Showing papers by "George M. Weinstock published in 2021"

Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice

Abstract: The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics1-5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.

Host genetic control of gut microbiome composition.

Abstract: The gut microbiome plays a significant role in health and disease, and there is mounting evidence indicating that the microbial composition is regulated in part by host genetics. Heritability estimates for microbial abundance in mice and humans range from (0.05-0.45), indicating that 5-45% of inter-individual variation can be explained by genetics. Through twin studies, genetic association studies, systems genetics, and genome-wide association studies (GWAS), hundreds of specific host genetic loci have been shown to associate with the abundance of discrete gut microbes. Using genetically engineered knock-out mice, at least 30 specific genes have now been validated as having specific effects on the microbiome. The relationships among of host genetics, microbiome composition, and abundance, and disease is now beginning to be unraveled through experiments designed to test causality. The genetic control of disease and its relationship to the microbiome can manifest in multiple ways. First, a genetic variant may directly cause the disease phenotype, resulting in an altered microbiome as a consequence of the disease phenotype. Second, a genetic variant may alter gene expression in the host, which in turn alters the microbiome, producing the disease phenotype. Finally, the genetic variant may alter the microbiome directly, which can result in the disease phenotype. In order to understand the processes that underlie the onset and progression of certain diseases, future research must take into account the relationship among host genetics, microbiome, and disease phenotype, and the resources needed to study these relationships.

The Gut Microbiome and Substance Use Disorder.

Abstract: Substance use disorders (SUDs) remain a significant public health challenge, affecting tens of millions of individuals worldwide each year. Often comorbid with other psychiatric disorders, SUD can be poly-drug and involve several different substances including cocaine, opiates, nicotine, and alcohol. SUD has a strong genetic component. Much of SUD research has focused on the neurologic and genetic facets of consumption behavior. There is now interest in the role of the gut microbiome in the pathogenesis of SUD. In this review, we summarize current animal and clinical evidence that the gut microbiome is involved in SUD, then address the underlying mechanisms by which the gut microbiome interacts with SUD through metabolomic, immune, neurological, and epigenetic mechanisms. Lastly, we discuss methods using various inbred and outbred mice models to gain an integrative understanding of the microbiome and host genetic controls in SUD.

Metagenomics and chemotherapy-induced nausea: A roadmap for future research

Abstract: Uncontrolled chemotherapy-induced nausea and vomiting can reduce patients' quality of life and may result in premature discontinuation of chemotherapy. Although nausea and vomiting are commonly grouped together, research has shown that antiemetics are clinically effective against chemotherapy-induced vomiting (CIV) but less so against chemotherapy-induced nausea (CIN). Nausea remains a problem for up to 68% of patients who are prescribed guideline-consistent antiemetics. Despite the high prevalence of CIN, relatively little is known regarding its etiology independent of CIV. This review summarizes a metagenomics approach to the study and treatment of CIN with the goal of encouraging future research. Metagenomics focuses on genetic risk factors and encompasses both human (ie, host) and gut microbial genetic variation. Little work to date has focused on metagenomics as a putative biological mechanism of CIN. Metagenomics has the potential to be a powerful tool in advancing scientific understanding of CIN by identifying new biological pathways and intervention targets. The investigation of metagenomics in the context of well-established demographic, clinical, and patient-reported risk factors may help to identify patients at risk and facilitate the prevention and management of CIN.

Alterations in subgingival microbiota during full-fixed appliance orthodontic treatment—A prospective study

Abstract: BACKGROUND Full-fixed appliance orthodontic treatment (commonly called braces) increases plaque accumulation and the risk of gingivitis and periodontitis. However, little consensus exists on changes to subgingival microbiota and specific periodontopathogens during treatment with braces. Prior studies have been hampered by selection biases due to dependence on culture conditions, candidate-based PCR and shallow sequencing methods. OBJECTIVE The objective was to provide the first longitudinal, culture-free and deep-sequence profiling of subgingival bacteria in subjects during early stages of full-fixed orthodontic treatment. METHODS We performed 16S rRNA next-generation sequencing (NGS) on 168 subgingival samples collected at 4 distinct mandibular tooth sites per subject before (0 weeks) and during (6 and 12 weeks) orthodontic intervention in 9 experimental and 5 control subjects not undergoing treatment. RESULTS Overall, we noted that orthodontic intervention led to increased microbial richness, accompanied by an increased incidence of localized gingivitis/mild periodontitis in subjects requiring orthodontic treatment compared to controls, as well as significant baseline variations in subgingival microbiomes in all subjects. Moreover, we confirmed individual- and site-dependent microbiome variability (in particular, the lingual site harboured higher microbiome diversity than buccal sites) that orthodontic bands may lead to more prolonged shifts in microbial changes compared to brackets, and evidence of adaptive enrichment of consensus bacteria with orthodontic intervention (12 novel, consensus bacterial species were identified). CONCLUSION Our study, along with evolving global profiling methods and data analyses, builds a strong foundation for further analyses of subgingival microbiomes during full-fixed orthodontic treatment.

Association of gut microbiota and environment in children with AD, comparison of three cohorts of children.

Abstract: Atopic dermatitis (AD) is one of the most common diseases in pediatric patients, with over 12.5% of US children diagnosed with the condition.1 Previous studies have shown that the impaired skin barrier caused by AD leads to the development of other atopic conditions later in life.2 The rate of AD among black children in Africa is similar to reported rates among African Americans (AA), while the rate of other atopic diseases such as asthma and food allergy (FA) in black children living in African countries are lower compared to most western populations. 3 The lower rate of asthma and FA, despite similar AD rates among rural African children, calls into question the critical role environment plays in protection against the progression of the atopic march. Previous evidence suggests gut microbiota differences are linked to the initiation and progression of atopic diseases.4 It is possible that changes in the environment including diet, exposure to microbes, and lifestyle factors result in alteration in the gut microbiome and contribute to the risk of atopic diseases. In certain African countries, many individuals still live in completely natural settings. Studying these populations provides the opportunity to evaluate the protective role of environment and lifestyle on gut microbiota and atopic diseases.