The influence of microbiota on ferroptosis in intestinal diseases

Figures & data

Figure 1. The iron cycle and metabolism. Iron is obtained from the diet in the form of heme or nonheme iron and is absorbed by enterocytes while Fe³⁺ is reduced to Fe²⁺ by reductase before being absorbed by the receptor DMT1. Macrophages phagocytose senescent blood cells, degrade heme via heme oxygenase and release free iron. The absorbed iron is then either stored in ferritin, used for the biosynthesis of iron-sulfur clusters, or exported by ferroportin1 with a multi-copper ferroxidase such as ceruloplasmin, which oxidizes Fe²⁺ to Fe³⁺ in the plasma membrane. Iron can also be exported with ferritin by multivesicular bodies. Iron in the blood is bound to transferrin, forming an iron-transferrin complex. This complex is transported to the liver for storage, to bone marrow cells for heme synthesis, and to other tissues for the synthesis of iron-containing enzymes. Cells take up iron through transferrin receptor 1-mediated endocytosis. Fe³⁺ is liberated from transferrin and subsequently reduced to Fe²⁺ by endosomal reductases. Hepcidin, secreted by the liver, either inhibits the degradation of ferroportin1 or directly blocks the channel, allowing iron to accumulate within the cell. DMT1, divalent metal-ion transporter-1.

Table 1. The compositions or metabolites of microbiota affect ferroptosis.

Microbiota	The function to the ferroptosis	Ref.
Lipopolysaccharides	Activation of ACSL4 by up-regulating special protein 1. Regulation of the secretion of serum ferritin. Aggravation of lipid metabolic disorders and ferroptosis in hepatocytes.	^Citation52,Citation53
Glycochenodeoxycholate	Promotion of TFR-ACSL4-mediated ferroptosis	^Citation38
Short-chain fatty acid	Facilitation of mitochondrial Ca2+ and GPX4-dependent ferroptosis. Inhibition of cystine/glutamate transporter system by the upstream molecular RBM3 or FFAR2-AKT-NRF2 axis and FFAR2-mTORC1 axis and c-Fos.	^Citation54–56 ^Citation57–59
	Reduction of the production of ROS, enhancing oxidative phosphorylation and β-oxidation in physiological conditions. Activation of the PGC1α signaling axis to promote mitochondrial biogenesis; Protection of mitochondria.
Indigenous bacteria (metabolites, reuterin and 1,3, diaminopropane)	Suppression of HIF-2α, the master transcription factor of intestinal iron absorption and transportation Increase in the iron storage protein ferritin.	^Citation60
Capsiate	Promotion of Gpx4 expression and restraint of ferroptosis via the overexpression of TRPV1 in intestinal I/R injury.	^Citation61
Urolithins	Increase in mitophagy and mitochondrial function by reducing excessive inflammation.	^Citation62
5-HT and 3-HA	Elimination of radicals to resist ferroptosis	^Citation63
Histamine	Histamine deficiency accelerates myocardial ferroptosis by repressing the activation of STAT3, accompanied by decreased expression of SLC7A11, a major modulator of ferroptosis.	^Citation64
Lactobacillus rhamnosus GG	Regulation of lipid metabolism to inhibit ferroptosis	^Citation24
Aeromonas hydrophila	Increase in the levels of MDA and Fe^2+ in brain tissues and decrease in GSH.	^Citation65
Pseudomonas aeruginosa	Elevation of levels of oxidized AA-phospholipids by expressing pLoxA (its mammalian orthologue is ALOX15).	^Citation66
Mycobacterium tuberculosis	Reduction in levels of GSH and Gpx4, along with increased levels of free iron, mitochondrial superoxide, and lipid peroxidation; alleviation of the disease is suppressed by Ferrostatin-1.	^Citation67
Porphyromonas gingivalis	Increase in ACSL4, Ptgs2, and Ncoa4 expression, while decreasing GPX4 and SLC7A11.	^Citation68
Lactiplantibacillus plantarum	Transformation of unsaturated fatty acids to resist ferroptosis and their derivatives promote antioxidative gene expression.	^Citation69
Escherichia coli	Increase in intracellular iron levels by inhibiting the expression of Ferroportin-1, followed by the induction of the Fenton reaction to release ROS.	^Citation70
Edwardsiella piscicida	Promotion of iron accumulation, mitochondrial dysfunction, and production of ROS	^Citation71

HIF-2α, Hypoxia inducible factor 2α; ACSL4, Acyl-CoA synthetase long-chain family 4; GPX4, glutathione peroxidase 4; RBM3, RNA-binding motif protein 3; FFAR2, Free fatty acid receptor 2; NRF2, Nuclear factor erythroid 2-related factor 2; mTORC1, mTORC1, mammalian target of rapamycin complex 1; TRPV1, transient receptor potential vanilloid 1; I/R, Ischemia-reperfusion; TFR, transferrin receptor; 5-HT, serotonin; STAT3, Signal Transducer and Activator of Transcription 3; SLC7A11, solute carrier family 7 member 11; MDA, Malondialdehyde; GSH, glutathione; AA, arachidonic acid; ALOX15, arachidonate 15-lipoxygenase; Ptgs2, prostaglandin-endoperoxide synthase 2; Ncoa4, Nuclear Receptor Coactivator 4; RBCs, Red blood cells; ROS, reactive oxygen species.

Figure 2. Intestinal microbiota affects iron metabolism. Microorganisms utilize various mechanisms to obtain different forms of iron (Fe³⁺, Fe²⁺, heme iron). Moreover, the microbiota reduces intestinal pH by producing essential amino acids or SCFAs to optimize dietary iron bioavailability, regulates the expression of hepcidin, transforms inorganic iron into organic forms to lower the toxicity of free iron and modulates the ferritin levels. The microbiota also activates the HO-1/CO pathway or NRF2/HO-1 to strengthen phagocytosis and increase macrophage processing of hemoglobin for iron release. SCFAs, Short-chain fatty acids; HO-1, heme oxygenase-1; CO, carbon monoxide; NRF2, Nuclear factor erythroid 2-related factor 2.

Figure 3. Intestinal microbiota affects oxidative stress. The induction of oxidative stress can be attributed to the iron-dependent Fenton reaction, as well as enzymes belonging to the NOX family and mitochondria. Microbes can remove substrates of the Fenton reaction, assimilate Fe²⁺, and decompose H₂O₂ using enzymes synthesized by the bacteria themselves. Microbes can also enhance mitochondrial functions, including oxidative phosphorylation and β-oxidation, under physiological stress or mitochondrial dysfunction by activating the PGC1α signaling pathway. Microbes can increase NOX1 levels and activate the NRF2 pathway, while suppressing histone deacetylase activity to prevent ROS formation. Additionally, SOD in microbes can reduce ROS levels in the host. The level of ROS can also affect the microbes themselves. NOX, nicotinamide adenine dinucleotide phosphate oxidase; H₂O_2, Hydrogen peroxide; PGC1α, peroxisome proliferator-activated receptor-gamma coactivator-1alpha; NRF2, Nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen stress; SOD, superoxide dismutases.

Figure 4. Fatty acid metabolism and intestinal microbiota. Exogenous PUFAs increase sensitivity to ferroptosis and shape the gut microbiota. The gut microbiota influences the balance of PUFAs by regulating lipid synthesis, degradation, and biotransformation. Microbiota can influence the expression of ACSL4, disturbing the esterification of PUFAs or facilitating the transformation of saturated fatty acids or PUFAs-derived intermediate metabolites, thereby influencing sensitivity to oxidation. PUFAs, Short-chain fatty acids; ACSL4, acyl-CoA synthetase long-chain family 4.

Figure 5. Intestinal microbiota affects lipid peroxidation. Different antioxidant systems are effective in preventing lipid peroxidation, including the cysteine/GSH/GPX4 axis, the FSP1-CoQ10 axis, the GCH1-BH4 axis, the thioredoxin system, and the iNOS/NO• system. On the other hand, lipid autoxidation and lipoxygenase can pose dangerous risk factors for inducing lipid peroxidation. Gut microbes can regulate both the antioxidant systems and lipoxygenase, influencing ferroptosis. GSH, glutathione; GPX4, glutathione peroxidase 4; FSP1, ferroptosis suppressor protein 1; CoQ10, Ubiquinone; GCH1, GTP cyclohydrolase-1; BH4, Tetrahydrobiopterin; iNOS, inducible nitric oxide synthase.

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