Review Series
Abstract
Asthma is a common chronic respiratory disease affecting people of all ages globally. The airway hosts diverse microbial communities increasingly recognized as influential in the development and disease course of asthma. Here, we review recent findings on the airway microbiome in asthma. As relationships between the airway microbiome and respiratory health take root early in life, we first provide an overview of the early-life airway microbiome and asthma development, where multiple cohort studies have identified bacterial genera in the infant airway associated with risk of future wheeze and asthma. We then address current understandings of interactions between environmental factors, the airway microbiome, and asthma, including the effects of rural/urban environments, pet ownership, smoking, viral illness, and antibiotics. Next, we delve into what has been observed about the airway microbiome and asthma phenotypes and endotypes, as airway microbiota have been associated with asthma control, severity, obesity-related asthma, and treatment effects as well as with type 2 high, type 2 low, and more newly described multi-omic asthma endotypes. We then discuss emerging approaches to shape the microbiome for asthma therapy and conclude the Review with perspectives on future research directions.
Authors
Young Jin Kim, Supinda Bunyavanich
Abstract
The maternal microbiome is emerging as an important factor that influences the neurological health of mothers and their children. Recent studies highlight how microbial communities in the maternal gut can shape early-life development in ways that inform long-term health trajectories. Research on the neurodevelopmental effects of maternal microbiomes is expanding our understanding of the microbiome-gut-brain axis to include signaling across the maternal-offspring unit during the perinatal period. In this Review, we synthesize existing literature on how the maternal microbiome modulates brain function and behavior in both mothers and their developing offspring. We present evidence from human and animal studies showing that the maternal microbiome interacts with environmental factors to impact risk for neurodevelopmental abnormalities. We further discuss molecular and cellular mechanisms that facilitate maternal-offspring crosstalk for neuromodulation. Finally, we consider how advancing understanding of these complex interactions could lead to microbiome-based interventions for promoting maternal and offspring health.
Authors
Stephanie B. Orchanian, Elaine Y. Hsiao
Abstract
Human skin acts as a physical barrier to prevent the entry of pathogenic microbes while simultaneously providing a home for commensal bacteria and fungi. Microbiome sequencing studies have demonstrated the unappreciated diversity and selectivity of these microbes. Functional studies have demonstrated the impact of specific strains to tune the immune system, sculpt the microbial community, provide colonization resistance, and promote epidermal barrier integrity. Recent studies have integrated the microbiome, immunity, and tissue integrity to understand their interplay in common disorders such as atopic dermatitis. In this Review, we explore microbiome shifts associated with cutaneous disorders with an eye toward how the microbiome can be mined to identify new therapeutic opportunities.
Authors
Tiffany C. Scharschmidt, Julia A. Segre
Abstract
Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome compared with that of patients who don’t respond. Fecal microbiota transplants (FMTs) from patients into mice phenocopy the patient tumor responses: FMTs from responders promote response to ICIs, whereas FMTs from nonresponders do not promote a response. In patients, FMTs from patients who have had a complete response to ICIs can overcome resistance in patients who progress on treatment. However, the responses to FMTs are variable. Though emerging studies indicate that gut bacteria can promote antitumor immunity in the absence of ICIs, this Review will focus on studies that demonstrate relationships between the gut microbiome and response to ICIs. We will explore studies investigating which bacteria promote response to ICIs in preclinical models, which bacteria are associated with response in patients with cancer receiving ICIs, the mechanisms by which gut bacteria promote antitumor immunity, and how microbiome-based therapies can be translated to the clinic.
Authors
Francesca S. Gazzaniga, Dennis L. Kasper
Abstract
Substance use disorders (SUDs) are highly prevalent and associated with excess morbidity, mortality, and economic costs. Thus, there is considerable interest in the early identification of individuals who may be more susceptible to developing SUDs and in improving personalized treatment decisions for those who have SUDs. SUDs are known to be influenced by both genetic and environmental factors. Polygenic scores (PGSs) provide a single measure of genetic liability that could be used as a biomarker in predicting disease development, progression, and treatment response. Although PGSs are rapidly being integrated into clinical practice, there is little information to guide clinicians in their responsible use and interpretation. In this Review, we discuss the potential benefits and pitfalls of the use of PGSs in the clinical care of SUDs, highlighting current research. We also provide suggestions for important considerations prior to implementing the clinical use of PGSs and recommend future directions for research.
Authors
Rachel L. Kember, Christal N. Davis, Kyra L. Feuer, Henry R. Kranzler
Abstract
Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.
Authors
Bernard Le Foll, Victor M. Tang, Sergio Rueda, Leanne V. Trick, Isabelle Boileau
Abstract
Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction–associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.
Authors
Eric O. Johnson, Heidi S. Fisher, Kyle A. Sullivan, Olivia Corradin, Sandra Sanchez-Roige, Nathan C. Gaddis, Yasmine N. Sami, Alice Townsend, Erica Teixeira Prates, Mirko Pavicic, Peter Kruse, Elissa J. Chesler, Abraham A. Palmer, Vanessa Troiani, Jason A. Bubier, Daniel A. Jacobson, Brion S. Maher
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.
Authors
Ohad Oren, Aeron M. Small, Peter Libby
Abstract
Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.
Authors
Koichi Takahashi, Daisuke Nakada, Margaret Goodell
Abstract
Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.
Authors
William G. Dunn, Matthew A. McLoughlin, George S. Vassiliou
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