Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner

Abstract

In both high-and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated. To address this, we compared the innate response and the stool microbiome of 2-y-old HEU and HUU children from Belgium, Canada, and South Africa to test the hypothesis that region-specific immune alterations directly correlate to differences in their stool microbiomes. We did not detect a universal immune or microbiome signature underlying differences between HEU versus HUU that was applicable to all children. But as hypothesized, population-specific differences in stool microbiomes were readily detected and included reduced abundances of short-chain fatty acid-producing bacteria in Canadian HEU children. Furthermore, we did not identify innate immune-microbiome associations that distinguished HEU from HUU children in any population. These findings suggest that maternal HIV infection is independently associated with differences in both innate immunity and the stool microbiome in a biogeographical population-specific way.

Evolution of the Gut Microbiome in HIV-Exposed Uninfected and Unexposed Infants during the First Year of Life

“…We found only two other studies in the literature that compared the gut microbiomes in HEU and HUU. Although each study enrolled only 9 to 25 children/group at around 2 years of age, they found similar alpha and beta diversity in the two groups, supporting our results ( 63 , 64 ).…”

“…Subsequently, D’Souza et al compared the structure of the gut microbiome at 6, 16, and 24 weeks of age in HEU receiving co-trimoxazole prophylaxis or not and showed that co-trimoxazole administration may also contribute to the dysbiosis observed in HEU ( 62 ). Two other cross-sectional studies that compared HEU and HUU gut microbiomes at approximately 2 years of life found similar alpha or beta diversities in the two groups ( 63 , 64 ).…”

Gut-dependent inflammation and alterations of the intestinal microbiota in individuals with perinatal HIV exposure and different HIV serostatus

“…Indeed, HEU infants display high morbidity and mortality from pneumonia, diarrheal disease and sepsis [13,14] as well as poor growth and neurodevelopment [15]. The underlying reasons for such clinical differences are most likely multifactorial and dependent on the geographical and social setting, maternal health status and breastfeeding [16][17][18][19]. Of note, recent data have demonstrated that maternal HIV infection is linked to modifications in the fecal microbiome of HEU with alterations in the abundance of several taxa and functional profiles, suggesting that gut dysbiosis may contribute to the clinical vulnerability in this setting [20,21].…”

The gut microbiome and early-life growth in a population with high prevalence of stunting

“…CHEU also receive prophylactic antibiotics, to prevent infectious morbidity associated with HIV exposure. Each of these exposures may influence the seeding and succession of the gut microbiome in CHEU (28, 29), which may contribute to the high prevalence of stunting observed in CHEU (30). Evidence of the effect of other early-life environmental exposures on the assembly of the infant gut microbiome in low resources settings is scarce but may provide insights into the influence of microbial and microbiota-modifying exposures on child growth in the context of undernutrition.…”