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.

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.

Blood group A mothers are more likely to develop anemia during antenatal intravenous immunoglobulin treatment of fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Incompatibility between parental platelet (PLT) antigens may lead to sensitization of mother and development of fetal and neonatal alloimmune thrombocytopenia (FNAIT) resulting in fetal thrombocytopenia. Intravenous immunoglobulin (IVIG) with or without prednisone is the most effective, evidence-based antenatal treatment for subsequent FNAIT-affected pregnancies. IVIG infusion causes hemolysis in other settings, the degree depending upon patient blood groups (BGs). STUDY DESIGN AND METHODS: In ClinicalTrials.gov NCT00194987, 102 pregnant women received randomized antenatal treatment: Arm A received 2 g/kg/week IVIG; Arm B received 1 g/kg/week IVIG + 0.5 mg/kg/day prednisone. This post hoc analysis explored BG and anemia in 69 FNAIT mothers treated with Arm A or Arm B without salvage treatment to explore the effects of IVIG and steroid treatment on development of anemia in these women. Mothers whose treatment changed, for example, those with insufficient or unknown fetal PLT response who received salvage therapy, were excluded. RESULTS: For Arm A, 17 of 21 (hemoglobin [Hb] < 10 g/dL) mothers with anemia but only three of 15 mothers without anemia had BG-A and/or BG-B (p = 0.0005). BG was unrelated to anemia in Arm B; only nine of 33 Arm B mothers became anemic during treatment. The mean decrease in Hb level in women with BG-non-O was 1.9 g/dL and in women with BG-O was 1.1 g/dL (p = 0.004). Anemia was not caused by iron deficiency; the lowest mean corpuscular volume was 79. CONCLUSION: FNAIT women with BG-non-O more frequently develop anemia secondary to high-dose IVIG infusion (2 g/kg/week), quite possibly from isohemagglutinin-mediated hemolysis; maternal Hb requires monitoring. IVIG at 1 g/kg/week did not cause anemia in women with BG-non-O; concomitant prednisone likely alleviated the IVIG effect. Maternal BG could influence selection of antenatal treatment for FNAIT.

Omission of fetal sampling in treatment of subsequent pregnancies in fetal-neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal-neonatal alloimmune thrombocytopenia affects approximately 1 of 1000 live births, most of which are not severely thrombocytopenic. Despite effective treatment with intravenous gammaglobulin and/or prednisone, antenatal management of a subsequent affected pregnancy is complicated by the risks associated with fetal blood sampling. Furthermore, there are no biomarker(s) of high risk other than the occurrence of intracranial hemorrhage in a previous sibling. Management of these high-risk pregnancies requires intensive treatment initiated at 12 weeks of gestation. OBJECTIVE: The objective of the study was to evaluate whether empiric escalation of therapy at 32 weeks allows the omission of fetal blood sampling in all fetal-neonatal alloimmune thrombocytopenia-affected patients. Specifically, we sought to determine whether intensive intravenous gammaglobulin-based regimens for the treatment of a subsequent fetal-neonatal alloimmune thrombocytopenia-affected pregnancy followed by empirically escalated intravenous gammaglobulin and prednisone treatment would increase the fetal platelet count and thus safely allow omission of fetal blood sampling in the antepartum management of these patients. STUDY DESIGN: In this prospective, multicenter, randomized controlled study, 99 women with fetal-neonatal alloimmune thrombocytopenia whose prior affected child did not have an intracranial hemorrhage were randomized to receive an intensive intravenous gammaglobulin-based regimen: 2 g/kg per week or intravenous gammaglobulin 1 g/kg per week plus prednisone 0.5 mg/kg per day, starting at 20-30 weeks of gestation. Escalated therapy (intravenous gammaglobulin 2 g/kg per week plus prednisone 0.5 mg/kg per day) was recommended and usually initiated at 32 weeks when fetal counts were <50,000/mL(3) or when fetal blood sampling was not performed. The preliminary report of this study from 2007 demonstrated the efficacy of both intravenous gammaglobulin-based regimens in most patients. Most patients who underwent fetal sampling had adequate fetal counts and therefore did not have their treatment escalated. This post hoc analysis describes the 29 fetuses who had their treatment escalated either because they had low counts at 32 weeks or when sampling was not performed. This study explored whether the empiric escalation of treatment at 32 weeks was sufficiently effective in increasing fetal platelet counts in these patients. RESULTS: Mean fetal and birth counts of fetuses randomized to each of the 2 initial treatment groups were all >100,000/mL(3). Three neonates had an intracranial hemorrhage; all 3 were grade 1 and all had birth platelet counts >130,000/mL(3). In a post hoc analysis, 19 fetuses undergoing fetal blood sampling at 32 weeks had fetal platelet counts <50,000/mL(3) despite their initial treatment. Of these 19, birth platelet counts were >50,000/mL(3) in 11 of 13 fetuses who received escalated treatment compared with only 1 of 6 of those who did not (P = .01); only 3 fetuses that received initial therapy followed by escalated treatment had birth platelet counts <50,000/mL(3) and none had an intracranial hemorrhage. The platelet counts of 14 of 15 fetuses that received empirically escalated treatment without sampling were >50,000/mL(3) at birth. In addition, none of these had an intracranial hemorrhage. CONCLUSION: The 2 recommended protocols of intensive initial treatment followed by empiric escalation of therapy at 32 weeks of gestation are reasonably safe, effective in increasing fetal platelet counts, and allow omission of fetal blood sampling by increasing the fetal platelet count in almost all cases.