Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD. METHODS: The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin. Breast milk proteomics was profiled using Olink inflammation panel. RESULTS: We analysed gut microbiota of 1034 faecal samples from 294 infants [80 born to mothers with and 214 to mothers without IBD]. Alpha diversity was driven by maternal IBD status and time point. The major influencers of the overall composition of the microbiota were mode of delivery, feeding, and maternal IBD status. Specific taxa were associated with these exposures, and maternal IBD was associated with a reduction in Bifidobacterium. In 312 breast milk samples [91 from mothers with IBD], mothers with IBD displayed lower abundance of proteins involved in immune regulation, such as thymic stromal lymphopoietin, interleukin-12 subunit beta, tumour necrosis factor-beta, and C-C motif chemokine 20, as compared with control mothers [adjusted p = 0.0016, 0.049, 0.049, and 0.049, respectively], with negative correlations with baby´s calprotectin, and microbiome at different time points. CONCLUSION: Maternal IBD diagnosis influences microbiota in their offspring during early life. The proteomic profile of breast milk of women with IBD differs from that of women without IBD, with distinct time-dependent associations with baby's gut microbiome and feacal calprotectin.

Wnt/ß-catenin activation and macrophage induction during liver cancer development following steatosis.

Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/ß-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/ß-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/ß-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/ß-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/ß-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.

The FIGO Save the Mothers Initiative: the Ethiopia-Sweden collaboration.

The overall goal of the FIGO Save the Mothers Fund was to establish basic and comprehensive emergency obstetric care (EmOC) with the specific objectives of increasing the availability and utilization of quality obstetric care as measured by the UN indicators. As a result of this commitment by FIGO, the Ethiopian Society of Obstetricians and Gynecologists (ESOG) launched the Save the Mothers Project (SMP) in West Showa Zone (WSZ), Ethiopia in 1998 to implement and test a demonstration project and evaluate the feasibility and impact of the intervention. The overall objectives matched FIGO's-reducing maternal deaths by promoting the availability, access and utilization of EmOC services for women with complications of pregnancy and childbirth. The intervention package included capacity building as a major activity, and physicians and other service providers from Ambo Hospital, Shenen and Ijaji Health Centers were trained in EmOC. This was intended to combat the high staff turnover in the area. Equipment, materials and supplies were also provided to the demonstration sites to enable them provide basic and comprehensive EmOC services. The interventions, begun in 1999, led to improvements in availability, utilization and met need, which suggests that such an approach may eventually lead to the reduction of maternal deaths. The cesarean section rate for Ambo Hospital increased from 3.7% in 1998 to 17.3% in 2001--an almost six-fold increase. At Ambo Hospital both the total number of deliveries and cases admitted with obstetric complications have increased from baseline. Patients with obstructed labor comprise 39% of all obstetric patients making it the leading cause of hospitalization. Obstetric hemorrhage comes next with 24% of all admissions. The case fatality rate (CFR) (for direct maternal deaths) decreased from 7.2% at baseline, to 4.6% in 2001--showing a definite trend of improvement. Currently, there is 24-h EmOC service at Ambo Hospital where an obstetrician and general medical practitioners with EmOC training are responsible for the service. Shenen and Ijaji health Centers are upgraded in terms of training of staff members, provision of equipment and supplies, and regular supervision so that the community in these areas has access to basic EmOC services. To replicate similar activities, in a setting like ours, EmOC projects have to be low cost to attract decision-makers. The SMP used almost US dollars 100,000 over 3 years to ensure availability of EmOC services for women in WSZ. A favorable political climate such as maintenance of relative peace, and flexibility in adapting to local conditions also contributed to the success of the SMP.