Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators
Abstract
1. Overview of Inflammatory Bowel Diseases (IBDs)
1.1. Epidemiology and Global Prevalence
1.2. Clinical Manifestations and Disease Course
2. Purpose of this Review: Are the Microbiota and Its Metabolites Key Players in Fibrogenesis in IBDs?
3. The Intestinal Barrier in Health and in IBDs
3.1. Dysbiosis: Alterations in the Intestinal Microbiota
3.2. Impairment of the Mucus Layer
3.3. Epithelial Dysfunction and Increased Permeability: The “Leaky Gut”
3.4. Dysregulation of Mucosal Immunity
4. The Role of Immune Dysregulation in Driving Epithelial-to-Mesenchymal Transition (EMT) and Fibrosis in IBDs
5. Microbial Metabolites: Established Players in Intestinal Homeostasis and IBD Inflammation, with Potential Implications in Fibrosis
5.1. Short-Chain Fatty Acids (SCFAs)
5.2. Lactic Acid (LA)
5.3. Indoles
IAA | IPA | ILA | IS | IC | |
---|---|---|---|---|---|
AhR | Kidney: IPA suppresses the IS effect on the receptor [147]. | Gut: Supplementation with L. acidophilus, or its metabolite ILA, attenuates inflammation and restores IL-22 levels through AhR signaling in mice [142]. Similar results were observed in a mice model of DSS-induced colitis supplemented with two strains of ILA-producing B. bifidum [143]. | Liver: IS is an agonist of the AhR receptor [147]. | Gut: depletion of dietary IC is fatal in AhR IEC-deficient mice and worsens chronic colitis in C57BL/6 mice; in contrast, its administration reduces the Th17/Treg ratio in the same model [145,148]. | |
TGF-β | Peritoneum: the novel IAA analogue MA-35 reduces TGF-β-positive cells in a murine model of peritoneal fibrosis [149]. | Kidney: IPA suppresses the IS effect on the receptor [147]. Liver: IPA aggravates CCl4-induced fibrosis by activating TGF-β1/Smads signaling in HSCs [150]. | Kidney: IS induces fibrosis through the stimulation of TGF-β1 [147]. | ||
Smads | Kidney: the IAA novel analogue, MA-35, inhibits the phosphorylation of Smad3, thus reducing TGF-β1 signaling and related renal fibrosis [151]. | Liver: IPA aggravates CCl4-induced fibrosis by activating TGF-β1/Smads signaling in HSCs [150]. | |||
PPAR-γ | Adipocytes: the administration of I3C restores the levels of PPAR-γ, which were deregulated in mice fed with a high-fat diet [146]. | ||||
ECM | Peritoneum: the treatment with the novel IAA analogue MA-35 reduces α-SMA-positive myofibroblasts in a murine model of peritoneal fibrosis [149]. | Liver: IPA reduces α-SMA and collagen deposition and MMP expression while inducing TIMPs in TGF-β1-stimulated hepatic stellate cells [152]. Liver: IPA aggravates CCl4-induced fibrosis by activating TGF-β1/Smads signaling in HSCs [150]. | Kidney: IS enhances α-SMA expression [147]. | ||
PXR | Gut: IPA reduces PXR-induced fibrosis in a mice model of colitis; IBD patients showed lower levels of PXR and fecal IPA [68]. |
QUERY | (“IBD” OR “Gut”) AND (“TGF-Beta” OR “Smad” OR “PPAR-Gamma” OR “Fibrosis” OR “EMT” OR “Alpha-SMA” OR “MMP” OR “PAI-1” OR “TIMP”) | Title and Abstract Check | |
---|---|---|---|
AND | |||
“butyrate” OR “butyric acid” | 83 | 16 | |
“acetate” OR “acetic acid” | 58 | 4 | |
“propionate” OR “propionic acid” | 41 | 5 | |
“lactic acid” | 27 | 1 | |
“indole-3-acetic acid” | 5 | 1 | |
“indole-3-carbinol” | 2 | 0 | |
“indole-3-lactic acid” | 0 | 0 | |
“indole-3-propionic acid” | 5 | 2 | |
“indoxyl sulfate” | 1 | 0 | |
“urolithin” | 5 | 1 | |
“hydrogen sulfide” | 1 | 0 | |
“trimethylamine” OR “TMAO” OR “trimethylamine-N-oxide” | 52 | 8 | |
Total | 280 | 38 |
5.4. Urolithins (Uros)
5.5. Hydrogen Sulfide (H2S)
5.6. Trimethylamine (TMA) and Trimethylamine-N-Oxide (TMAO)
6. Discussion: Current Knowledge and Therapeutic Perspectives of Microbiota Metabolite Modulation in Intestinal Fibrogenesis
7. Methods
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Phylum | Class | Order | Family | Genus | Species | CD | Ref. | UC | Ref. |
---|---|---|---|---|---|---|---|---|---|
Firmicutes | Clostridia | ↓ | [9] | ↓ | [9] | ||||
Clostridiales | Lachnospiraceae | Roseburia | R. hominis | ↓ | [10] | ||||
R. intestinalis | ↓ | [11] | ↓ | [11] | |||||
Ruminococcus | R. albus | ↓ | [12] | ||||||
R. callidus | ↓ | [12] | |||||||
R. bromii | ↓ | [12] | |||||||
R. gnavus | ↑ | [13] | ↑ | [13] | |||||
R. torques | ↑ | [13] | ↑ | [13] | |||||
Acidaminococcaceae | Dialister | D. invisus | ↓ | [14] | |||||
Eubacteriaceae | Eubacterium | E. rectale | ↓ | [12] | |||||
Clostridiaceae | Clostridium | C. difficile | ↑ | [12] | |||||
C. coccoides | ↓ | [15] | ↓ | [15,16] | |||||
C. leptum | ↓ | [12,15,16] | ↓ | [15] | |||||
Faecalibacterium | F. prausnitzii | ↑ | [17] | ↓ | [10,11,15] | ||||
↓ | [11,12,14,15] | ||||||||
Bacilli | ↑ | [9] | ↑ | [9] | |||||
Bacillales | Listeriaceae | Listeria | ↑ | [12] | |||||
Lactobacillales | Enterococcaceae | Enterococcus | ↑ | [12] | |||||
Lactobacillaceae | Lactobacillus | ↑ ↓ | [12,18] [19] | ↓ | [20] | ||||
Bacteroidetes | Bacteroidetes | ↓ | [9] | ↓ | [9] | ||||
Bacteroidales | Bacteroidaceae | Bacteroides | B. fragilis | ↓ | [11,12] | ↓ | [11] | ||
↑ | [21] | ||||||||
B. vulgatus | ↓ | [11,12] | ↓ | [11] | |||||
↑ | [21] | ||||||||
Actinobacteria | Actinobacteria | ↑ | [9] | ↓ | [22] | ||||
Bifidobacteriales | Bifidobacteriaceae | Bifidobacterium | B. longum | ↑ | [11] | ||||
B. bifidum | ↓ | [22] | |||||||
Proteobacteria | ↑ | [9] | ↑ | [9] | |||||
δ | Desulfovibrionales | Desulfovibrionaceae | Desulfovibrio | ↑ | [23] | ||||
γ | Enterobacteriales | Enterobacteriaceae | Escherichia | ↑ | [11,21] | ||||
Shigella | ↑ | [11] | |||||||
S. flexneri | ↑ | [12] | |||||||
Pseudomonadales | Moraxellaceae | Acinetobacter | A. junii | ↑ | [21] | ||||
Verrucomicrobia | Verrucomicrobiae | ↓ | [13,24] | ↓ | [13,24] | ||||
Verrucomicrobiales | Verrucomicrobiaceae | Akkermansia | A. muciniphila | ↓ | [13,24] | ↓ | [13,24] |
Main Effects on the Parts of the Gut Barrier | |||||||
---|---|---|---|---|---|---|---|
Microbial Metabolites | Precursor | Species Involved in the Metabolism | Microbiota | Mucus | Epithelium | IIS | Ref. |
Short-chain fatty acids (SCFAs)
| Non-digestible dietary fibers, amino acids, and lactate. |
| SCFAs interact with other bacteria such as Lactobacilli and Bifidobacteria, enhancing their growth. | SCFAs stimulate goblet cells and induce the MUC2 gene. | SCFAs are the principal energetic source for colonocytes and contribute to the integrity of the APC. | SCFAs regulate TLR and FFAR activation, the differentiation of Tregs, and IL-10 secretion. | [70,71,72,73] |
Lactic acid (LA) | Fermented foods: carbohydrate fermentation. | “LAB”, Gram-positive catalase-negative bacteria resistant to low pH, mainly belonging to the Lactobacillus genus. | LAB produce bacteriocins, peptides involved in the mucosal defense. | Various strains of LAB differently affect goblet cell functions and the expression of mucus-related genes, MUC2 included. | LA promotes the TCA for energy production, maintains the cellular redox state, stimulates the ACC for fatty acid synthesis, and contributes to normal epithelial proliferation. | LAB administration promotes macrophage M2 polarization and a reduction in pro-inflammatory cytokines (e.g., IL-1β and IL-6) | [74,75,76,77] |
Indoles | Tryptophan, the essential amino acid found in meat, fish, dairy, eggs, nuts, seeds, legumes, and whole grains. | Tryptophanase-expressing bacteria, such as Clostridium, Bacteroides, Lactobacillus, and Bifidobacterium spp. | Indoles influence bacterial communication, limiting virulence gene expression and bacterial invasiveness, in a dose-dependent manner. | Indoles boost MUC2 and MUC4 expression and goblet cell activity. | Indoles reduce the epithelial permeability by enhancing tight junctions. | [78,79,80,81,82] | |
Urolithin A (UA) | Polyphenolic compounds (ellagitannins) in fruits, nuts, and tea. | In the small intestine, ellagitannins are hydrolyzed to ellagic and gallic acid intermediates, and further metabolized by Gordonibacter urolithinfaciens and Ellagibactrer into UA. Only about 40% of elderly humans possess a suitable gut microbiota able to produce UA. | UA and its synthetic analogue, UAS03, have been reported to upregulate tight junction proteins. | UA reduces the production of ROS and suppresses the TLR4, MAPK, and PI3K pathways, with decrease in the expression of pro-inflammatory mi-RNA and cytokines (IL-1β, IL-6, and TNF-α). | [83,84,85] | ||
Hydrogen sulfide (H2S) | Sulfate (SO42−) derived from amino acids (mainly cysteine and methionine), additives, preservatives, and IEC production (CBS activity). | Sulfate-reducing bacteria (SRB), like colonic Desulfovibrio, Desulfotomaculum, and Bilophila, utilize SO42− as a terminal electron acceptor in their metabolic pathways, reducing it to H2S. | Exogenous H2S confers to the bacteria’s high resistance to oxidative stress. | High concentrations of H2S destabilize the disulfide bonds of the mucin-2 network, resulting in increased contact between bacteria and the epithelium. | H2S is the primary mineral energy substrate for colonocytes, but in high concentrations, it inhibits the mitochondrial respiratory chain. Also, it negatively interferes with butyrate metabolism. | [86,87,88,89,90,91,92] | |
Trimethylamine (TMA) | Choline, carnitine, and betaine, contained in red meat, eggs, fish, and dairy. | Several bacterial species (e.g., E. coli, Enterococcus, Clostridium, Proteus, Shigella, Klebsiella, and Providentia spp.) transform the precursors in TMA, which is further oxidized in the liver to form TMAO. | TMA and TMAO modulate the composition of the microbiota. | [93,94] |
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Cicchinelli, S.; Gemma, S.; Pignataro, G.; Piccioni, A.; Ojetti, V.; Gasbarrini, A.; Franceschi, F.; Candelli, M. Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators. Pharmaceuticals 2024, 17, 490. https://doi.org/10.3390/ph17040490
Cicchinelli S, Gemma S, Pignataro G, Piccioni A, Ojetti V, Gasbarrini A, Franceschi F, Candelli M. Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators. Pharmaceuticals. 2024; 17(4):490. https://doi.org/10.3390/ph17040490
Chicago/Turabian StyleCicchinelli, Sara, Stefania Gemma, Giulia Pignataro, Andrea Piccioni, Veronica Ojetti, Antonio Gasbarrini, Francesco Franceschi, and Marcello Candelli. 2024. "Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators" Pharmaceuticals 17, no. 4: 490. https://doi.org/10.3390/ph17040490
APA StyleCicchinelli, S., Gemma, S., Pignataro, G., Piccioni, A., Ojetti, V., Gasbarrini, A., Franceschi, F., & Candelli, M. (2024). Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators. Pharmaceuticals, 17(4), 490. https://doi.org/10.3390/ph17040490