The gut microbiota metabolite trimethylamine-N-oxide in children with β-thalassemia: potential implication for iron-induced renal tubular dysfunction

Asmaa A Ghalwash; Rehab M El-Gohary; Doaa El Amrousy; Lamia M Morad; Shaima S Kassem; Islam Ibrahim Hegab; Asmaa H Okasha

doi:10.1038/s41390-024-03639-w

The gut microbiota metabolite trimethylamine-N-oxide in children with β-thalassemia: potential implication for iron-induced renal tubular dysfunction

Pediatr Res. 2024 Oct 25. doi: 10.1038/s41390-024-03639-w. Online ahead of print.

Authors

Asmaa A Ghalwash¹, Rehab M El-Gohary¹, Doaa El Amrousy², Lamia M Morad³, Shaima S Kassem⁴, Islam Ibrahim Hegab⁵, Asmaa H Okasha¹

Affiliations

¹ Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
² Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt. [email protected].
³ Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
⁴ Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
⁵ Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.

PMID: 39448817
DOI: 10.1038/s41390-024-03639-w

Abstract

Background: Renal tubular dysfunction is common in transfusion-dependent β thalassemia (β-TM). Iron overload, chronic anemia, and hypoxia are precipitating factors for renal insult. However, gut microbiota engagement in the renal insult has not been explored. Our work aimed to assess the potential link between iron overload, gut leakage/dysbiosis, and kidney dysfunction in these children.

Methods: We enrolled 40 children with β-TM and 40 healthy controls. Gut leakage/dysbiosis biomarkers (trimethylamine-N-oxide [TMAO] and fecal short-chain fatty acids [SCFAs]), oxidative stress and inflammatory biomarkers, TMAO-regulated proteins such as serum sirtuin 1 (S.SIRT1) and serum high mobility box group-1 (S.HMGB1), and tubular dysfunction biomarkers were assessed. Correlations and regression analysis were performed to assess the relation between different parameters.

Results: Iron overload, redox imbalance, and generalized inflammation were evident in children with β-TM. Renal tubular dysfunction biomarkers and S.TMAO were significantly elevated in the patient group. Furthermore, fecal SCFAs were significantly lower with upregulation of the investigated genes in the patient group. The correlation studies affirmed the close relationship between circulating ferritin, TMAO, and renal dysfunction and strongly implicated SIRT1/HMGB1 axis in TMAO action.

Conclusions: Gut dysbiosis may have a role in the pathogenesis of renal injury in children with β-TM.

Impact: Renal tubular dysfunction is a prominent health issue in β thalassemia major (β-TM). Iron overload, chronic anemia, and hypoxia are known precipitating factors. However, gut microbiota engagement in renal insult in these patients has not yet been explored. We aimed to assess potential link between iron overload, gut leakage/dysbiosis, and kidney dysfunction in β-TM children and to highlight the SIRT1/HMGB1 axis, a signal motivated by the gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO), involvement in such insults. We found that gut leakage/dysbiosis may have a role in kidney dysfunction in β-TM children by exacerbating the iron-motivated oxidative stress, inflammation, ferroptosis, and modulating SIRT1/HMGB1 axis.