Gut bacteria-derived serotonin promotes immune tolerance in early life.

The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell-mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.

The Gut-Liver Axis in Pediatric Liver Health and Disease.

There has been growing interest in the complex host-microbe interactions within the human gut and the role these interactions play in systemic health and disease. As an essential metabolic organ, the liver is intimately coupled to the intestinal microbial environment via the portal venous system. Our understanding of the gut-liver axis comes almost exclusively from studies of adults; the gut-liver axis in children, who have unique physiology and differing gut microbial communities, remains poorly understood. Here, we provide a comprehensive overview of common pediatric hepatobiliary conditions and recent studies exploring the contributions of the gut microbiota to these conditions or changes of the gut microbiota due to these conditions. We examine the current literature regarding the microbial alterations that take place in biliary atresia, pediatric non-alcoholic fatty liver disease, Wilson's disease, cystic fibrosis, inflammatory bowel disease, and viral hepatitis. Finally, we propose potential therapeutic approaches involving modulation of the gut microbiota and the gut-liver axis to mitigate the progression of pediatric liver disease.

SARS CoV-2 detected in neonatal stool remote from maternal COVID-19 during pregnancy.

BACKGROUND: In utero transmission of SARS coronavirus 2 (SARS-CoV-2) has not been fully investigated. We investigated whether newborns of mothers with COVID-19 during pregnancy might harbor SARS-CoV-2 in the gastrointestinal tract. METHODS: This cohort study investigated stool from 14 newborns born at 25-41 weeks admitted at delivery to our urban academic hospital whose mothers had COVID-19 during pregnancy. Eleven mothers had COVID-19 resolved more than 10 weeks before delivery. Newborn stool was evaluated for SARS-CoV-2 RNA, Spike protein, and induction of inflammatory cytokines interleukin-6 (IL-6) and interferon-γ (IFN-γ) in macrophages. RESULTS: Despite negative SARS CoV-2 nasal PCRs from all newborns, viral RNAs and Spike protein were detected in the stool of 11 out of 14 newborns as early as the first day of life and increased over time in 6. Stool homogenates from all 14 newborns elicited elevated inflammatory IL-6 and IFN-γ from macrophages. Most newborns were clinically well except for one death from gestational autoimmune liver disease and another who developed necrotizing enterocolitis. CONCLUSIONS: These findings suggest in utero transmission of SARS-CoV-2 and possible persistent intestinal viral reservoirs in the newborns. Further investigation is required to understand the mechanisms and their clinical implications. IMPACT: SARS-CoV-2 RNAs or Spike protein was detected in the stool of 11 out of 14 preterm newborns born to mothers with resolved COVID-19 weeks prior to delivery despite negative newborn nasal PCR swabs. These novel findings suggest risk of in utero SARS-CoV-2 transmission to the fetal intestine during gestation. The presence of SARS-CoV-2 RNAs and Spike protein in the intestines of newborns may potentially impact the development of the gut microbiome and the immune system; the long-term health impact on the preterm infants should be further investigated.

Maternal Microbiome and Infections in Pregnancy.

Pregnancy induces unique changes in maternal immune responses and metabolism. Drastic physiologic adaptations, in an intricately coordinated fashion, allow the maternal body to support the healthy growth of the fetus. The gut microbiome plays a central role in the regulation of the immune system, metabolism, and resistance to infections. Studies have reported changes in the maternal microbiome in the gut, vagina, and oral cavity during pregnancy; it remains unclear whether/how these changes might be related to maternal immune responses, metabolism, and susceptibility to infections during pregnancy. Our understanding of the concerted adaption of these different aspects of the human physiology to promote a successful pregnant remains limited. Here, we provide a comprehensive documentation and discussion of changes in the maternal microbiome in the gut, oral cavity, and vagina during pregnancy, metabolic changes and complications in the mother and newborn that may be, in part, driven by maternal gut dysbiosis, and, lastly, common infections in pregnancy. This review aims to shed light on how dysregulation of the maternal microbiome may underlie obstetrical metabolic complications and infections.

Exploring background mutational processes to decipher cancer genetic heterogeneity.

Much remains unknown about the progression and heterogeneity of mutational processes in different cancers and their diagnostic and clinical potential. A growing body of evidence supports mutation rate dependence on the local DNA sequence context for various types of mutations. We propose several tools for the analysis of cancer context-dependent mutations, which are implemented in an online computational framework MutaGene. The framework explores DNA context-dependent mutational patterns and underlying somatic cancer mutagenesis, analyzes mutational profiles of cancer samples, identifies the combinations of underlying mutagenic processes including those related to infidelity of DNA replication and repair machinery, and various other endogenous and exogenous mutagenic factors. As a result, the combination of mutagenic processes can be identified in any query sample with subsequent comparison to mutational profiles derived from malignant and benign samples. In addition, mutagen or cancer-specific mutational background models are applied to calculate expected DNA and protein site mutability to decouple relative contributions of mutagenesis and selection in carcinogenesis, thus elucidating the site-specific driving events in cancer. MutaGene is freely available at https://www.ncbi.nlm.nih.gov/projects/mutagene/.