The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV
Abstract
1. Introduction
2. Gut Microbiota Alterations in People Living with HIV
3. Metabolomic Alterations in HIV Infection and Type 2 Diabetes Associated with Intestinal Microbiota Dysbiosis
3.1. Metabolites Derived from Tryptophan Catabolism
3.1.1. Kynurenine Pathway (Trp-KYN)
3.1.2. Indole Pathway
3.2. Serotonin and γ-Aminobutyric Acid
3.3. Short-Chain Fatty Acids
3.4. Branched-Chain Amino Acids
3.5. Bile Acids
3.6. Trimethylamine N-Oxide
3.7. Imidazole Propionate
3.8. Therapeutic and Diagnostic Opportunities
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
HIV | Human immunodeficiency virus |
AIDS | Acquired immunodeficiency syndrome |
PLWHIV | People living with HIV |
ART | Antiretroviral therapy |
T2D | Type 2 diabetes |
GM | Gut microbiota |
GALT | Gut-associated lymphoid tissue |
LPS | Lipopolysaccharides |
Trp-KYN | Kynurenine pathway |
TDO | Tryptophan 2,3-dioxygenase |
IDO | Indoleamine 2,3-dioxygenase |
KYN | Kynurenine |
KYNA | Kynurenic acid |
AA | Anthranilic acid |
3-HK | 3-hydroxykynurenine |
QUIN | Quinolinic acid |
TNF-α | Tumor Necrosis Factor alpha |
IL-1β | Interleukin 1 beta |
IR | Insulin resistance |
IAA | Indole-3-acetic acid |
IAld | Indole-3-aldehyde |
IPA | Indole-3-propionic acid |
IAAld | Indole-3-acetaldehyde |
AhR | Aryl hydrocarbon receptor |
PXR | Pregnane X receptor |
TFF3 | Trefoil factor family 3 |
RELMβ | Resistin-like molecule beta |
5-HT | 5-hydroxytryptamine |
HOMA-IR | Homeostatic model assessment of insulin resistance |
GLP-1 | Glucagon-like peptide-1 |
GABA | γ-Aminobutyric acid |
PI3K/AKT | Phosphoinositide 3-kinase/protein kinase B |
IRS1 | insulin receptor substrate 1 |
GLUT4 | Glucose transporter type 4 |
IFN-γ | Interferon gamma |
SCFAs | Short-chain fatty acids |
GPCRs | G protein-coupled receptors |
FFAR | Free fatty acid receptor |
ERK1/2 | Extracellular signal-regulated kinases 1 and 2 |
cAMP | Cyclic adenosine monophosphate |
PYY | Peptide YY |
AMPK | AMP-activated protein kinase |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PPARs | Peroxisome proliferator-activated receptors |
ATGL | Adipose triglyceride lipase |
UCPs | Uncoupling proteins |
PWT2D | People with type 2 diabetes |
BCAAs | Branched-chain amino acids |
BCAT2 | Branched-chain aminotransferase 2 |
mTORC1 | Mechanistic target of rapamycin complex 1 |
BAs | Bile acids |
CA | Cholic acid |
CDCA | Chenodeoxycholic acid |
DCA | Deoxycholic acid |
LCA | Lithocholic acid |
TGR5 | Takeda G-protein-coupled receptor 5 |
ZO-1 | Zonula Occludens-1 |
TMA | Trimethylamine |
FMO3 | Flavin-containing monooxygenase 3 enzyme |
TMAO | Trimethylamine N-oxide |
PERK | PKR-like Endoplasmic Reticulum Kinase |
MCP-1 | Monocyte chemoattractant protein-1 |
TGF-β1 | Transforming growth factor beta 1 |
α-SMA | Alpha-smooth muscle actin |
NLRP3 | NOD-like receptor family pyrin domain-containing 3 |
ImP | Imidazole propionate |
MAPK | Mitogen-activated protein kinase |
S6K1 | Ribosomal protein S6 kinase beta-1 |
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Metabolites | Main Microbial Sources | Key Metabolic Pathways | Relevance in HIV | Relevance in T2D |
---|---|---|---|---|
Kynurenine pathway-derived metabolites | Pseudomonas, Xanthomonas, Burkholderia, Stenotrophomonas, and Shewanella, and members of the genus Bacillus | Multiple pathways promoting oxidative stress, chronic immune activation, and inflammation | Associated with disease progression, CD4+ T cell depletion, and systemic immune dysfunction. An imbalance between Th17 and Treg cells exacerbates immunosuppression and intestinal epithelial damage | Linked to increased IR through chronic low-grade inflammation, oxidative stress, and decreased tryptophan availability for the synthesis of protective metabolites |
Indole Pathway-derived metabolites | Roseburia, Eubacterium, Lachnospira, Coprobacter Peptostreptococcus russellii, Lactobacillus spp., Clostridium sporogenes, and Clostridium paraputrificum | Acts on AhR and PXR receptors, modulating immune functions, intestinal barrier integrity, and cytokine production | Reduced production is associated with decreased IL-12, impaired intestinal epithelial barrier integrity, and dysbiosis | Protective metabolite associated with lower fasting glucose, enhanced insulin secretion, and improved insulin sensitivity. Levels are reduced in T2D |
Serotonin | Streptococcus, Escherichia, Enterococcus, Hafnia alvei, Klebsiella pneumoniae, Lactobacillus plantarum, Morganella morganii, Akkermansia, Alistipes, and Roseburia | - Serotonylation of specific GTPases enhances GLUT4 translocation, increases insulin secretion, and inhibits glucagon release | An imbalance of GM significantly affects serotonin production | Results are contradictory |
- Can induce hyperglycemia through adrenaline release and alter glycogen synthesis | ||||
GABA | Escherichia coli, Listeria monocytogenes, Bifidobacterium spp., Bacteroides spp., and lactic acid bacteria like Lactobacillus, Lactococcus, and Streptococcus | Acts on specific type A receptors, modulating glucose-induced insulin secretion. Activates the PI3K/AKT pathway, enhancing IRS1 and GLUT4 expression | Exhibits anti-inflammatory effects. HIV is associated with reduced abundance of GABA-producing intestinal bacteria | Increase insulin sensitivity and secretion. Reduces hepatic glucose production and lipid accumulation |
SCFAs | Faecalibacterium, Roseburia, Coprococcus, and Eubacterium | Activates GPCRs, inhibits HDAC2, stimulates PPAR activity for fatty acid oxidation, and modulates key metabolic regulators (ATGL, UCPs) | Significant decrease in SCFA-producing bacteria, which may compromise intestinal barrier function and contribute to microbial translocation and chronic immune activation characteristic of the infection | Enhances intestinal barrier and hormone secretion (GLP-1, PYY, leptin), improves insulin sensitivity, glucose uptake, and lipid metabolism, and preserves β-cell mass |
BCAAs | Prevotella copri, Bacteroides vulgatus, and Clostridium sporogenes | Incomplete catabolism of BCAAs leads to the accumulation of intermediate metabolites such as α-ketoisocaproic acid. BCAAs can continuously activate the mTORC1 cellular pathway, which negatively affects the function of IRS1 | Strong and relevant association with intestinal dysbiosis and IR, suggesting a significant impact on metabolic pathophysiology and chronic inflammation in the context of HIV | Elevated BCAAs are associated with IR, impaired glucose uptake, and lipotoxicity. Accumulation of catabolic intermediates disrupts insulin signaling. Gut bacteria modulate circulating BCAA levels, influencing T2D risk |
Bile Acids (Primary and Secondary) | Lactobacillus, Bifidobacterium, Staphylococcus, Clostridium perfringens and members of the Lachnospiraceae y Ruminococcaceae | FXR/TGR5 activation: improves glucose metabolism, insulin sensitivity, appetite regulation, and thermogenesis; DCA cytotoxic at high levels; LCA protective | Elevated concentrations of primary and secondary BAs in PLWHIV with chronic hepatitis C virus coinfection and a history of depression, related to significant alterations in intestinal microbiota composition. Much remains to be investigated | Trend toward higher total BA concentrations. Many results are contradictory |
TMAO | Anaerococcus hydrogenalis, Clostridium asparagiforme, Clostridium hathewayi, Clostridium sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri and Salmonella enterica | Activates PERK pathway; promotes hyperglycemia and IR; increases adipose inflammation (↑ MCP-1, ↓ IL-10); stimulates hepatic gluconeogenesis; implicated in renal fibrosis and NLRP3 inflammasome activation | Many studies have reported higher TMAO levels, especially associated with ART, but this has not been consistent in other research | TMAO has been widely studied for its potential role in the development and progression of disease. Elevated levels of this metabolite have been associated with IR, impaired glucose tolerance, and increased systemic inflammation |
ImP | Clostridium baumannii, Clostridium parasymbiotics, Ruminococcus gnavus, and Veillonella | Activates MAPK p38γ, which triggers phosphorylation of the p62 protein, abnormally activating the mTORC1 pathway and inducing defective phosphorylation of IRS, promoting its degradation and thus favoring the development of IR | In PLWHIV, ImP has gained attention as a potential indicator of dysbiosis and cardiovascular risk. Several studies report consistent findings linking this metabolite to intestinal dysbiosis in HIV | Positive correlations have been reported between ImP levels, systemic inflammatory markers, and IR in people with T2D |
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Díaz-Rodríguez, Y.L.; Anaya-Ambriz, E.J.; Méndez-Ríos, P.C.; Andrade-Villanueva, J.F.; González-Hernández, L.A.; Holguín-Aguirre, T.E.; Martínez-Ayala, P.; Ruiz-Herrera, V.V.; Alvarez-Zavala, M.; Sánchez-Reyes, K. The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV. Metabolites 2025, 15, 627. https://doi.org/10.3390/metabo15090627
Díaz-Rodríguez YL, Anaya-Ambriz EJ, Méndez-Ríos PC, Andrade-Villanueva JF, González-Hernández LA, Holguín-Aguirre TE, Martínez-Ayala P, Ruiz-Herrera VV, Alvarez-Zavala M, Sánchez-Reyes K. The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV. Metabolites. 2025; 15(9):627. https://doi.org/10.3390/metabo15090627
Chicago/Turabian StyleDíaz-Rodríguez, Yusnier Lázaro, Elsa Janneth Anaya-Ambriz, Paula Catalina Méndez-Ríos, Jaime F. Andrade-Villanueva, Luz A. González-Hernández, Tania Elisa Holguín-Aguirre, Pedro Martínez-Ayala, Vida V. Ruiz-Herrera, Monserrat Alvarez-Zavala, and Karina Sánchez-Reyes. 2025. "The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV" Metabolites 15, no. 9: 627. https://doi.org/10.3390/metabo15090627
APA StyleDíaz-Rodríguez, Y. L., Anaya-Ambriz, E. J., Méndez-Ríos, P. C., Andrade-Villanueva, J. F., González-Hernández, L. A., Holguín-Aguirre, T. E., Martínez-Ayala, P., Ruiz-Herrera, V. V., Alvarez-Zavala, M., & Sánchez-Reyes, K. (2025). The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV. Metabolites, 15(9), 627. https://doi.org/10.3390/metabo15090627