Impact of Human Immunodeficiency Virus–Related Gut Microbiota Alterations on Metabolic Comorbid Conditions

Gelpi, Marco; Vestad, Beate; Hansen, Simen Hyll; Holm, Kristian; Drivsholm, Ninna; Goetz, Alexandra; Kirkby, Nikolai; Lindegaard, Birgitte; Lebech, Anne‐Mette; Hoel, Hedda; Michelsen, Annika; Ueland, Thor; Gerstoft, Jan; Lundgren, Jens D; Hov, Johannes Espolin Roksund; Nielsen, Susanne Dam; Trøseid, Marius

doi:10.1093/cid/ciz1235

Cited by 46 publications

(57 citation statements)

References 34 publications

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“…A previous report from our group demonstrated a polymicrobic flora in the blood of HIV-infected subjects with inadequate immune recovery on cART (30), raising the question of whether blood microbiota merely reflects the microbial composition in the gut or actively contributes to HIV pathogenesis. In keeping with this observation, recent studies have demonstrated a role of blood microbiota in the onset of diabetes and athero-thrombotic disease in the general population (31,32), possibly confirming a role of blood dysbiosis in non-AIDS related co-morbidities (33).…”

Section: Introductionsupporting

confidence: 65%

Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes

et al. 2021

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Background: We explored the long-term effects of cART on markers of gut damage, microbial translocation, and paired gut/blood microbiota composition, with a focus on the role exerted by different drug classes.Methods: We enrolled 41 cART naïve HIV-infected subjects, undergoing blood and fecal sampling prior to cART (T0) and after 12 (T12) and 24 (T24) months of therapy. Fifteen HIV-uninfected individuals were enrolled as controls. We analyzed: (i) T-cell homeostasis (flow cytometry); (ii) microbial translocation (sCD14, EndoCab, 16S rDNA); (iii) intestinal permeability and damage markers (LAC/MAN, I-FABP, fecal calprotectin); (iv) plasma and fecal microbiota composition (alpha- and beta-diversity, relative abundance); (v) functional metagenome predictions (PICRUSt).Results: Twelve and twenty four-month successful cART resulted in a rise in EndoCAb (p = 0.0001) and I-FABP (p = 0.039) vis-à-vis stable 16S rDNA, sCD14, calprotectin and LAC/MAN, along with reduced immune activation in the periphery. Furthermore, cART did not lead to substantial modifications of microbial composition in both plasma and feces and metabolic metagenome predictions. The stratification according to cART regimens revealed a feeble effect on microbiota composition in patients on NNRTI-based or INSTI-based regimens, but not PI-based regimens.Conclusions: We hereby show that 24 months of viro-immunological effective cART, while containing peripheral hyperactivation, exerts only minor effects on the gastrointestinal tract. Persistent alteration of plasma markers indicative of gut structural and functional impairment seemingly parallels enduring fecal dysbiosis, irrespective of drug classes, with no effect on metabolic metagenome predictions.

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Section: Introductionsupporting

confidence: 65%

Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes

et al. 2021

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“…Moreover, gut microbiota–derived metabolites such as short-chain fatty acids (SCFAs) have been shown to protect the gut epithelial barrier and reduce inflammation levels in PWH receiving ART [ 36–38 ]. Composition of the gut microbiota has been associated with disease outcome in ART-treated PWH [ 26 , 31 , 33 , 39 , 40 ].…”

mentioning

confidence: 99%

Repurposing Metformin in Nondiabetic People With HIV: Influence on Weight and Gut Microbiota

Isnard

Lin

Fombuena

et al. 2020

Open Forum Infectious Diseases

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Background People living with HIV (PLWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PLWH. The anti-diabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PLWH receiving ART, especially those with low CD4/CD8 ratio. Methods In the Lilac pilot trial, we recruited 23 non-diabetic PLWH receiving ART for more than 2 years with a low CD4/CD8 ratio (<0.7). Blood and stool samples were collected during study visits at baseline, after a 12-week metformin treatment, and 12 weeks after discontinuation. Microbiota composition was analyzed by 16S rDNA gene sequencing and markers of inflammation were assessed in plasma. Results Metformin decreased PLWH weight and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila. Conclusions Our study provides the first evidence that a 12-week metformin treatment decreased weight and favoured anti-inflammatory bacteria abundance in the microbiota of non-diabetic ART-treated PLWH. A larger randomized, placebo controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PLWH.

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“…Although prior studies have connected LBP-associated inflammation with worse metabolic health (27, 28, 63); the strength of this relationship is disease specific with less clear results in obesity-associated metabolic disease (29, 30). An importance of bacterial translocation in HIV-associated metabolic syndrome was demonstrated in a recent study of metabolic comorbidities in HIV-positive individuals which found that lower CD4 nadir and/or AIDS events, HIV-associated microbiota, and low alpha diversity was correlated with increases in sCD14 and LBP and increase risk of metabolic syndrome (31). Additionally, in our study LBP was correlated with age and BMI, a relationship that was previously observed in a cohort of HIV-negative men of African ancestry with this trio being further associated with adiposity and pre-diabetes (64).…”

Section: Discussionmentioning

confidence: 99%

“…hemodialysis patients) has been described (27), however there are mixed data regarding a role in obesity associated metabolic disease (28)(29)(30). Additionally, a recent study of metabolic syndrome in PLWH found greater immune dysfunction and a more HIV-associated microbiome associated with risk of metabolic syndrome (31).…”

mentioning

confidence: 99%

Systems analysis of gut microbiome influence on metabolic disease in HIV and high-risk populations

Armstrong

Quinn

et al. 2021

Preprint

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Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV (PLWH) and has been linked with inflammation, anti-retroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease is associated with gut microbiome composition outside the context of HIV but has not been deeply explored in HIV infection nor in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the contribution of increased bacterial translocation and associated systemic inflammation that has been described in HIV-positive and HR-MSM individuals has not been explored. We used a multi-omic approach to explore relationships between gut microbes, immune phenotypes, diet, and metabolic health across ART-treated PLWH with and without LD; untreated PLWH; and HR-MSM. For PLWH on ART, we further explored associations with the plasma metabolome. Sixty-nine measures of diet, gut microbes, inflammation, and demographics were associated with impaired metabolic health defined using fasting blood markers including lipids, glucose and hormones. We found microbiome-associated metabolites associated with metabolic disease including the microbially produced metabolites, dehydroalanine and bacteriohopane-32,33,34,35-tetrol. Our central result was that elevated plasma lipopolysaccharide binding protein (LBP) was the most important predictor of metabolic disease in PLWH and HR-MSM, with network analysis of predictors showing that LBP formed a hub joining correlated microbial and immune predictors of metabolic disease. Our results suggest the role of inflammatory processes linked with bacterial translocation (measured by LBP) and interaction with dietary components and the gut microbiome in metabolic disease among PLWH and HR-MSM.

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Impact of Human Immunodeficiency Virus–Related Gut Microbiota Alterations on Metabolic Comorbid Conditions

Cited by 46 publications

References 34 publications

Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes

Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes

Repurposing Metformin in Nondiabetic People With HIV: Influence on Weight and Gut Microbiota

Systems analysis of gut microbiome influence on metabolic disease in HIV and high-risk populations

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