Abstract
An emerging paradigm suggests that gut glycosylation is a key force in maintaining the homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how gut glycosylation contributes to the HIV-associated microbial translocation and inflammation that persist despite viral suppression and contribute to the development of several comorbidities. We examined terminal ileum, right colon, and sigmoid colon biopsies from HIV-infected virally-suppressed individuals and found that gut glycomic patterns are associated with distinct microbial compositions and differential levels of chronic inflammation and HIV persistence. In particular, high levels of the pro-inflammatory hypo-sialylated T-antigen glycans and low levels of the anti-inflammatory fucosylated glycans were associated with higher abundance of glycan-degrading microbial species (in particular, Bacteroides vulgatus), a less diverse microbiome, higher levels of inflammation, and higher levels of ileum-associated HIV DNA. These findings are linked to the activation of the inflammasome-mediating eIF2 signaling pathway. Our study thus provides the first proof-of-concept evidence that a previously unappreciated factor, gut glycosylation, is a force that may impact the vicious cycle between HIV infection, microbial translocation, and chronic inflammation.
Highlights
HIV infection causes changes in gut structure and a breakdown of the epithelial barrier, which can increase permeability to gut microbes and microbial products.[1]
The gut glycome is compartmentalized between the terminal ileum, right colon, and sigmoid colon of HIV+ antiretroviral therapy (ART)-suppressed individuals We collected biopsies from the terminal ileum, right colon, and sigmoid colon of 20 HIV+ ART-suppressed individuals and examined the glycosylation patterns using lectin microarray technology
Given that sialic acid catabolism and proper gut fucosylation play an important role in regulating microbial translocation and gut inflammation,[28,29,30,33] we examined the associations between gut sialylation or fucosylation and both microbial translocation and inflammation during ARTsuppressed HIV infection
Summary
HIV infection causes changes in gut structure and a breakdown of the epithelial barrier, which can increase permeability to gut microbes and microbial products.[1] This microbial translocation is thought to be a major cause of local and systemic immune activation and inflammation that may further increase or sustain HIV replication, resulting in a positive feedback cycle.[1,2,3,4] Immune activation and inflammation contribute to the development of non-AIDS comorbidities such as cardiovascular diseases and neurological impairments,[1,5,6] and possibly viral persistence.[2,4]. We start to investigate whether an unappreciated factor—gut glycosylation—plays a role in the positive feedback cycle between
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