Short-Chain Fatty Acids and Human Health: From Metabolic Pathways to Current Therapeutic Implications
Abstract
:1. Introduction
2. Methods
2.1. Literature Search Strategy
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction and Analysis
2.4. Quality Assessment
3. Results
3.1. Production of SCFAs in the Gastrointestinal Tract
3.1.1. Cross-Feeding and Production of SCFAs in the Human Intestine
3.1.2. Production of Acetate by the Intestinal Microbiota
3.1.3. Production of Propionate by the Intestinal Microbiota
3.1.4. Production of Butyrate by the Intestinal Microbiota
3.1.5. Cross-Feeding Lays the Basis of Butyrate Production by Intestinal Microbiota
3.2. Absorption of SCFAs in the Intestine and SCFAs Supplements
3.2.1. Absorption of Butyrate
3.2.2. Butyrate Supplements
3.2.3. Absorption of Propionate
3.2.4. Propionate Supplements
3.2.5. Absorption of Acetate
3.2.6. Acetate Supplements
4. Implications of SCFAs in Human Gastrointestinal and Metabolic Health
4.1. Gastrointestinal Diseases
4.1.1. Inflammatory Bowel Disease
4.1.2. Colorectal Cancer
4.1.3. Disorders of the Gut-Brain Axis
4.2. Metabolic Diseases
4.2.1. Obesity
4.2.2. Type 2 Diabetes
4.2.3. Metabolic Dysfunction–Associated Steatotic Liver Disease
4.3. Therapeutic Implications
4.3.1. Fecal Microbiota Transplantation
4.3.2. Dietary Intervention
4.3.3. Prebiotic and Probiotic Applications
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AMPK | 5’ Adenosine Monophosphate-Activated Protein Kinase |
AOM | Azoxymethane |
APP | Amyloid Precursor Protein, Precursor Protein 695 |
Aβ | Amyloid Β |
BAD | Bile Acid Diarrhea |
BAT | Brown Adipose Tissue |
BCoAT | Butyryl-Coa:Acetate Coatransferase |
BCRP | Breast Cancer Resistance Protein |
C2 | Acetate |
C3 | Propionate |
C4 | Butyrate |
CaBu | Calcium Butyrate |
CD | Crohn’s Disease |
CRC | Colorectal Cancer |
DGBI | Disorder Of Gut-Brain Interaction |
DSS | Dextran Sodium Sulfate |
F. prausnitzii | Faecalibacterium prausnitzii |
FAD | Familial Alzheimer’s Disease |
FAP | Familial Adenomatous Polyposis |
FGF | Fibroblast Growth Factor |
FMT | Fecal Microbiota Transplantation |
FOS | Fructooligosaccharides |
FXR | Farnesoid X Receptor |
GLP-1/2 | Glucagon-Like Peptide-1/2 |
GLUT4 | Glucose Transporter Type 4 |
GOS | Galactooligosaccharides |
GPCRs = GPR41-GPR43-109a | G-Protein-Coupled-Receptors 41-43-109a |
Gpr43(−/−) | GPR43-Deficient |
HbA1c | Glycated Hemoglobin |
HDACs | Histone Deacetylases |
HFD | High-Fat Diet |
HOMA-IR | Homeostatic Model Assessment Of Insulin Resistance |
IBD | Inflammatory Bowel Diseases |
IBS, IBS-C, IBS-D, IBS-M | Irritable Bowel Syndrome, Constipation, Diarrhea, Mixed Stool |
IGN | Intestinal Gluconeogenesis |
IL-6,10,17,18 | (Cytokine) Interleukine-6-10-17-18 |
LPS | Lipopolysaccharides |
MAFLD | Metabolic-Associated Fatty Liver Disease |
MASLD | Metabolic-Dysfunction Associated Steatotic Liver Disease |
MCT1-4 | Monocarboxylate Transporters 1-4 |
MPTP | 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine |
MS | Multiple Sclerosis |
MSI-h | Microsatellite Instability-High |
MYD88/NF-κB | TLR4/Myeloid Differentiation Primary Response 88 |
NaBu | Sodium Butyrate |
NAFLD | Non-Alcoholic Fatty Liver Disease |
NF-κB | Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells |
Ngn3 | Neurogenin-3 |
NLRP3 | Nod-Like Receptor Family Pyrin Domain Containing 3 |
NOD | Nonobese Diabetic |
PD | Parkinson’s Disease |
PGC-1α | Peroxisome Coactivator-1 Alpha |
PKM2 | Pyruvate Kinase Muscle Isozyme 2 |
PPARγ | Peroxisome Proliferator-Activated Receptor-γ |
PSC | Primary Sclerosing Cholangitis |
PSEN1 | Presenilin-1 |
PYY | Peptide YY |
rCDI | Recurrent Clostridioides Difficile Infection |
RCT | Randomized Controlled Trial |
SCFAs | Short-Chain Fatty Acids |
SLAB51 | A Mixture Of Lactic Acid Bacteria And Bifidobacteria |
SMCT1 | Sodium-Coupled Monocarboxylate Transporter 1 |
SRY | Sex Determining Region Y |
SRY Sox2 | (Sex Determining Region Y)-Box 2 |
T1/2D | Type 1/2 Diabetes |
T2DM | Type 2 Diabetes Mellitus |
Th1- Th17 | T-Helper 1 Cells- T-Helper 17 Cells |
TLRs- TLR4- TLR2 | Toll-Like Receptors-4-2 |
TNF-α | Tumor Necrosis Factor-Alpha |
Treg | Regulatory T Cells |
UC | Ulcerative Colitis |
ZO-1 | Zonula Occludens-1 |
5XFAD | Transgenic Mice Overexpress Mutant Human Amyloid Beta |
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SCFAs | Metabolic Pathway | Bacteria Involved in the Production |
---|---|---|
Acetate | Acetogenesis | Acetobacterium, Acetoanaerobium, Acetogenium, Butyrbacterium, Clostridium, Eubacterium, Pelobacter |
Carbon fixation | Bacteroides succinogenes, Clostridium butyricum, Syntrophomonas sp. | |
Propionate | Succinate | Firmicutes (Negativicutes) and Bacteroidetes |
Propanediol | Lachnospiraceae (Roseburia inulinivorans, Balutia sp.) | |
Butyrate | Butyryl-CoA: acetate-CoA transferase | Eubacterium, Roseburia, Anaerostipes, Faecalibacterium prausnitzii |
Butyrate kinase | Coprococcus and Clostridium specific spp. |
Ref. | Delivery | Year | Groups (n) | Design | Duration | Dosage Butyrate | Drugs (ad) | Improvement |
---|---|---|---|---|---|---|---|---|
[66] | enema | 1991 | DC (13) | DB | 2 w | 40 mmol/L | nr | ns |
[67] | enema | 1992 | UC (10) | SB crossover | 2 w | 100 mmol/L | A-S | s |
[68] | enema | 1994 | UC (10) | open label | 6 w | 80 mmol/L | A-S | 60% |
[69] | enema | 1995 | UC (40) | DB-RCT | 6 w | 200 mL/d mix | A-S | s |
[70] | enema | 1996 | UC (38) | RCT | 6 w | 80 mmol/d | A/S | not impr. |
[71] | enema | 1996 | UC (47) | DB-RCT | 6 w | 80 mmol/d | nr | not impr. |
[72] | enema | 1999 | CRP (17) | DB-RCT | 5 w | 80 mmol/d | nr | s |
[73] | enema | 2000 | UC (30) | RCT | 6 w | 4 gr/d | A | ns |
[74] | enema | 2000 | APR (20) | RCT crossover | 3 w | 80 mmol/L | nr | s |
[75] | enema | 2002 | UC (11) | RCT | 8 w | 100 mM | A/S/steroid | s |
[76] | enema | 2003 | UC (51) | DB-RCT | 6 w | 80 mmol/L | M/steroid | S |
[77] | oral | 2005 | CD (13) | open label | 8 w | 4 gr/d | A/S | 69% |
[78] | oral | 2008 | UC (216) | open label | 24 w | 921 mg/d | A + S | 82.4% |
[79] | enema | 2009 | IBS (11) | DB-RCT | 1 w | 50/100 mmol/L/d | nr | s |
[80] | enema | 2010 | UC (35) | DB-RCT crossover | 20 d | 100 mmol/d | nr | s |
[81] | oral | 2013 | IBS (66) | RCT | 12 w | 300 mg/d | std | s |
[82] | oral | 2014 | DC (63) | RCT | 12 month | 300 mg/d | nr | s |
[83] | oral | 2014 | TD (42) | RCT | 3 d + trip | 1500 mg/d | various | s |
[84] | enema | 2014 | APR (166) | RCT | 3 w | 1–2–4 gr/d | nr | ns |
[85] | enema | 2016 | Mix (20) | DB-RCT | 4 w | 600 mmol/L | nr | s |
[86] | oral | 2017 | DM (40) | DB-RCT | 45 d | 600 mg/d | +inulin | s(+ inulin) |
[87] | oral | 2020 | UC (39) | Prospective | 12 months | 1 g/d | std | s |
[64] | oral | 2020 | IBD (49) | DB-RCT | 8 w | 600 mg/d | std | ps |
[88] | oral | 2020 | DT1 (30) | DB-RCT | 4 w | 4 g/d | nr | ns |
[89] | oral | 2022 | Ob ped (54) | QB-RCT | 13 months | 20 mg/kg | std | s |
[90] | oral | 2022 | IBD ped (80) | RCT | 12 w | 150 mg/d | std | ns |
[91] | oral | 2022 | DT2 (42) | TB-RCT | 6 w | 600 mg/d | nr | s |
[92] | oral | 2024 | COPD (121) | RCT | 12 w | 300 mg/d | nr | s |
Ref. | Delivery | Year | Groups (n) | Design | Duration | Dosage Propionate | Formula | Improvement |
---|---|---|---|---|---|---|---|---|
[102] | oral | 2015 | Obese (60) | DB-RCT | 24 w | 10 g/d | IPE | s |
[103] | oral | 2019 | Obese (12) | DB-RCT cross over | 42 d | 20 g/d | IPE | s |
[104] | oral | 2019 | HovF (20) | RCT | 4 w | 10 g/d | IPE | s |
[101] | oral | 2020 | MS (36)/Healthy (68) | proof-of-concept | 2 w | 1 g/d | NaP | s |
[105] | oral | 2022 | ACVD (62) | DB-RCT | 8 w | 1 g/d | propionic acid | s |
Name of Trial | Type | Identifier/Status | Condition | Intervention | Location |
---|---|---|---|---|---|
Combination of Medium Cut-off Dialyzer Membrane and Diet Modification to Alleviate Residual Uremic Syndrome of Dialysis Patients | RCT | NCT04247867/recruiting | Uremic syndrome | Psyllium-inulin/sodium propionate | University medical Centre Ljubljana, Ljubljana, Slovenia |
The Effect of Combining Medium Cut-Off Dialysis Membrane and Diet Modification on Reducing Inflammation Response | RCT | NCT04260412/recruiting | Uremic syndrome | Psyllium-inulin/sodium propionate | University medical Centre Ljubljana, Ljubljana, Slovenia |
Ref. | Delivery | Year | Groups (n) | Design | Duration | Dosage Propionate | Formula | Improvement |
---|---|---|---|---|---|---|---|---|
[111] | Rectally and intravenous | 2010 | HinsF (6) | open label | 4 times | 60 mmol/L rectal + 20 mmon/Lintravenous | NaAcetate | s |
[112] | Intravenous | 2012 | Overweight normoglycemic and hyperglycemic subjects (9) | open label | 90 | 140 mmol/L | NaAcetate | no |
[113] | Proximal and distal colonic | 2016 | Obese (6) | DB-RCT crossover | 3 d | 100–180 mmol/L | Acetate | s |
[114] | Colonic infusions | 2017 | Obese (12) | DB-RCT crossover | 4 d | 200 mmol/L mix | (acetate, propionate, and butyrate) | s |
Disease | Supposed Mechanisms of SCFAs Protection/Risk |
---|---|
Inflammatory Bowel Disease | 1. Anti-inflammatory effects: Butyrate, a primary energy source for colonocytes, inhibits NF-κB activation, reducing proinflammatory gene expression. |
2. Maintenance of gut barrier integrity: SCFAs promote mucus production and tighten epithelial cell junctions, enhancing the intestinal epithelial barrier. | |
3. Modulation of immune responses: SCFAs influence the differentiation and function of regulatory T cells (Tregs), suppressing excessive immune reactions. They engage with receptors like GPR43 and GPR109A to stimulate Treg production. | |
4. Tissue repair and healing: SCFAs promote the proliferation and differentiation of epithelial cells, facilitating tissue repair processes within the gut damaged by inflammation in IBD. | |
Colon Cancer | 1. Protective effects against CRC development: SCFAs exert protective effects against colorectal cancer by regulating gene expression, promoting apoptosis, and inhibiting CRC cell proliferation and metabolism. |
2. Anti-inflammatory actions: SCFAs mitigate inflammation in CRC by inhibiting NF-κB activation, decreasing pro-inflammatory cytokine expression, and promoting anti-inflammatory cytokines and regulatory T-cell differentiation. | |
3. Potential DNA damage modulation: While SCFAs are anticipated to decrease DNA damage in CRC cells, reports suggest they may exacerbate DNA damage accumulation in some instances, possibly due to disruptions in DNA repair mechanisms. Further evidence is needed. | |
Disorders of the Gut-Brain Axis | 1. Neuroprotective effects: SCFAs exert neuroprotective effects by influencing brain function, regulating blood flow, and modulating neuroinflammation via interactions with specific receptors and epigenetic modulation. |
2. Role in neurodegenerative diseases: Reduced SCFAs levels are implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s. They contribute to intestinal barrier impairment, the release of pro-inflammatory molecules, and microglial activation, ultimately impacting disease progression. | |
3. Gut barrier function and motility: SCFAs promote mucus secretion and strengthen intestinal tight junctions, improving barrier integrity. SCFAs can influence nerve activity, neurotransmitters, and muscle contractions. |
Disease | Proposed Mechanisms of SCFAs Protection/Risk |
---|---|
Obesity | 1. Appetite Regulation: SCFAs can stimulate the release of Peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from gut endocrine cells. These hormones act centrally in the hypothalamus to signal satiety and decrease appetite. |
2. Fat Storage and Metabolism: Increased SCFAs-mediated adipocyte activity might favor fat storage in subcutaneous adipose tissue. SCFAs might enhance brown adipose tissue (BAT) activity, promoting thermogenesis and potentially increasing energy expenditure. | |
3. Metabolic effects: SCFAs activate GPR41 and GPR43 receptors on fat and immune cells, potentially influencing insulin sensitivity, fat metabolism, inflammation, and, thus, weight regulation. | |
Type 2 Diabetes | 1. Effects on glucose metabolism: SCFAs act as secretagogues for hormones such as GLP-1 and PYY, which enhance satiety and decrease appetite. GLP-1 enhances insulin secretion from the pancreas and reduces glucagon secretion, lowering blood sugar levels. In the liver, SCFAs inhibit glycolysis and gluconeogenesis, promoting glycogen synthesis and fatty acid oxidation. In skeletal muscle and adipose tissue, they improve glucose uptake and glycogen synthesis. |
2. Role in intestinal gluconeogenesis (IGN): SCFAs promote IGN production, which is crucial for glucose and energy homeostasis. | |
3. Gut Health: SCFAs promote a healthy gut environment, which may be linked to a lower risk of developing diabetes. | |
Metabolic Dysfunction–Associated Steatotic Liver Disease | 1. Improved Insulin Sensitivity: SCFAs can activate GPR43 on adipocytes and hepatocytes. GPR43 activation can stimulate insulin signaling pathways, leading to increased glucose uptake by these cells and potentially improving overall insulin sensitivity. SCFAs might also suppress gluconeogenesis in the liver. |
2. Anti-inflammatory Effects: SCFAs can modulate the activity of immune cells like macrophages in the liver. They might suppress pro-inflammatory cytokine production (e.g., TNF-α, IL-6) and promote the activity of regulatory T cells, creating an anti-inflammatory environment. SCFAs inhibit the NF-κB signaling pathway, a key player in inflammatory responses. | |
3. Gut-Liver Axis: SCFAs might also influence Fibroblast Growth Factor (FGF) signaling pathways in the gut-liver axis, potentially impacting bile acid metabolism and hepatocyte function. SCFAs might stimulate the enterohepatic circulation of bile acids. SCFAs-mediated bile acid signaling can activate FXR, a nuclear receptor in the liver, potentially influencing hepatic lipid metabolism and reducing steatosis. |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Facchin, S.; Bertin, L.; Bonazzi, E.; Lorenzon, G.; De Barba, C.; Barberio, B.; Zingone, F.; Maniero, D.; Scarpa, M.; Ruffolo, C.; et al. Short-Chain Fatty Acids and Human Health: From Metabolic Pathways to Current Therapeutic Implications. Life 2024, 14, 559. https://doi.org/10.3390/life14050559
Facchin S, Bertin L, Bonazzi E, Lorenzon G, De Barba C, Barberio B, Zingone F, Maniero D, Scarpa M, Ruffolo C, et al. Short-Chain Fatty Acids and Human Health: From Metabolic Pathways to Current Therapeutic Implications. Life. 2024; 14(5):559. https://doi.org/10.3390/life14050559
Chicago/Turabian StyleFacchin, Sonia, Luisa Bertin, Erica Bonazzi, Greta Lorenzon, Caterina De Barba, Brigida Barberio, Fabiana Zingone, Daria Maniero, Marco Scarpa, Cesare Ruffolo, and et al. 2024. "Short-Chain Fatty Acids and Human Health: From Metabolic Pathways to Current Therapeutic Implications" Life 14, no. 5: 559. https://doi.org/10.3390/life14050559