Functional and structural damage of the intestinal mucosal barrier significantly contribute to translocation of gut microbial products into the bloodstream and are largely involved in HIV-1 associated chronic immune activation. This microbial translocation is largely due to a progressive exhaustion of intestinal macrophage phagocytic function, which leads to extracellular accumulation of microbial derived components and results in HIV-1 disease progression. This study aims to better understand whether the modulation of gut microbiota promotes an intestinal immune restoration in people living with HIV (PLWH). Long-term virologically suppressed PLWH underwent blood, colonic, and fecal sampling before (T0) and after 6 months (T6) of oral bacteriotherapy. Age- and gender-matched uninfected controls (UC) were also included. 16S rRNA gene sequencing was applied to all participants' fecal microbiota. Apoptosis machinery, mitochondria, and apical junctional complex (AJC) morphology and physiological functions were analyzed in gut biopsies. At T0, PLWH showed a different pattern of gut microbial flora composition, lower levels of occludin (p = 0.002) and zonulin (p = 0.01), higher claudin-2 levels (p = 0.002), a reduction of mitochondria number (p = 0.002), and diameter (p = 0.002), as well as increased levels of lipopolysaccharide (LPS) (p = 0.018) and cCK18 (p = 0.011), compared to UC. At T6, an increase in size (p = 0.005) and number (p = 0.008) of mitochondria, as well as amelioration in AJC structures (p < 0.0001) were observed. Restoration of bacterial richness (Simpson index) and biodiversity (Shannon index) was observed in all PLWH receiving oral bacteriotherapy (p < 0.05). Increased mitochondria size (p = 0.005) and number (p = 0.008) and amelioration of AJC structure (p < 0.0001) were found at T6 compared to T0. Moreover, increased occludin and zonulin concentration were observed in PLWH intestinal tracts and decreased levels of claudin-2, LPS, and cCK18 were found after oral bacteriotherapy (T0 vs. T6, p < 0.05 for all these measures). Oral bacteriotherapy supplementation might restore the balance of intestinal flora and support the structural and functional recovery of the gut mucosa in antiretroviral therapy treated PLWH.

The crosstalk between gut barrier impairment, mitochondrial dysfunction, and microbiota alterations in people living with hiv / Santinelli, Letizia; Rossi, Giacomo; Gioacchini, Giorgia; Verin, Ranieri; Maddaloni, Luca; Cavallari, Eugenio N; Lombardi, Francesca; Piccirilli, Alessandra; Fiorucci, Stefano; Carino, Adriana; Marchianò, Silvia; Lofaro, Chiara M; Caiazzo, Sara; Ciccozzi, Massimo; Scagnolari, Carolina; Mastroianni, Claudio M; Ceccarelli, Giancarlo; D'Ettorre, Gabriella. - In: JOURNAL OF MEDICAL VIROLOGY. - ISSN 0146-6615. - (2023). [10.1002/jmv.28402]

The crosstalk between gut barrier impairment, mitochondrial dysfunction, and microbiota alterations in people living with hiv

Santinelli, Letizia;Maddaloni, Luca;Cavallari, Eugenio N;Ciccozzi, Massimo;Scagnolari, Carolina;Mastroianni, Claudio M;Ceccarelli, Giancarlo
;
d'Ettorre, Gabriella
2023

Abstract

Functional and structural damage of the intestinal mucosal barrier significantly contribute to translocation of gut microbial products into the bloodstream and are largely involved in HIV-1 associated chronic immune activation. This microbial translocation is largely due to a progressive exhaustion of intestinal macrophage phagocytic function, which leads to extracellular accumulation of microbial derived components and results in HIV-1 disease progression. This study aims to better understand whether the modulation of gut microbiota promotes an intestinal immune restoration in people living with HIV (PLWH). Long-term virologically suppressed PLWH underwent blood, colonic, and fecal sampling before (T0) and after 6 months (T6) of oral bacteriotherapy. Age- and gender-matched uninfected controls (UC) were also included. 16S rRNA gene sequencing was applied to all participants' fecal microbiota. Apoptosis machinery, mitochondria, and apical junctional complex (AJC) morphology and physiological functions were analyzed in gut biopsies. At T0, PLWH showed a different pattern of gut microbial flora composition, lower levels of occludin (p = 0.002) and zonulin (p = 0.01), higher claudin-2 levels (p = 0.002), a reduction of mitochondria number (p = 0.002), and diameter (p = 0.002), as well as increased levels of lipopolysaccharide (LPS) (p = 0.018) and cCK18 (p = 0.011), compared to UC. At T6, an increase in size (p = 0.005) and number (p = 0.008) of mitochondria, as well as amelioration in AJC structures (p < 0.0001) were observed. Restoration of bacterial richness (Simpson index) and biodiversity (Shannon index) was observed in all PLWH receiving oral bacteriotherapy (p < 0.05). Increased mitochondria size (p = 0.005) and number (p = 0.008) and amelioration of AJC structure (p < 0.0001) were found at T6 compared to T0. Moreover, increased occludin and zonulin concentration were observed in PLWH intestinal tracts and decreased levels of claudin-2, LPS, and cCK18 were found after oral bacteriotherapy (T0 vs. T6, p < 0.05 for all these measures). Oral bacteriotherapy supplementation might restore the balance of intestinal flora and support the structural and functional recovery of the gut mucosa in antiretroviral therapy treated PLWH.
2023
apical junctional complex; apoptosis; intestinal damage; microbiota; mitochondria; oral bacteriotherapy; probiotic
01 Pubblicazione su rivista::01a Articolo in rivista
The crosstalk between gut barrier impairment, mitochondrial dysfunction, and microbiota alterations in people living with hiv / Santinelli, Letizia; Rossi, Giacomo; Gioacchini, Giorgia; Verin, Ranieri; Maddaloni, Luca; Cavallari, Eugenio N; Lombardi, Francesca; Piccirilli, Alessandra; Fiorucci, Stefano; Carino, Adriana; Marchianò, Silvia; Lofaro, Chiara M; Caiazzo, Sara; Ciccozzi, Massimo; Scagnolari, Carolina; Mastroianni, Claudio M; Ceccarelli, Giancarlo; D'Ettorre, Gabriella. - In: JOURNAL OF MEDICAL VIROLOGY. - ISSN 0146-6615. - (2023). [10.1002/jmv.28402]
File allegati a questo prodotto
File Dimensione Formato  
Santinelli_postprint_crosstalk_2022.pdf

Open Access dal 15/12/2023

Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: Creative commons
Dimensione 1.74 MB
Formato Adobe PDF
1.74 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1672762
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 5
social impact