Gut microbiome shifts in adolescents after sleeve gastrectomy with increased oral-associated taxa and pro-inflammatory potential.

Background: Bariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown. Objectives: 1) To comprehensively examine gut microbiome and metabolome changes after laparoscopic vertical sleeve gastrectomy (VSG) in adolescents and 2) to assess whether the microbiome/metabolome changes observed with VSG influence phenotype using germ-free murine models. Design: 1) A longitudinal observational study in adolescents undergoing VSG with serial stool samples undergoing shotgun metagenomic microbiome sequencing and metabolomics (polar metabolites, bile acids and short chain fatty acids) and 2) a human-to-mouse fecal transplant study. Results: We show adolescents exhibit significant gut microbiome and metabolome shifts several months after VSG, with increased alpha diversity and notably with enrichment of oral-associated taxa. To assess causality of the microbiome/metabolome changes in phenotype, pre-VSG and post-VSG stool was transplanted into germ-free mice. Post-VSG stool was not associated with any beneficial outcomes such as adiposity reduction compared pre-VSG stool. However, post-VSG stool exhibited an inflammatory phenotype with increased intestinal Th17 and decreased regulatory T cells. Concomitantly, we found elevated fecal calprotectin and an enrichment of proinflammatory pathways in a subset of adolescents post-VSG. Conclusion: We show that in some adolescents, microbiome changes post-VSG may have inflammatory potential, which may be of importance considering the increased incidence of inflammatory bowel disease post-VSG. What is already known on this topic: Bariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown. What this study adds: Significant gut microbiome and metabolome shifts were found several months after vertical sleeve gastrectomy in adolescents, notably with enrichment of oral-associated taxa. Using human to germ-free mice fecal transplant studies, the post-surgery changes in the gut microbiome/metabolome were shown to have inflammatory potential. Furthermore, raised fecal calprotectin and inflammatory systemic pathways were seen in a subset of adolescents post-surgery. How this study might affect research practice or policy: These findings may be of importance given the growing recognition of an increased incidence of inflammatory bowel disease after bariatric surgery and warrants further investigation.

Fecal transplant from vaginally seeded infants decreases intraabdominal adiposity in mice.

Exposing C-section infants to the maternal vaginal microbiome, coined "vaginal seeding", partially restores microbial colonization. However, whether vaginal seeding decreases metabolic disease risk is unknown. Therefore, we assessed the effect of vaginal seeding of human infants on adiposity in a murine model. Germ-free mice were colonized with transitional stool from human infants who received vaginal seeding or control (placebo) seeding in a double-blind randomized trial. There was a reduction in intraabdominal adipose tissue (IAAT) volume in male mice that received stool from vaginally seeded infants compared to control infants. Higher levels of isoleucine and lower levels of nucleic acid metabolites were observed in controls and correlated with increased IAAT. This suggests that early changes in the gut microbiome and metabolome caused by vaginal seeding have a positive impact on metabolic health.

A comprehensive survey of coronaviral main protease active site diversity in 3D: Identifying and analyzing drug discovery targets in search of broad specificity inhibitors for the next coronavirus pandemic.

Although the rapid development of therapeutic responses to combat SARS-CoV-2 represents a great human achievement, it also demonstrates untapped potential for advanced pandemic preparedness. Cross-species efficacy against multiple human coronaviruses by the main protease (MPro) inhibitor nirmatrelvir raises the question of its breadth of inhibition and our preparedness against future coronaviral threats. Herein, we describe sequence and structural analyses of 346 unique MPro enzymes from all coronaviruses represented in the NCBI Virus database. Cognate substrates of these representative proteases were inferred from their polyprotein sequences. We clustered MPro sequences based on sequence identity and AlphaFold2-predicted structures, showing approximate correspondence with known viral subspecies. Predicted structures of five representative MPros bound to their inferred cognate substrates showed high conservation in protease:substrate interaction modes, with some notable differences. Yeast-based proteolysis assays of the five representatives were able to confirm activity of three on inferred cognate substrates, and demonstrated that of the three, only one was effectively inhibited by nirmatrelvir. Our findings suggest that comprehensive preparedness against future potential coronaviral threats will require continued inhibitor development. Our methods may be applied to candidate coronaviral MPro inhibitors to evaluate in advance the breadth of their inhibition and identify target coronaviruses potentially meriting advanced development of alternative countermeasures.

The Gut Microbiome of Children during the COVID-19 Pandemic.

The gut microbiome has been shown to play a critical role in maintaining a healthy state. Dysbiosis of the gut microbiome is involved in modulating disease severity and potentially contributes to long-term outcomes in adults with COVID-19. Due to children having a significantly lower risk of severe illness and limited sample availability, much less is known about the role of the gut microbiome in children with COVID-19. It is well recognized that the developing gut microbiome of children differs from that of adults, but it is unclear if this difference contributes to the different clinical presentations and complications. In this review, we discuss the current knowledge of the gut microbiome in children with COVID-19, with gut microbiome dysbiosis being found in pediatric COVID-19 but specific taxa change often differing from those described in adults. Additionally, we discuss possible mechanisms of how the gut microbiome may mediate the presentation and complications of COVID-19 in children and the potential role for microbial therapeutics.