Prospective association of the infant gut microbiome with social behaviors in the ECHO consortium.

BACKGROUND: Identifying modifiable risk factors of autism spectrum disorders (ASDs) may inform interventions to reduce financial burden. The infant/toddler gut microbiome is one such feature that has been associated with social behaviors, but results vary between cohorts. We aimed to identify consistent overall and sex-specific associations between the early-life gut microbiome and autism-related behaviors. METHODS: Utilizing the Environmental influences on Children Health Outcomes (ECHO) consortium of United States (U.S.) pediatric cohorts, we gathered data on 304 participants with fecal metagenomic sequencing between 6-weeks to 2-years postpartum (481 samples). ASD-related social development was assessed with the Social Responsiveness Scale (SRS-2). Linear regression, PERMANOVA, and Microbiome Multivariable Association with Linear Models (MaAsLin2) were adjusted for sociodemographic factors. Stratified models estimated sex-specific effects. RESULTS: Genes encoding pathways for synthesis of short-chain fatty acids were associated with higher SRS-2 scores, indicative of ASDs. Fecal concentrations of butyrate were also positively associated with ASD-related SRS-2 scores, some of which may be explained by formula use. LIMITATIONS: The distribution of age at outcome assessment differed in the cohorts included, potentially limiting comparability between cohorts. Stool sample collection methods also differed between cohorts. Our study population reflects the general U.S. population, and thus includes few participants who met the criteria for being at high risk of developing ASD. CONCLUSIONS: Our study is among the first multicenter studies in the U.S. to describe prospective microbiome development from infancy in relation to neurodevelopment associated with ASDs. Our work contributes to clarifying which microbial features associate with subsequent diagnosis of neuropsychiatric outcomes. This will allow for future interventional research targeting the microbiome to change neurodevelopmental trajectories.

Deciduous teeth from the New Hampshire birth cohort study: Early life environmental and dietary predictors of dentin elements.

BACKGROUND: Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE: To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS: Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS: We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE: These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.

A rare case of Gardner syndrome in an African adult male: A case report.

Gardner's syndrome with the complete manifestation of colonic and extracolonic features is uncommon. Therefore, every clinician should view extracolonic features with a high index of suspicion. This may be key to early diagnosis, definitive management in these patients and importantly, helps prevent malignant transformation of existing colonic polyps.

Impact of perinatal HIV exposure and infection on salivary properties among Nigerian children.

BACKGROUND: There is growing evidence that perinatal HIV infection and exposure affect salivary pH and flow rate in children in most parts of the world, but not against the background of caries and the African demographic. This study aimed to evaluate the impact of HIV infection as well as exposure on salivary properties and their influence upon the dental caries experience among school-aged children in Nigeria. METHOD: This cross-sectional study assessed the salivary flow rates and salivary pH of HIV infected and exposed school-aged (4-11) children receiving care at a Nigerian tertiary hospital. A total of 266 consenting participants which comprised of three groups as follows: (1) HIV Infected (HI) (n = 87), (2) HIV Exposed and Uninfected (HEU) (n = 82) and (3) HIV Unexposed and Uninfected (HUU) (n = 97) were recruited for the study. Questionnaires completed by parents/guardians were used for data collection. Three calibrated dentists performed oral examinations for dental caries. International Caries Detection and Assessment Scores (ICDAS) was used and presented as dmft/DMFT. Salivary pH was measured using MColourpHast™ pH indicator strips, while salivary flow rate was determined by collecting unstimulated whole saliva using the suction method. Data analysis relied on comparative statistics to determine the correlation between HIV exposure and infection on salivary pH and flow rates. RESULT: Across the groups, (HI, HEU, and HUU) mean pH of the HI was significantly less than that of HEU and HUU. Similarly, there was a statistically significant difference in the SFR across the three groups (p = 0.004). Other variables such as gender, age and oral hygiene status expressed by the gingival inflammatory scores had no significant influence on the pH and SFR of study participants. There was a rather unexpected positive correlation of DMFT of HI and HEU groups with increasing salivary flow rate; though, the relationship was weak and not significant. CONCLUSION: Perinatal HIV exposure and infection significantly impact salivary pH and flow rate among school-aged children in Nigeria. The findings of this study imply that HIV infection influenced the salivary pH, while HIV maternal exposure (without infection) impacted salivary flow rates when compared to the controls.

Quantified retrospective biomonitoring of fetal and infant elemental exposure using LA-ICP-MS analysis of deciduous dentin in three contrasting human cohorts.

BACKGROUND: Spatial elemental analysis of deciduous tooth dentin combined with odontochronological estimates can provide an early life (in utero to ~2 years of age) history of inorganic element exposure and status. OBJECTIVE: To demonstrate the importance of data normalization to a certified reference material to enable between-study comparisons, using populations with assumed contrasting elemental exposures. METHODS: We used laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) of dentin to derive a history of elemental composition from three distinct cohort studies: a present day rural cohort, (the New Hampshire Birth Cohort Study (NHBCS; N = 154)), an historical cohort from an urban area (1958-1970), (the St. Louis Baby Tooth Study (SLBT; N = 78)), and a present-day Nigerian cohort established to study maternal HIV transmission (Dental caries and its association with Oral Microbiomes and HIV in young children-Nigeria (DOMHaIN; N = 31)). RESULTS: We report Li, Al, Mn, Cu, Zn, Sr, Ba and Pb concentrations (µg/g) and qualitatively examine As, Cd and Hg across all three cohorts. Rates of detection were highest, both overall and for each cohort individually, for Zn, Sr, Ba and Li. Zinc was detected in 100% of samples and was stably present in teeth at a concentration range of 64 - 86 µg/g. Mercury, As and Cd detection rates were the lowest, and had high variability within individual ablated spots. We found the highest concentrations of Pb in the pre- and postnatal dentin of the SLBT cohort, consistent with the prevalent use of Pb as an additive to gasoline prior to 1975. The characteristic decline in Mn after the second trimester was observed in all cohorts. IMPACT: Spatially resolved elemental analysis of deciduous teeth combined with methods for estimating crown formation times can be used to reconstruct an early-life history of elemental exposure inaccessible via other biomarkers. Quantification of data into absolute values using an external standard reference material has not been conducted since 2012, preventing comparison between studies, a common and highly informative component of epidemiology. We demonstrate, with three contrasting populations, that absolute quantification produces data with the lowest variability, compares well with available data and recommends that future tooth biomarker studies report data in this way.

A 2-arm randomized controlled study to improve the oral health of children living with HIV in Nigeria: Protocol and study design.

Background: Good oral health is an integral part of overall child health. However, immune-deficient states like the presence of Human Immunodeficiency Virus (HIV) will compromise oral health and salivary bacterial composition, leading to adverse oral conditions. Nigeria has 1.9 million HIV-positive residents, and 0.2% of incident HIV infections occur among children below 15 years. Aim: This study aims to determine through a randomized control study, the effect of an educational intervention on the oral health status and oral health-related quality of life (OHRQoL) of HIV-positive children presenting to five pediatric HIV clinics in Kano, Nigeria. Methods/Design: This 2-arm randomized control study will be conducted in five pediatric HIV outpatient clinics in Kano State, Nigeria over a period of 6 months. Eligible participants will include 172 HIV-infected frequency matched children aged 8-16 years (they can self-implement the oral health intervention with minimal supervision from the caregivers) who will be randomized and allocated into control and intervention groups. The evaluation and oral health assessment will be carried out by five examiners who will be trained and calibrated. Discussion: Our findings will help inform policies to improve the oral health and OHRQoL of HIV-positive Nigerian children and inform the need to integrate oral health care services into HIV programs in similar settings. Trial registration: ClinicalTrails.gov ID: National Clinical Trial (NCT) NCT05540171. Registered on 12th September 2022.

Supragingival mycobiome of HIV-exposed-but-uninfected children reflects a stronger correlation with caries-free-associated taxa compared to HIV-infected or uninfected children.

IMPORTANCE: Globally, caries is among the most frequent chronic childhood disease, and the fungal component of the microbial community responsible is poorly studied despite evidence that fungi contribute to increased acid production exacerbating enamel demineralization. HIV infection is another global health crisis. Perinatal HIV exposure with infection are caries risk factors; however, the caries experience in the context of perinatal HIV exposure without infection is less clear. Using high-throughput amplicon sequencing, we find taxonomic differences that become pronounced during late-stage caries. Notably, we show a stronger correlation with health-associated taxa for HIV-exposed-but-uninfected children when compared to unexposed and uninfected children. This aligns with a lower incidence of caries in primary teeth at age 6 or less for exposed yet uninfected children. Ultimately, these findings could contribute to improved risk assessment, intervention, and prevention strategies such as biofilm disruption and the informed design of pro-, pre-, and synbiotic oral therapies.

Development of the intestinal microbiome in cystic fibrosis in early life.

Cystic fibrosis (CF) is a heritable disease that causes altered physiology at mucosal sites; these changes result in chronic infections in the lung, significant gastrointestinal complications as well as dysbiosis of the gut microbiome, although the latter has been less well explored. Here, we describe the longitudinal development of the gut microbiome in a cohort of children with CF (cwCF) from birth through early childhood (0-4 years of age) using 16S rRNA gene amplicon sequencing of stool samples as a surrogate for the gut microbiota. Similar to healthy populations, alpha diversity of the gut microbiome increases significantly with age, but diversity plateaus at ~2 years of age for this CF cohort. Several taxa that have been associated with dysbiosis in CF change with age toward a more healthy-like composition; notable exceptions include Akkermansia, which decreases with age, and Blautia, which increases with age. We also examined the relative abundance and prevalence of nine taxa associated with CF lung disease, several of which persist across early life, highlighting the possibility of the lung being seeded directly from the gut early in life. Finally, we applied the Crohn's Dysbiosis Index to each sample, and found that high Crohn's-associated dysbiosis early in life (<2 years) was associated with significantly lower Bacteroides in samples collected from 2 to 4 years of age. Together, these data comprise an observational study that describes the longitudinal development of the CF-associated gut microbiota and suggest that early markers associated with inflammatory bowel disease may shape the later gut microbiota of cwCF. IMPORTANCE Cystic fibrosis is a heritable disease that disrupts ion transport at mucosal surfaces, causing a buildup of mucus and dysregulation of microbial communities in both the lungs and the intestines. Persons with CF are known to have dysbiotic gut microbial communities, but the development of these communities over time beginning at birth has not been thoroughly studied. Here, we describe an observation study following the development of the gut microbiome of cwCF throughout the first 4 years of life, during the critical window of both gut microbiome and immune development. Our findings indicate the possibility of the gut microbiota as a reservoir of airway pathogens and a surprisingly early indication of a microbiota associated with inflammatory bowel disease.

Impact of HIV on the Oral Microbiome of Children Living in Sub-Saharan Africa, Determined by Using an rpoC Gene Fragment Metataxonomic Approach.

Children living with HIV have a higher prevalence of oral diseases, including caries, but the mechanisms underlying this higher prevalence are not well understood. Here, we test the hypothesis that HIV infection is associated with a more cariogenic oral microbiome, characterized by an increase in bacteria involved in the pathogenesis of caries. We present data generated from supragingival plaques collected from 484 children representing three exposure groups: (i) children living with HIV (HI), (ii) children who were perinatally exposed but uninfected (HEU), and (iii) unexposed and therefore uninfected children (HUU). We found that the microbiome of HI children is distinct from those of HEU and HUU children and that this distinction is more pronounced in diseased teeth than healthy teeth, suggesting that the impact of HIV is more severe as caries progresses. Moreover, we report both an increase in bacterial diversity and a decrease in community similarity in our older HI cohort compared to our younger HI cohort, which may in part be a prolonged effect of HIV and/or its treatment. Finally, while Streptococcus mutans is often a dominant species in late-stage caries, it tended to be found at lower frequency in our HI cohort than in other groups. Our results highlight the taxonomic diversity of the supragingival plaque microbiome and suggest that broad and increasingly individualistic ecological shifts are responsible for the pathogenesis of caries in children living with HIV, coupled with a diverse and possibly severe impact on known cariogenic taxa that potentially exacerbates caries. IMPORTANCE Since its recognition as a global epidemic in the early 1980s, approximately 84.2 million people have been diagnosed with HIV and 40.1 million people have died from AIDS-related illnesses. The development and increased global availability of antiretroviral treatment (ART) regimens have dramatically reduced the mortality rate of HIV and AIDS, yet approximately 1.5 million new infections were reported in 2021, 51% of which are in sub-Saharan Africa. People living with HIV have a higher prevalence of caries and other chronic oral diseases, the mechanisms of which are not well understood. Here, we used a novel genetic approach to characterize the supragingival plaque microbiome of children living with HIV and compared it to the microbiomes of uninfected and perinatally exposed children to better understand the role of oral bacteria in the etiology of tooth decay in the context of HIV exposure and infection.

Prevalence and associated factors of enamel developmental defects among Nigerian children with perinatal HIV exposure.

To evaluate the prevalence and pattern of developmental defects of the enamel (DDE) and their risk factors among children born infected with Human Immunodeficiency Virus (HIV) and those born to HIV-infected mothers compared with their unexposed counterparts (i.e., children born to uninfected mothers). This was an analytic cross-sectional study evaluating the presence and pattern of distribution of DDE in three groups of school-aged children (age, 4-11 years) receiving care and treatment at a Nigerian tertiary hospital, comprising: (1) HIV-infected (HI) on antiretroviral therapy (ART) (n = 184), (2) HIV-exposed but uninfected (HEU) (n = 186) and (3) HIV-unexposed and uninfected (HUU) (n = 184). Data capture forms and questionnaires were used to record the children's medical and dental history based on clinical chart review and recall from their parents/guardians. Dental examinations were performed by calibrated dentists blinded to the study grouping. CD4+ (Cluster of Differentiation) T-cell counts were assayed for all participants. The diagnosis of DDE corresponded with the codes enumerated in the World Dental Federation's modified DDE Index. Analyses relied on comparative statistics to determine risk factors associated with DDE. A total of 103 participants distributed among the three groups presented with at least one form of DDE, which indicated a prevalence of 18.59%. The HI group had the highest frequency of DDE-affected teeth (4.36%), while that of the HEU and HUU groups were 2.73% and 2.05%, respectively. Overall, the most encountered DDE was code 1 (Demarcated Opacity), accounting for 30.93% of all codes. DDE codes 1, 4 and 6 showed significant associations with the HI and HEU groups in both dentitions (p < 0.05). We found no significant association DDE and either very low birth weight or preterm births. A marginal association with CD4+ lymphocyte count was observed in HI participants. DDE is prevalent in school-aged children, and HIV infection is a significant risk factor for hypoplasia, a common form of DDE. Our results were consistent with other research linking controlled HIV (with ART) to oral diseases and reinforce advocacies for public policies targeted at infants exposed/infected perinatally with HIV.

Age-specific associations with dental caries in HIV-infected, exposed but uninfected and HIV-unexposed uninfected children in Nigeria.

BACKGROUND: HIV infection and its management confer a substantial health burden to affected individuals and have been associated with increased risk of oral and dental diseases. In this study, we sought to quantify HIV-associated differences in the prevalence and severity of dental caries in the primary and permanent dentition of 4-11-year-old Nigerian Children. METHODS: We used clinical, laboratory, demographic, and behavioral data obtained from an ongoing cohort study of age-matched HIV-infected (HI, n = 181), HIV-exposed-but-uninfected (HEU, n = 177), and HIV-unexposed-and-uninfected (HUU, n = 186) children. Measures of dental caries experience (i.e., prevalence and severity) were based on dmft/DMFT indices recorded by trained and calibrated clinical examiners. Differences in primary and permanent dentition caries experience between HI, HEU, and HUU were estimated using multivariable logistic and negative binomial regression modeling. RESULTS: HI children had significantly higher caries experience (33%) compared to HEU (15%) and HUU (22%) children. This difference persisted in fully adjusted analyses [odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.0-2.6], was most pronounced in the permanent dentition (OR = 3.4; 95% CI = 1.2-9.5), and mirrored differences in caries severity. While molars were predominantly affected in both primary and permanent dentitions, caries lesion patterns differed between dentitions. Caries severity was significantly associated with hypoplastic primary teeth, gingival inflammation, and lower CD4 counts. CONCLUSIONS: We found that the higher prevalence and severity of dental caries among HI children was driven by increased burden of permanent dentition caries compared to their uninfected counterparts. The dentition-specific associations identified in this study highlight the need to design and implement age-specific caries prevention strategies. These may include intensified oral hygiene regimens aimed at mitigating the cariogenic impact of hyposalivation among HI children. Similarly, the long-lasting impacts of developmental defects of the enamel in the primary and permanent dentitions must not be ignored.

The Pragmatic Return to Effective Dental Infection Control Through Triage and Testing (PREDICT) Study: Protocol for a Prospective Clinical Study in the National Dental Practice-Based Research Network.

BACKGROUND: Dental practice has been greatly affected by the COVID-19 pandemic. As SARS-CoV-2 infection is transmitted by respiratory fluids, dental practice techniques, which include aerosol-generating procedures, can increase the risk of transmission causing heightened safety concerns for both dental health care workers (DHCWs) and patients. These concerns have resulted in the reduction in patient volume and the available workforce within dental practices across the United States. Standardized methods for COVID-19 triage and testing may lead to increased safety and perceptions of safety for DHCWs and their patients and promote willingness to provide and access oral health care services. OBJECTIVE: This study is designed to develop procedures that test the feasibility of enhanced COVID-19 triage and testing in dental offices. It will provide preliminary data to support a larger network-wide study grant application aimed at developing protocols to address safety concerns of patients and DHCWs in a peri-COVID-19 pandemic era. METHODS: The feasibility study is being conducted in 4 private dental practices, each of which has a dentist member of the National Dental Practice-Based Research Network. Participants include the DHCWs and patients of the dental practice. Study procedures include completion of COVID-19 triage, completion of COVID-19 testing (point-of-care [POC] or laboratory-based [LAB] SARS-CoV-2 viral, antigen, and antibody tests based on office designation), and administration of perception and attitude surveys for participating DCHWs and patients of the dental practice over a defined study period. The office designation and the participant's role in the practice determines which testing protocol is executed within the office. There are 4 study groups following 4 distinct protocols: (1) POC DHCWs, (2) POC patients, (3) LAB DHCWs, and (4) LAB patients. RESULTS: Data collection began in December of 2021 and concluded in March 2022. Study results are expected to be published in fall 2022. CONCLUSIONS: The results of this feasibility study will help identify the viability and functionality of COVID-19 triage and testing in dental practices and inform a larger network-wide study grant application that develops protocols that address safety concerns of patients and DHCWs in a COVID-19 environment. TRIAL REGISTRATION: ClinicalTrials.gov NTC05123742; https://clinicaltrials.gov/ct2/show/NCT05123742?term=NCT05123742. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38386.

Metagenomic analysis reveals associations between salivary microbiota and body composition in early childhood.

Several studies have shown that body mass index is strongly associated with differences in gut microbiota, but the relationship between body weight and oral microbiota is less clear especially in young children. We aimed to evaluate if there is an association between child growth and the saliva microbiome. We hypothesized that associations between growth and the saliva microbiome would be moderate, similarly to the association between growth and the gut microbiome. For 236 toddlers participating in the New Hampshire Birth Cohort Study, we characterized the association between multiple longitudinal anthropometric measures of body height, body weight and body mass. Body Mass Index (BMI) z-scores were calculated, and dual-energy x-ray absorptiometry (DXA) was used to estimate body composition. Shotgun metagenomic sequencing of saliva samples was performed to taxonomically and functionally profile the oral microbiome. We found that within-sample diversity was inversely related to body mass measurements while community composition was not associated. Although the magnitude of associations were small, some taxa were consistently associated with growth and modified by sex. Certain taxa were associated with decreased weight or growth (including Actinomyces odontolyticus and Prevotella melaninogenica) or increased growth (such as Streptococcus mitis and Corynebacterium matruchotii) across anthropometric measures. Further exploration of the functional significance of this relationship will enhance our understanding of the intersection between weight gain, microbiota, and energy metabolism and the potential role of these relationships on the onset of obesity-associated diseases in later life.

MarZIC: A Marginal Mediation Model for Zero-Inflated Compositional Mediators with Applications to Microbiome Data.

BACKGROUND: The human microbiome can contribute to pathogeneses of many complex diseases by mediating disease-leading causal pathways. However, standard mediation analysis methods are not adequate to analyze the microbiome as a mediator due to the excessive number of zero-valued sequencing reads in the data and that the relative abundances have to sum to one. The two main challenges raised by the zero-inflated data structure are: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are not zero (i.e., false zeros). METHODS: We develop a novel marginal mediation analysis method under the potential-outcomes framework to address the issues. We also show that the marginal model can account for the compositional structure of microbiome data. RESULTS: The mediation effect can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the application in a real microbiome study showcase our approach in comparison with existing approaches. CONCLUSIONS: When analyzing the zero-inflated microbiome composition as the mediators, MarZIC approach has better performance than standard causal mediation analysis approaches and existing competing approach.

Impact of antibiotics on off-target infant gut microbiota and resistance genes in cohort studies.

BACKGROUND: Young children are frequently exposed to antibiotics, with the potential for collateral consequences to the gut microbiome. The impact of antibiotic exposures to off-target microbes (i.e., bacteria not targeted by treatment) and antibiotic resistance genes (ARGs) is poorly understood. METHODS: We used metagenomic sequencing data from paired stool samples collected prior to antibiotic exposure and at 1 year from over 200 infants and a difference-in-differences approach to assess the relationship between subsequent exposures and the abundance or compositional diversity of microbes and ARGs while adjusting for covariates. RESULTS: By 1 year, the abundance of multiple species and ARGs differed by antibiotic exposure. Compared to infants never exposed to antibiotics, Bacteroides vulgatus relative abundance increased by 1.72% (95% CI: 0.19, 3.24) while Bacteroides fragilis decreased by 1.56% (95% CI: -4.32, 1.21). Bifidobacterium species also exhibited opposing trends. ARGs associated with exposure included class A beta-lactamase gene CfxA6. Among infants attending day care, Escherichia coli and ARG abundance were both positively associated with antibiotic use. CONCLUSION: Novel findings, including the importance of day care attendance, were identified through considering microbiome data at baseline and post-intervention. Thus, our study design and approach have important implications for future studies evaluating the unintended impacts of antibiotics. IMPACT: The impact of antibiotic exposure to off-target microbes and antibiotic resistance genes in the gut is poorly defined. We quantified these impacts in two cohort studies using a difference-in-differences approach. Novel to microbiome studies, we used pre/post-antibiotic data to emulate a randomized controlled trial. Compared to infants unexposed to antibiotics between baseline and 1 year, the relative abundance of multiple off-target species and antibiotic resistance genes was altered. Infants who attended day care and were exposed to antibiotics within the first year had a higher abundance of Escherichia coli and antibiotic resistance genes; a novel finding warranting further investigation.

The Developing Microbiome From Birth to 3 Years: The Gut-Brain Axis and Neurodevelopmental Outcomes.

The volume and breadth of research on the role of the microbiome in neurodevelopmental and neuropsychiatric disorders has expanded greatly over the last decade, opening doors to new models of mechanisms of the gut-brain axis and therapeutic interventions to reduce the burden of these outcomes. Studies have highlighted the window of birth to 3 years as an especially sensitive window when interventions may be the most effective. Harnessing the powerful gut-brain axis during this critical developmental window clarifies important investigations into the microbe-human connection and the developing brain, affording opportunities to prevent rather than treat neurodevelopmental disorders and neuropsychiatric illness. In this review, we present an overview of the developing intestinal microbiome in the critical window of birth to age 3; and its prospective relationship with neurodevelopment, with particular emphasis on immunological mechanisms. Next, the role of the microbiome in neurobehavioral outcomes (such as autism, anxiety, and attention-deficit hyperactivity disorder) as well as cognitive development are described. In these sections, we highlight the importance of pairing mechanistic studies in murine models with large scale epidemiological studies that aim to clarify the typical health promoting microbiome in early life across varied populations in comparison to dysbiosis. The microbiome is an important focus in human studies because it is so readily alterable with simple interventions, and we briefly outline what is known about microbiome targeted interventions in neurodevelopmental outcomes. More novel examinations of known environmental chemicals that adversely impact neurodevelopmental outcomes and the potential role of the microbiome as a mediator or modifier are discussed. Finally, we look to the future and emphasize the need for additional research to identify populations that are sensitive to alterations in their gut microbiome and clarify how interventions might correct and optimize neurodevelopmental outcomes.

Sex-specific relationships of the infant microbiome and early-childhood behavioral outcomes.

BACKGROUND: A link between the gut microbiome and behavior is hypothesized, but most previous studies are cross-sectional or in animal models. The modifying role of host sex is poorly characterized. We aimed to identify sex-specific prospective associations between the early-life gut microbiome and preschool-age neurobehavior. METHODS: In a prospective cohort, gut microbiome diversity and taxa were estimated with 16S rRNA sequencing at 6 weeks, 1 year, and 2 years. Species and gene pathways were inferred from metagenomic sequencing at 6 weeks and 1 year. When subjects were 3 years old, parents completed the Behavioral Assessment System for Children, second edition (BASC-2). A total of 260 children contributed 523 16S rRNA and 234 metagenomics samples to analysis. Models adjusted for sociodemographic characteristics. RESULTS: Higher diversity at 6 weeks was associated with better internalizing problems among boys, but not girls [ßBoys = -1.86 points/SD Shannon diversity; 95% CI (-3.29, -0.42), pBoys = 0.01, ßGirls = 0.22 (-1.43, 1.87), pGirls = 0.8, pinteraction = 0.06]. Among other taxa-specific associations, Bifidobacterium at 6 weeks was associated with Adaptive Skills scores in a sex-specific manner. We observed relationships between functional features and BASC-2 scores, including vitamin B6 biosynthesis pathways and better Depression scores. CONCLUSIONS: This study advances our understanding of microbe-host interactions with implications for childhood behavioral health. IMPACT: This is one of the first studies to examine the early-life microbiome and neurobehavior, and the first to examine prospective sex-specific associations. Infant and early-childhood microbiomes relate to neurobehavior including anxiety, depression, hyperactivity, and social behaviors in a time- and sex-specific manner. Our findings suggest future studies should evaluate whether host sex impacts the relationship between the gut microbiome and behavioral health outcomes.

Dental caries and its association with the oral microbiomes and HIV in young children-Nigeria (DOMHaIN): a cohort study.

BACKGROUND: This study seeks to understand better the mechanisms underlying the increased risk of caries in HIV-infected school-aged Nigerian children by examining the relationship between the plaque microbiome and perinatal HIV infection and exposure. We also seek to investigate how perinatal HIV infection and exposure impact tooth-specific microbiomes' role on caries disease progression. METHODS: The participants in this study were children aged 4 to 11 years recruited from the University of Benin Teaching Hospital (UBTH), Nigeria, between May to November 2019. Overall, 568 children were enrolled in three groups: 189 HIV-infected (HI), 189 HIV-exposed but uninfected (HEU) and 190 HIV-unexposed and uninfected (HUU) as controls at visit 1 with a 2.99% and 4.90% attrition rate at visit 2 and visit 3 respectively. Data were obtained with standardized questionnaires. Blood samples were collected for HIV, HBV and HCV screening; CD4, CD8 and full blood count analysis; and plasma samples stored for future investigations; oral samples including saliva, buccal swabs, oropharyngeal swab, tongue swab, dental plaque were collected aseptically from participants at different study visits. CONCLUSIONS: Results from the study will provide critical information on how HIV exposure, infection, and treatment, influence the oral microbiome and caries susceptibility in children. By determining the effect on community taxonomic structure and gene expression of dental microbiomes, we will elucidate mechanisms that potentially create a predisposition for developing dental caries. As future plans, the relationship between respiratory tract infections, immune and inflammatory markers with dental caries in perinatal HIV infection and exposure will be investigated.

HIV-Associated Interactions Between Oral Microbiota and Mucosal Immune Cells: Knowledge Gaps and Future Directions.

Even with sustained use of antiretroviral therapy (ART), HIV-infected individuals have an increased risk of systemic comorbid conditions and oral pathologies, including opportunistic infections, oral mucosal inflammation, and gingival and periodontal diseases. The immune-mediated mechanisms that drive this increased risk, in the context of sustained viral suppression, are unclear. HIV infection, even when controlled, alters microbial communities contributing to a chronic low-grade inflammatory state that underlies these non-HIV co-morbidities. The higher prevalence of dental caries, and mucosal and periodontal inflammation reported in HIV-infected individuals on ART is often associated with differentially abundant oral microbial communities, possibly leading to a heightened susceptibility to inflammation. This mini-review highlights current gaps in knowledge regarding the microbe-mediated oral mucosal immunity with HIV infection while discussing opportunities for future research investigations and implementation of novel approaches to elucidate these gaps. Interventions targeting both inflammation and microbial diversity are needed to mitigate oral inflammation-related comorbidities, particularly in HIV-infected individuals. More broadly, additional research is needed to bolster general models of microbiome-mediated chronic immune activation and aid the development of precise microbiota-targeted interventions to reverse or mitigate adverse outcomes.