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Many infants consume both human milk and infant formula (mixed-fed); however, few studies have investigated how mixed feeding affects the gut microbiome composition and metabolic profiles compared to exclusive breastfeeding or formula feeding. Herein, how delivery mode and early nutrition affect the microbiome and metabolome of 6-week-old infants in the STRONG Kids2 cohort was investigated. Fecal samples were collected from exclusively breastfed (BF; n = 25), formula-fed (FF; n = 25) or mixed-fed (MF; n = 25) participants. Within each feeding group, infants were either delivered vaginally (VD; n = 13) or by Cesarean section (CS; n = 12). Feeding mode affects the fecal microbiome diversity, composition, and functional potential, as well as metabolomic profiles regardless of delivery mode. Alpha and beta diversity of MF differed from that of BF (p < 0.05) but were comparable to FF infants. Functional analyses have shown 117 potential metabolic pathways differed between BF and FF, 112 between BF and MF, and 8 between MF and FF infants (p < 0.05, q < 0.10). Fecal metabolomic profiles of MF and FF clustered together and separated from BF infants. In total, 543 metabolites differed between BF and FF, 517 between BF and MF, and 3 between MF and FF (p < 0.05, q < 0.10). Delivery mode affected overall microbial composition (p = 0.022) at the genus level and 24 potential functional pathways, with 16 pathways being higher in VD than CS infants (p < 0.05, q < 0.10). Metabolomic analysis identified 47 differential metabolites between CS and VD, with 39 being lower in CS than VD (p < 0.05, q < 0.10). In summary, fecal microbiota composition and function and metabolite profiles of 6-week-old MF infants are closer to FF than BF infants.

Differential past exposure to microorganisms over time has contributed to the evolution of the primate immune system, including the microbiome in the immune compartment. The functional consequences of such microbial-induced evolution of hosts and within lifetime epigenetic changes include alterations to host relationships with other microorganisms and might contribute to observed inter-species differences in immune responses to infection. Blood is a very important immune compartment containing a high density of professional immune cells and the blood microbiome may help explain the divergence of humans’ immune responses from other primates. The nonhuman primate blood microbiome, however, remains uncharacterized and its relationship to blood immune functions are not known. To better understand the evolution of the human blood microbiome and its association with disease susceptibility, this study characterizes the blood microbiome of major clades of primates. This dissertation develops a multi-measure assessment of resident bacterial life of blood through amplicon sequencing of resident microbial DNA, bacterial culturing, and measurements of circulating microbial components (lipopolysaccharide or LPS) in the blood of species from four primate groups (Human Homo sapiens, rhesus macaque Macaca mulatta, common marmoset Callithrix jacchus, and ring-tailed lemur Lemur catta), and assess if inter-species differences in blood microbiome are correlated with species-specific disease susceptibility and blood transcriptome profiles. The results of this analysis are described in chapter 3. I found that blood LPS content is associated with known species-specific sensitivity to this molecule, with more sensitive species (e.g., human and marmoset) having lower LPS levels. I also found variations in blood microbiome compositions in primates that seem to be sourced from the gut and linked to phylogeny. Moreover, pathways and genes that are important in immune response to LPS are differently enriched and expressed in primates. The results from this chapter confirm that the blood bacterial and LPS content and gene expression in primates are linked with their immune response and disease susceptibility differences. Our findings will help shedding light on some of the mechanisms behind microbe-host interactions in primates and increase our understanding of the evolution of humans and their immune system responses to pathogens. In chapter 2, I review the microbiome literature to describe current knowledge of blood microbiome (both pathogenic and commensals), and correlate this information to known disease and immune related facts. The aim of chapter 2 is to show the relationship between microbiome of the blood as one of the most important immunity body sites with disease susceptibility and immune system responses in primates. In chapter 4, I describe various factors that can affect the primate microbiome. I use current information in the literature, which is mostly focused on the gut, to study various environmental (diet, medication, exercise, etc.) and host related factors (genetics, phylogeny, etc.) to investigate which factors are more important in shaping our microbiome. Additionally, I used 1307 published datasets from 10 studies on 31 primate species to study some of these important factors together. I found that the results, in terms of effect size of a factor on shaping microbiome, depend on purpose and scale of the study with diet being generally more important among all factors including individual’s genetics in smaller scales and phylogeny/species being more important at larger scales when various species of primates are studied. I further discuss that some of these factors are also correlated and might be working together in shaping the microbiota.

Trichomoniasis, caused by Trichomonas vaginalis (TV), is the most common non-viral sexually transmitted infection (STI) worldwide, affecting over 174 million people annually and is frequently associated with reproductive co-morbidities. However, its detection can be time-consuming, subjective, and expensive for large cohort studies. This case–control study, conducted at the Mount Sinai Adolescent Health Center in New York City, involved 36 women with prevalent TV infections and 36 controls. The objective was to examine Internal Transcribed Spacer region-1 (ITS1) amplicon-derived communities for the detection of prevalent TV infections with the same precision as clinical microscopy and the independent amplification of the TV-specific TVK3/7 gene. DNA was isolated from clinician-collected cervicovaginal samples and amplified using ITS1 primers in a research laboratory. Results were compared to microscopic wet-mount TV detection of concurrently collected cervicovaginal samples and confirmed against TV-specific TVK3/7 gene PCR. The area under the receiver operating characteristics curve (AUC) for diagnosing TV using ITS1 communities was 0.92. ITS1 amplicons displayed an intra-class correlation coefficient (ICC) of 0.96 (95% CI: 0.93–0.98) compared to TVK3/7 PCR fragment testing. TV cases showed an increased risk of bacterial vaginosis (BV) compared to the TV-negative controls (OR = 8.67, 95% CI: 2.24–48.54, p-value = 0.0011), with no significant differences regarding genital yeast or chlamydia infections. This study presents a bioinformatics approach to ITS1 amplicon next-generation sequencing that is capable of detecting prevalent TV infections. This approach enables high-throughput testing for TV in stored DNA from large-scale epidemiological studies.

Trichomoniasis, caused by Trichomonas vaginalis (TV), is the most common non-viral sexually transmitted infection (STI) worldwide, affecting over 174 million people annually and is frequently associated with reproductive co-morbidities. However, its detection can be time-consuming, subjective, and expensive for large cohort studies. This case–control study, conducted at the Mount Sinai Adolescent Health Center in New York City, involved 36 women with prevalent TV infections and 36 controls. The objective was to examine Internal Transcribed Spacer region-1 (ITS1) amplicon-derived communities for the detection of prevalent TV infections with the same precision as clinical microscopy and the independent amplification of the TV-specific TVK3/7 gene. DNA was isolated from clinician-collected cervicovaginal samples and amplified using ITS1 primers in a research laboratory. Results were compared to microscopic wet-mount TV detection of concurrently collected cervicovaginal samples and confirmed against TV-specific TVK3/7 gene PCR. The area under the receiver operating characteristics curve (AUC) for diagnosing TV using ITS1 communities was 0.92. ITS1 amplicons displayed an intra-class correlation coefficient (ICC) of 0.96 (95% CI: 0.93–0.98) compared to TVK3/7 PCR fragment testing. TV cases showed an increased risk of bacterial vaginosis (BV) compared to the TV-negative controls (OR = 8.67, 95% CI: 2.24–48.54, p-value = 0.0011), with no significant differences regarding genital yeast or chlamydia infections. This study presents a bioinformatics approach to ITS1 amplicon next-generation sequencing that is capable of detecting prevalent TV infections. This approach enables high-throughput testing for TV in stored DNA from large-scale epidemiological studies.