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While rapid demographic changes in Asia are driving the incidence of chronic aging-related diseases, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun-metagenomic sequencing for high-resolution taxonomic and functional characterization of their gut microbiomes (n = 234). Joint species-level analysis with other Asian cohorts identified distinct age-associated shifts characterized by reduction in microbial richness, and specific Alistipes and Bacteroides species enrichment (e.g., Alistipes shahii and Bacteroides xylanisolvens). Functional analysis confirmed these changes correspond to metabolic potential expansion in aging towards alternate pathways synthesizing and utilizing amino-acid precursors, vis-à-vis dominant microbial guilds producing butyrate in gut from pyruvate (e.g., Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species (e.g., Parabacteroides goldsteinii) and pathobionts (e.g., Klebsiella pneumoniae), highlighting the microbiome's role as biomarkers and potential targets for promoting healthy aging., (© 2024. The Author(s).)

Long-term colonization of the gut microbiome by carbapenemase-producing Enterobacteriaceae (CPE) is a growing area of public health concern as it can lead to community transmission and rapid increase in cases of life-threatening CPE infections. Here, leveraging the observation that many subjects are decolonized without interventions within a year, we used longitudinal shotgun metagenomics (up to 12 timepoints) for detailed characterization of ecological and evolutionary dynamics in the gut microbiome of a cohort of CPE-colonized subjects and family members (n = 46; 361 samples). Subjects who underwent decolonization exhibited a distinct ecological shift marked by recovery of microbial diversity, key commensals and anti-inflammatory pathways. In addition, colonization was marked by elevated but unstable Enterobacteriaceae abundances, which exhibited distinct strain-level dynamics for different species (Escherichia coli and Klebsiella pneumoniae). Finally, comparative analysis with whole-genome sequencing data from CPE isolates (n = 159) helped identify substrain variation in key functional genes and the presence of highly similar E. coli and K. pneumoniae strains with variable resistance profiles and plasmid sharing. These results provide an enhanced view into how colonization by multi-drug-resistant bacteria associates with altered gut ecology and can enable transfer of resistance genes, even in the absence of overt infection and antibiotic usage., (© 2022. The Author(s).)

Conclusion: BEEM-Static provides new opportunities for mining ecologically interpretable interactions and systems insights from the growing corpus of microbiome data., Competing Interests: The authors have declared that no competing interests exist.

Loss of diversity in the gut microbiome can persist for extended periods after antibiotic treatment, impacting microbiome function, antimicrobial resistance and probably host health. Despite widespread antibiotic use, our understanding of the species and metabolic functions contributing to gut microbiome recovery is limited. Using data from 4 discovery cohorts in 3 continents comprising >500 microbiome profiles from 117 individuals, we identified 21 bacterial species exhibiting robust association with ecological recovery post antibiotic therapy. Functional and growth-rate analysis showed that recovery is supported by enrichment in specific carbohydrate-degradation and energy-production pathways. Association rule mining on 782 microbiome profiles from the MEDUSA database enabled reconstruction of the gut microbial 'food web', identifying many recovery-associated bacteria as keystone species, with the ability to use host- and diet-derived energy sources, and support repopulation of other gut species. Experiments in a mouse model recapitulated the ability of recovery-associated bacteria (Bacteroides thetaiotaomicron and Bifidobacterium adolescentis) to promote recovery with synergistic effects, providing a boost of two orders of magnitude to microbial abundance in early time points and faster maturation of microbial diversity. The identification of specific species and metabolic functions promoting recovery opens up opportunities for rationally determining pre- and probiotic formulations offering protection from long-term consequences of frequent antibiotic usage.

Background: The dynamics of microbial communities is driven by a range of interactions from symbiosis to predator-prey relationships, the majority of which are poorly understood. With the increasing availability of high-throughput microbiome taxonomic profiling data, it is now conceivable to directly learn the ecological models that explicitly define microbial interactions and explain community dynamics. The applicability of these approaches is severely limited by the lack of accurate absolute cell density measurements (biomass)., Methods: We present a new computational approach that resolves this key limitation in the inference of generalized Lotka-Volterra models (gLVMs) by coupling biomass estimation and model inference with an expectation-maximization algorithm (BEEM)., Results: BEEM outperforms the state-of-the-art methods for inferring gLVMs, while simultaneously eliminating the need for additional experimental biomass data as input. BEEM's application to previously inaccessible public datasets (due to the lack of biomass data) allowed us to construct ecological models of microbial communities in the human gut on a per-individual basis, revealing personalized dynamics and keystone species., Conclusions: BEEM addresses a key bottleneck in "systems analysis" of microbiomes by enabling accurate inference of ecological models from high throughput sequencing data without the need for experimental biomass measurements.

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher β-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo., Conclusion: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295)., (© 2017 by the American Association for the Study of Liver Diseases.)

Cholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty primary CCA tumors and matched normals, from both liver fluke (Opisthorchis viverrini) associated (OVa, n=28) and non-O. viverrini associated (non-OVa, n=32) cancers, were profiled using high-throughput 16S rRNA sequencing. A distinct, tissue-specific microbiome dominated by the bacterial families Dietziaceae, Pseudomonadaceae and Oxalobacteraceae was observed in bile duct tissues. Systemic perturbation of the microbiome was noted in tumor and paired normal samples (vs non-cancer normals) for several bacterial families with a significant increase in Stenotrophomonas species distinguishing tumors vs paired normals. Comparison of parasite associated (OVa) vs non-associated (non-OVa) groups identified enrichment for specific enteric bacteria (Bifidobacteriaceae, Enterobacteriaceae and Enterococcaceae). One of the enriched families, Bifidobacteriaceae, was found to be dominant in the O. viverrini microbiome, providing a mechanistic link to the parasite. Functional analysis and comparison of CCA microbiomes revealed higher potential for producing bile acids and ammonia in OVa tissues, linking the altered microbiota to carcinogenesis. These results define how the unique microbial communities resident in the bile duct, parasitic infections and the tissue microenvironment can influence each other, and contribute to cancer., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)