Maternal prebiotic supplementation during pregnancy and lactation modifies the microbiome and short chain fatty acid profile of both mother and infant.

BACKGROUND & AIMS: Improving maternal gut health in pregnancy and lactation is a potential strategy to improve immune and metabolic health in offspring and curtail the rising rates of inflammatory diseases linked to alterations in gut microbiota. Here, we investigate the effects of a maternal prebiotic supplement (galacto-oligosaccharides and fructo-oligosaccharides), ingested daily from <21 weeks' gestation to six months' post-partum, in a double-blinded, randomised placebo-controlled trial. METHODS: Stool samples were collected at multiple timepoints from 74 mother-infant pairs as part of a larger, double-blinded, randomised controlled allergy intervention trial. The participants were randomised to one of two groups; with one group receiving 14.2 g per day of prebiotic powder (galacto-oligosaccharides GOS and fructo-oligosaccharides FOS in ratio 9:1), and the other receiving a placebo powder consisting of 8.7 g per day of maltodextrin. The faecal microbiota of both mother and infants were assessed based on the analysis of bacterial 16S rRNA gene (V4 region) sequences, and short chain fatty acid (SCFA) concentrations in stool. RESULTS: Significant differences in the maternal microbiota profiles between baseline and either 28-weeks' or 36-weeks' gestation were found in the prebiotic supplemented women. Infant microbial beta-diversity also significantly differed between prebiotic and placebo groups at 12-months of age. Supplementation was associated with increased abundance of commensal Bifidobacteria in the maternal microbiota, and a reduction in the abundance of Negativicutes in both maternal and infant microbiota. There were also changes in SCFA concentrations with maternal prebiotics supplementation, including significant differences in acetic acid concentration between intervention and control groups from 20 to 28-weeks' gestation. CONCLUSION: Maternal prebiotic supplementation of 14.2 g per day GOS/FOS was found to favourably modify both the maternal and the developing infant gut microbiome. These results build on our understanding of the importance of maternal diet during pregnancy, and indicate that it is possible to intervene and modify the development of the infant microbiome by dietary modulation of the maternal gut microbiome.

Systematic characterization of antibody-drug conjugate targets in central nervous system tumors.

BACKGROUND: Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors. METHODS: We analyzed publicly available RNA-sequencing and proteomic data from the children's brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575). RESULTS: Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development. CONCLUSIONS: CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted.

A mentored hands-on training model for scaling up implementation and intervention research in India: "connecting the dots".

Despite the high burden of mental disorders in low- and middle-income countries (LMICs), less than 25% of those in need have access to appropriate services, in part due to a scarcity of locally relevant, evidence-based interventions and models of care. To address this gap, researchers from India and the United States and the Indian Council of Medical Research (ICMR) collaboratively developed a "Grantathon" model to provide mentored research training to 24 new principal investigators (PIs). This included a week-long didactic training, a customized web-based data entry/analysis system and a National Coordination Unit (NCU) to support PIs and track process objectives. Outcome objectives were assessed via scholarly output including publications, awards received and subsequent grants that were leveraged. Multiple mentorship strategies including collaborative problem-solving approaches were used to foster single-centre and multicentre research. Flexible, approachable and engaged support from mentors helped PIs overcome research barriers, and the NCU addressed local policy and day-to-day challenges through informal monthly review meetings. Bi-annual formal review presentations by all PIs continued through the COVID-19 pandemic, enabling interim results reporting and scientific review, also serving to reinforce accountability. To date, more than 33 publications, 47 scientific presentations, 12 awards, two measurement tools, five intervention manuals and eight research grants have been generated in an open-access environment. The Grantathon is a successful model for building research capacity and improving mental health research in India that could be adopted for use in other LMICs.

Changes to the Gut Microbiome in Young Children Showing Early Behavioral Signs of Autism.

The human gut microbiome has increasingly been associated with autism spectrum disorder (ASD), which is a neurological developmental disorder, characterized by impairments to social interaction. The ability of the gut microbiota to signal across the gut-brain-microbiota axis with metabolites, including short-chain fatty acids, impacts brain health and has been identified to play a role in the gastrointestinal and developmental symptoms affecting autistic children. The fecal microbiome of older children with ASD has repeatedly shown particular shifts in the bacterial and fungal microbial community, which are significantly different from age-matched neurotypical controls, but it is still unclear whether these characteristic shifts are detectable before diagnosis. Early microbial colonization patterns can have long-lasting effects on human health, and pre-emptive intervention may be an important mediator to more severe autism. In this study, we characterized both the microbiome and short-chain fatty acid concentrations of fecal samples from young children between 21 and 40 months who were showing early behavioral signs of ASD. The fungal richness and acetic acid concentrations were observed to be higher with increasing autism severity, and the abundance of several bacterial taxa also changed due to the severity of ASD. Bacterial diversity and SCFA concentrations were also associated with stool form, and some bacterial families were found with differential abundance according to stool firmness. An exploratory analysis of the microbiome associated with pre-emptive treatment also showed significant differences at multiple taxonomic levels. These differences may impact the microbial signaling across the gut-brain-microbiota axis and the neurological development of the children.

Fecal sample collection methods and time of day impact microbiome composition and short chain fatty acid concentrations.

Associations between the human gut microbiome and health outcomes continues to be of great interest, although fecal sample collection methods which impact microbiome studies are sometimes neglected. Here, we expand on previous work in sample optimization, to promote high quality microbiome data. To compare fecal sample collection methods, amplicons from the bacterial 16S rRNA gene (V4) and fungal (ITS2) region, as well as short chain fatty acid (SCFA) concentrations were determined in fecal material over three timepoints. We demonstrated that spot sampling of stool results in variable detection of some microbial members, and inconsistent levels of SCFA; therefore, sample homogenization prior to subsequent analysis or subsampling is recommended. We also identify a trend in microbial and metabolite composition that shifts over two consecutive stool collections less than 25 h apart. Lastly, we show significant differences in bacterial composition that result from collecting stool samples in OMNIgene·Gut tube (DNA Genotec) or Stool Nucleic Acid Collection and Preservation Tube (NORGEN) compared to immediate freezing. To assist with planning fecal sample collection and storage procedures for microbiome investigations with multiple analyses, we recommend participants to collect the first full bowel movement of the day and freeze the sample immediately after collection.

The Microbiome of the Gastrointestinal Tract of a Range-Shifting Marine Herbivorous Fish.

Globally, marine species' distributions are being modified due to rising ocean temperatures. Increasing evidence suggests a circum-global pattern of poleward extensions in the distributions of many tropical herbivorous species, including the ecologically important rabbitfish Siganus fuscescens. Adaptability of a species to such new environments may be heavily influenced by the composition of their gastrointestinal microbe fauna, which is fundamentally important to animal health. Siganus fuscescens thus provides an opportunity to assess the stability of gastrointestinal microbes under varying environmental conditions. The gastrointestinal microbial communities of S. fuscescens were characterized over 2,000 km of Australia's western coast, from tropical to temperate waters, including near its current southern distributional limit. Sequencing of the 16S rRNA gene demonstrated that each population had a distinct hindgut microbial community, and yet, 20 OTUs occurred consistently in all samples. These OTUs were considered the 'core microbiome' and were highly abundant, composing between 31 and 54% of each population. Furthermore, levels of short chain fatty acids, an indicator of microbial fermentation activity, were similar among tropical and temperate locations. These data suggest that flexibility in the hindgut microbiome may play a role in enabling such herbivores to colonize new environments beyond their existing range.

Long-term effects of the booster-enhanced READY-Girls preconception counseling program on intentions and behaviors for family planning in teens with diabetes.

OBJECTIVE: To examine 12-month effects of a booster-enhanced preconception counseling (PC) program (READY-Girls) on family planning for teen girls with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants 13-19 years of age (n = 109) were randomized to a standard care control group (CG) or intervention group (IG) that received PC over three consecutive clinic visits. Prepost data were collected at baseline, 3- and 6-month booster sessions, and a 12-month follow-up visit. RESULTS: Mean age was 15.8 years; 9 (8%) subjects had type 2 diabetes; and 18 (17%) subjects were African American. At baseline, 20% (n = 22 of 109) had been sexually active, and of these, 50% (n = 11) had at least one episode of unprotected sex. Over time, IG participants retained greater PC knowledge (F[6, 541] = 4.05, P = 0.0005) and stronger intentions regarding PC (significant group-by-time effects) especially after boosters. IG participants had greater intentions to discuss PC (F[6, 82.4] = 2.56, P = 0.0254) and BC (F[6, 534] = 3.40, P = 0.0027) with health care providers (HCPs) and seek PC when planning a pregnancy (F[6, 534] = 2.58, P = 0.0180). Although not significant, IG participants, compared with CG, showed a consistent trend toward lower rates of overall sexual activity over time: less sexual debut (35 vs. 41%) and higher rates of abstinence (44 vs. 32%). No pregnancies were reported in either group throughout the study. CONCLUSIONS: READY-Girls appeared to have long-term sustaining effects on PC knowledge, beliefs, and intentions to initiate discussion with HCPs that could improve reproductive health behaviors and outcomes. Strong boosters and providing PC at each clinic visit could play important roles in sustaining long-term effects.