Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show ...that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.
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•The enteric virome is abnormal in multiple inflammatory bowel disease patient cohorts•The enteric virome richness increases in Crohn’s disease and ulcerative colitis•Decreases in bacterial diversity and richness in IBD do not explain virome changes•Virome changes in Crohn’s disease and ulcerative colitis are disease specific
The enteric virome is abnormal in multiple cohorts of inflammatory bowel disease patients, exhibiting disease-specific features that are not explained by changes in bacterial diversity and richness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, ...whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.
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•In HIV-infected Ugandans, low CD4 T cells were linked to enteric adenovirus expansion•Low CD4 T cell numbers were also associated with alterations in the bacterial microbiome•These changes in the virome and bacterial microbiome were independent of ART treatment•These changes may contribute to AIDS-associated enteropathy and disease progression
Monaco et al. characterize the enteric virome and bacterial microbiome in an HIV-infected Ugandan patient cohort. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and bacterial microbiome alterations, including increases in Enterobacteriaceae, each of which may contribute to AIDS-associated enteropathy and disease progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Advanced sequencing techniques have shown that bacteria are not the only complex and important microbes in the human intestine. Nonbacterial organisms, particularly the virome and the mycobiome, are ...important regulators of intestinal immunity and inflammation. The virome is mucosal and systemic; it can alter the host response to bacteria and interact with host genes and bacteria to contribute to disease pathogenesis. The human mycobiome is also complex and can contribute to intestinal inflammation. We review what has recently been learned about the nonbacterial and nonarchaeal microbes in the gastrointestinal tract, discussing their potential effects on health and disease and analytical approaches for their study. Studies of associations between the microbiome and intestinal pathology should incorporate kingdom-agnostic approaches if we are to fully understand intestinal health and disease.
Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy, which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used ...next-generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not nonpathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence by using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis.
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► The enteric virome expands during pathogenic, but not nonpathogenic, SIV infection ► Pathogenic SIV-infected rhesus monkeys shed multiple enteric viruses ► Viruses are associated with intestinal pathology during SIV infection ► Metagenomic analysis of the enteric virome is important to study AIDS pathogenesis
Monkeys infected with pathogenic SIV manifest an expanded enteric virome that includes examples of previously uncharacterized viruses. Viruses within the cohort are associated with intestinal damage, suggesting a link to the intestinal pathologies that develop in HIV-infected patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bacteriophages, or phages, are viruses that infect bacteria and archaea. Phages have diverse morphologies and can be coded in DNA or RNA and as single or double strands with a large range of genome ...sizes. With the increasing use of metagenomic sequencing approaches to analyze complex samples, many studies generate massive amounts of "viral dark matter", or sequences of viral origin unable to be classified either functionally or taxonomically. Metagenomic analysis of phages is still in its infancy, and uncovering novel phages continues to be a challenge. Work over the past two decades has begun to uncover key roles for phages in different environments, including the human gut. Recent studies in humans have identified expanded phage populations in both healthy infants and in inflammatory bowel disease patients, suggesting distinct phage activity during development and in specific disease states. In this review, we examine our current knowledge of phage biology and discuss recent efforts to improve the analysis and discovery of novel phages. We explore the roles phages may play in human health and disease and discuss the future of phage research.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To quantify the current burden of severe intraventricular hemorrhage (IVH), describe time trends in severe IVH, identify IVH-associated risk factors, and determine the contribution of mediating ...factors.
The retrospective cohort included infants 220/7-316/7 weeks of gestation without severe congenital anomalies, born at hospitals in the California Perinatal Quality Care Collaborative between 2005 and 2015. The primary study outcome was severe (grade III or IV) IVH.
Of 44 028 infants, 3371 (7.7%) had severe IVH. The incidence of severe IVH decreased significantly across California from 9.7% in 2005 to 5.9% in 2015. After stratification by gestational age, antenatal steroid exposure was the only factor associated with a decreased odds of severe IVH for all gestational age subgroups. Other factors, including delivery room intubation, were associated with an increased odds of severe IVH, though significance varied by gestational age. Factors analyzed in the mediation analysis accounted for 45.6% (95% CI 38.7%-71.8%) of the reduction in severe IVH, with increased antenatal steroid administration and decreased delivery room intubation mediating a significant proportion of this decrease, 19.4% (95% CI 13.9%-27.5%) and 27.3% (95% CI 20.3%-39.2%), respectively. The unaccounted proportion varied by gestational age.
The incidence of severe IVH decreased across California, associated with changes in antenatal steroid exposure and delivery room intubation. Maternal, patient, and delivery room factors accounted for less than one-half of the decrease in severe IVH. Study of other factors, specifically neonatal intensive care unit and hospital-level factors, may provide new insights into policies to reduce severe IVH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E ...(ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex- and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies ...against variant strains of SARS-CoV-2
, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in ...white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.
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•Adipocytes transfer their mitochondria to macrophages in vivo•Mitochondria transfer from adipocytes to macrophages is decreased in obesity•Mitochondria uptake by macrophages is mediated by heparan sulfates•Mice that lack heparan sulfates on macrophages exhibit metabolic dysfunction
Brestoff et al. show that adipose-tissue-resident macrophages acquire mitochondria from neighboring adipocytes in a heparan-sulfate-dependent process that is impaired in obesity. Genetic disruption of mitochondria uptake by macrophages reduces energy expenditure and exacerbates diet-induced obesity in mice, indicating that intercellular mitochondria transfer to macrophages mediates systemic metabolic homeostasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The diverse enteric viral communities that infect microbes and the animal host collectively constitute the gut virome. Although recent advances in sequencing and analysis of metaviromes have revealed ...the complexity of the virome and facilitated discovery of new viruses, our understanding of the enteric virome is still incomplete. Recent studies have uncovered how virome-host interactions can contribute to beneficial or detrimental outcomes for the host. Understanding the complex interactions between enteric viruses and the intestinal immune system is a prerequisite for elucidating their role in intestinal diseases. In this review, we provide an overview of the enteric virome composition and summarize recent findings about how enteric viruses are sensed by and, in turn, modulate host immune responses during homeostasis and disease.
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