Infant microbes and metabolites point to childhood neurodevelopmental disorders.

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.

RESCUE: a validated Nanopore pipeline to classify bacteria through long-read, 16S-ITS-23S rRNA sequencing.

Despite the advent of third-generation sequencing technologies, modern bacterial ecology studies still use Illumina to sequence small (~400 bp) hypervariable regions of the 16S rRNA SSU for phylogenetic classification. By sequencing a larger region of the rRNA gene operons, the limitations and biases of sequencing small portions can be removed, allowing for more accurate classification with deeper taxonomic resolution. With Nanopore sequencing now providing raw simplex reads with quality scores above Q20 using the kit 12 chemistry, the ease, cost, and portability of Nanopore play a leading role in performing differential bacterial abundance analysis. Sequencing the near-entire rrn operon of bacteria and archaea enables the use of the universally conserved operon holding evolutionary polymorphisms for taxonomic resolution. Here, a reproducible and validated pipeline was developed, RRN-operon Enabled Species-level Classification Using EMU (RESCUE), to facilitate the sequencing of bacterial rrn operons and to support import into phyloseq. Benchmarking RESCUE showed that fully processed reads are now parallel or exceed the quality of Sanger, with median quality scores of approximately Q20+, using the R10.4 and Guppy SUP basecalling. The pipeline was validated through two complex mock samples, the use of multiple sample types, with actual Illumina data, and across four databases. RESCUE sequencing is shown to drastically improve classification to the species level for most taxa and resolves erroneous taxa caused by using short reads such as Illumina.

Infant gut microbiota and environment associate with juvenile idiopathic arthritis many years prior to disease onset, especially in genetically vulnerable children.

BACKGROUND: The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk. METHODS: Data was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n = 17,055), 111 of whom later acquired JIA (ABISJIA). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed. FINDINGS: ABISJIA had higher abundance of Acidaminococcales, Prevotella 9, and Veillonella parvula and lower abundance of Coprococcus, Subdoligranulum, Phascolarctobacterium, Dialister spp., Bifidobacterium breve, Fusicatenibacter saccharivorans, Roseburia intestinalis, and Akkermansia muciniphila (q's < 0.05). Parabacteroides distasonis greatly increased the odds of later contracting JIA (OR = 6.7; 1.81-24.84, p = 0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition. INTERPRETATION: Microbial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis. FUNDING: Barndiabetesfonden; Swedish Council for Working Life and Social Research; Swedish Research Council; Östgöta Brandstodsbolag; Medical Research Council of Southeast Sweden; JDRF-Wallenberg Foundation; Linköping.

Infant gut microbiome composition correlated with type 1 diabetes acquisition in the general population: the ABIS study.

AIMS/HYPOTHESIS: While autoantibodies are traditional markers for type 1 diabetes development, we identified gut microbial biomarkers in 1-year-old infants associated with future type 1 diabetes up to 20 years before diagnosis. METHODS: Infants enrolled in the longitudinal general population cohort All Babies In Southeast Sweden (ABIS) provided a stool sample at a mean age of 12.5 months. Samples (future type 1 diabetes, n=16; healthy controls, n=268) were subjected to 16S ribosomal RNA (rRNA) sequencing and quantitative PCR. Microbial differences at the taxonomic and core microbiome levels were assessed. PICRUSt was used to predict functional content from the 16S rRNA amplicons. Sixteen infants, with a future diagnosis of type 1 diabetes at a mean age of 13.3±5.4 years, and one hundred iterations of 32 matched control infants, who remained healthy up to 20 years of age, were analysed. RESULTS: Parasutterella and Eubacterium were more abundant in healthy control infants, while Porphyromonas was differentially more abundant in infants with future type 1 diabetes diagnosis. Ruminococcus was a strong determinant in differentiating both control infants and those with future type 1 diabetes using random forest analysis and had differing trends of abundance when comparing control infants and those with future type 1 diabetes. Flavonifractor and UBA1819 were the strongest factors for differentiating control infants, showing higher abundance in control infants compared with those with future type 1 diabetes. Alternatively, Alistipes (more abundant in control infants) and Fusicatenibacter (mixed abundance patterns when comparing case and control infants) were the strongest factors for differentiating future type 1 diabetes. Predicted gene content regarding butyrate production and pyruvate fermentation was differentially observed to be higher in healthy control infants. CONCLUSIONS/INTERPRETATION: This investigation suggests that microbial biomarkers for type 1 diabetes may be present as early as 1 year of age, as reflected in the taxonomic and functional differences of the microbial communities. The possibility of preventing disease onset by altering or promoting a 'healthy' gut microbiome is appealing. DATA AVAILABILITY: The forward and reverse 16S raw sequencing data generated in this study are available through the NCBI Sequence Read Archive under BioProject PRJNA875929. Associated sample metadata used for statistical comparison are available in the source data file. R codes used for statistical comparisons and figure generation are available at: https://github.com/PMilletich/T1D_Pipeline .

Gut microbiome markers in subgroups of HLA class II genotyped infants signal future celiac disease in the general population: ABIS study.

Although gut microbiome dysbiosis has been illustrated in celiac disease (CD), there are disagreements about what constitutes these microbial signatures and the timeline by which they precede diagnosis is largely unknown. The study of high-genetic-risk patients or those already with CD limits our knowledge of dysbiosis that may occur early in life in a generalized population. To explore early gut microbial imbalances correlated with future celiac disease (fCD), we analyzed the stool of 1478 infants aged one year, 26 of whom later acquired CD, with a mean age of diagnosis of 10.96 ± 5.6 years. With a novel iterative control-matching algorithm using the prospective general population cohort, All Babies In Southeast Sweden, we found nine core microbes with prevalence differences and seven differentially abundant bacteria between fCD infants and controls. The differences were validated using 100 separate, iterative permutations of matched controls, which suggests the bacterial signatures are significant in fCD even when accounting for the inherent variability in a general population. This work is the first to our knowledge to demonstrate that gut microbial differences in prevalence and abundance exist in infants aged one year up to 19 years before a diagnosis of CD in a general population.

Saliva microbiome, dietary, and genetic markers are associated with suicidal ideation in university students.

Here, salivary microbiota and major histocompatibility complex (MHC) human leukocyte antigen (HLA) alleles were compared between 47 (12.6%) young adults with recent suicidal ideation (SI) and 325 (87.4%) controls without recent SI. Several bacterial taxa were correlated with SI after controlling for sleep issues, diet, and genetics. Four MHC class II alleles were protective for SI including DRB1*04, which was absent in every subject with SI while present in 21.7% of controls. Increased incidence of SI was observed with four other MHC class II alleles and two MHC class I alleles. Associations between these HLA alleles and salivary bacteria were also identified. Furthermore, rs10437629, previously associated with attempted suicide, was correlated here with SI and the absence of Alloprevotella rava, a producer of an organic acid known to promote brain energy homeostasis. Hence, microbial-genetic associations may be important players in the diathesis-stress model for suicidal behaviors.

A Six-Day, Lifestyle-Based Immersion Program Mitigates Cardiovascular Risk Factors and Induces Shifts in Gut Microbiota, Specifically Lachnospiraceae, Ruminococcaceae, Faecalibacterium prausnitzii: A Pilot Study.

Cardiovascular disease (CVD) prevalence remains elevated globally. We have previously shown that a one-week lifestyle "immersion program" leads to clinical improvements and sustained improvements in quality of life in moderate to high atherosclerotic CVD (ASCVD) risk individuals. In a subsequent year of this similarly modeled immersion program, we again collected markers of cardiovascular health and, additionally, evaluated intestinal microbiome composition. ASCVD risk volunteers (n = 73) completed the one-week "immersion program" involving nutrition (100% plant-based foods), stress management education, and exercise. Anthropometric measurements and CVD risk factors were compared at baseline and post intervention. A subgroup (n = 22) provided stool, which we analyzed with 16S rRNA sequencing. We assessed abundance changes within-person, correlated the abundance shifts with clinical changes, and inferred functional pathways using PICRUSt. Reductions in blood pressure, total cholesterol, and triglycerides, were observed without reduction in weight. Significant increases in butyrate producers were detected, including Lachnospiraceae and Oscillospirales. Within-person, significant shifts in relative abundance (RA) occurred, e.g., increased Lachnospiraceae (+58.8% RA, p = 0.0002), Ruminococcaceae (+82.1%, p = 0.0003), Faecalibacterium prausnitzii (+54.5%, p = 0.002), and diversification and richness. Microbiota changes significantly correlated with body mass index (BMI), blood pressure (BP), cholesterol, high-sensitivity C-reactive protein (hsCRP), glucose, and trimethylamine N-oxide (TMAO) changes. Pairwise decreases were inferred in microbial genes corresponding to cancer, metabolic disease, and amino acid metabolism. This brief lifestyle-based intervention improved lipids and BP and enhanced known butyrate producers, without significant weight loss. These results demonstrate a promising non-pharmacological preventative strategy for improving cardiovascular health.

A review of the validity of computerized neurocognitive assessment tools in mild traumatic brain injury assessment.

Computerized neurocognitive assessment tools (NCATs) offer potential advantages over traditional neuropsychological tests in postconcussion assessments. However, their psychometric properties and clinical utility are still questionable. The body of research regarding the validity and clinical utility of NCATs suggests some support for aspects of validity (e.g., convergent validity) and some ability to distinguish between concussed individuals and controls, though there are still questions regarding the validity of these tests and their clinical utility, especially outside of the acute injury timeframe. In this paper, we provide a comprehensive summary of the existing validity literature for four commonly used and studied NCATs (automated neuropsychological assessment metrics, CNS vital signs, cogstate and immediate post-concussion and cognitive testing) and lay the groundwork for future investigations.