib Khan, and Sang Geon Kim. 2024. "Intestinal Inflammation and Regeneration–Interdigitating Processes Controlled by Dietary Lipids in Inflammatory Bowel Disease" International Journal of Molecular Sciences 25, no. 2: 1311. https://doi.org/10.3390/ijms25021311