The gut microbiome is established in the newborn period and is recognised to interact with the host to influence metabolism. Different environmental factors that are encountered during this critical period may influence the gut microbial composition, potentially impacting upon later disease risk, such as asthma, metabolic disorder, and inflammatory bowel disease. The sterility dogma of the foetus in utero is challenged by studies that identified bacteria, bacterial DNA, or bacterial products in meconium, amniotic fluid, and the placenta; indicating the initiation of maternal-to-offspring microbial colonisation in utero. This narrative review aims to provide a better understanding of factors that affect the development of the gastrointestinal (GI) microbiome during prenatal, perinatal to postnatal life, and their reciprocal relationship with GI tract development in neonates.

Background: Non-alcoholic fatty liver disease (NAFLD) can be ameliorated by weight loss although difficult to maintain. Emerging evidence indicates that prebiotics and antibiotics improve NAFLD. Aim: To determine whether inulin supplementation after brief metronidazole therapy is effective in reducing alanine aminotransferase (ALT) and maintaining weight loss achieved through a very-low-calorie diet (VLCD) among people with NAFLD. Methods: Sixty-two people with NAFLD commenced 4-week VLCD using Optifast meal replacements (600 kcal/day). Sixty were then randomised into a 12-week double-blind, placebo-controlled, parallel three-arm trial: (1) 400 mg metronidazole twice daily in Week 1 then inulin 4 g twice daily OR (2) placebo twice daily in week one then inulin OR (3) placebo-placebo. Main outcomes were ALT and body weight at 12 weeks. Fecal microbiota changes were also evaluated. Results: Mean body mass index (BMI) and ALT reduced after VLCD by 2.4 kg/m² and 11 U/L, respectively. ALT further decreased after metronidazole-inulin compared to after placebo-placebo (mean ALT change −19.6 vs. −0.2 U/L, respectively; p = 0.026); however, weight loss maintenance did not differ. VLCD treatment decreased the ratio of Firmicutes/Bacteroidetes (p = 0.002). Conclusion: Brief metronidazole followed by inulin supplementation can reduce ALT beyond that achieved after VLCD in patients with NAFLD.

Purpose: Peritoneal metastases (PM) in colorectal cancer portend a poor prognosis. We sought to elucidate molecular features differentiating primary tumors (PT) from PMs and actionable targets facilitating transcoelomic dissemination and progression. Experimental Design: We performed multiomic profiling of 227 samples from 136 patients, including 56 PTs and 120 synchronous PMs comprising 34 matched PT–PM pairs. Whole-exome and bulk RNA sequencing analyses were conducted to identify underlying genomic aberrations and transcriptomic differences between primary and peritoneal lesions. We spatially characterized the microenvironment of tumor–stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. Results: Whole-exome sequencing found that genomic alterations and clonality patterns between PTs and PMs remain broadly similar. Transcriptomic profiles, however, suggest a transition as tumors reach the peritoneum toward a more mesenchymal tumor profile and fibrotic tumor microenvironment. Applying spatial profiling, we identify a fibro-collagenous and immune-infiltrated stromal phenotype [stromal cluster (SC) 2] characterized by increased cancer-associated fibroblasts, memory B cells, M2 macrophages, and T-cell exhaustion. These findings were orthogonally validated by multiplex IHC. Patients with SC2 stroma had poorer survival and were characterized by high SERPINE-1 (PAI-1) expression. PMs in patients with SC2 stroma were associated with enriched oncogenic pathways such as TGF-β. PAI-1 inhibition of colorectal cancer PM cell lines with a novel biologic demonstrated reduced IL2–STAT5 and TGF-β pathways and cell death. Conclusions: Our findings unveil distinctive and actionable molecular signatures, offering deeper insights into the intricate cross-talk between tumor cells and stromal microenvironments enabling PM in colorectal cancer.

Nutritional supplementation is a common clinical intervention to support the growth of preterm infants. There is little information on how nutritional supplementation interacts with the developing microbiome of the small intestine, the major site for nutrient metabolism and absorption. We investigated the effect of preterm birth and nutritional supplementation on the mucosal and luminal microbiota along the gastrointestinal tract (GIT) of preterm lambs. Preterm lambs (n = 24) were enterally supplemented with branched-chain amino acids (BCAAs), carbohydrate (maltodextrin), or water for two weeks from birth. Term lambs (n = 7) received water. Mucosal scrapings and luminal samples were collected from the duodenum, jejunum, ileum (small intestine) and colon at six weeks post-term age and analysed by 16S rRNA amplicon sequencing. Anatomical site explained 54% (q = 0.0004) of the variance and differences between the term and preterm groups explained 5.7% (q = 0.024) of the variance in microbial beta-diversities. The colon was enriched with Tenericutes and Verrucomicrobia compared to the small intestine, while Actinobacteria, and superphylum Patescibacteria were present in higher abundance in the small intestine compared to the colon. Our findings highlight that early-life short-term nutritional supplementation in preterm lambs does not alter the microbial community residing in the small intestine and colon.

Supplementary Table 1. Cohort and sample overview.

Supplementary Table 3. Spatial QC metrics and cell type markers.