Digesting the complex metabolic effects of diet on the host and microbiome.

The past 50 years of interdisciplinary research in humans and model organisms has delivered unprecedented insights into the mechanisms through which diet affects energy balance. However, translating these results to prevent and treat obesity and its associated diseases remains challenging. Given the vast scope of this literature, we focus this Review on recent conceptual advances in molecular nutrition targeting the management of energy balance, including emerging dietary and pharmaceutical interventions and their interactions with the human gut microbiome.

Microbial transmission in the social microbiome and host health and disease.

Although social interactions are known to drive pathogen transmission, the contributions of socially transmissible host-associated mutualists and commensals to host health and disease remain poorly explored. We use the concept of the social microbiome-the microbial metacommunity of a social network of hosts-to analyze the implications of social microbial transmission for host health and disease. We investigate the contributions of socially transmissible microbes to both eco-evolutionary microbiome community processes (colonization resistance, the evolution of virulence, and reactions to ecological disturbance) and microbial transmission-based processes (transmission of microbes with metabolic and immune effects, inter-specific transmission, transmission of antibiotic-resistant microbes, and transmission of viruses).

IĸB Protein BCL3 as a Controller of Osteogenesis and Bone Health.

Objective: IĸB protein B cell lymphoma 3-encoded protein (BCL3) is a regulator of the NF-κB family of transcription factors. NF-κB signaling fundamentally influences the fate of bone-forming osteoblasts and bone-resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance, and osteoarthritic pathology.

Comparing measured dietary variation within and between tropical hunter-gatherer groups to the Paleo Diet.

Background: Although human diets varied considerably before the spread of agriculture, public perceptions of preagricultural diets have been strongly influenced by the Paleo Diet, which prescribes percentage calorie ranges of 19-35% protein, 22-40% carbohydrate, and 28-47% fat, and prohibits foods with added sugar, dairy, grains, most starchy tubers, and legumes. However, the empirical basis for Paleolithic nutrition remains unclear, with some of its assumptions challenged by the archaeological record and theoretical first principles.

Objectives: We assessed the variation in diets among tropical hunter-gatherers, including the effect of collection methods on implied macronutrient percentages.

The gut microbiome modifies the associations of short- and long-term physical activity with body weight changes.

Background: The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA).

Methods: Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and blood samples in 2012-2013. Data from cohort long-term follow-ups and from the accelerometer, doubly labeled water, and plasma biomarker measurements during the time of stool collection were used to assess long-term and short-term associations of PA with adiposity.

Roles of the gut microbiome in weight management.

Overweight, obesity, undernutrition and their respective sequelae have devastating tolls on personal and public health worldwide. Traditional approaches for treating these conditions with diet, exercise, drugs and/or surgery have shown varying degrees of success, creating an urgent need for new solutions with long-term efficacy. Owing to transformative advances in sequencing, bioinformatics and gnotobiotic experimentation, we now understand that the gut microbiome profoundly impacts energy balance through diverse mechanisms affecting both sides of the energy balance equation.

Weanling gut microbiota composition of a mouse model selectively bred for high voluntary wheel-running behavior.

We compared the fecal microbial community composition and diversity of four replicate lines of mice selectively bred for high wheel-running activity over 81 generations (HR lines) and four non-selected control lines. We performed 16S rRNA gene sequencing on fecal samples taken 24 h after weaning, identifying a total of 2074 bacterial operational taxonomic units. HR and control mice did not significantly differ for measures of alpha diversity, but HR mice had a higher relative abundance of the family Clostridiaceae.

Multiomics assessment of dietary protein titration reveals altered hepatic glucose utilization.

Dietary protein restriction (PR) has rapid effects on metabolism including improved glucose and lipid homeostasis, via multiple mechanisms. Here, we investigate responses of fecal microbiome, hepatic transcriptome, and hepatic metabolome to six diets with protein from 18% to 0% of energy in mice. PR alters fecal microbial composition, but metabolic effects are not transferable via fecal transplantation.

The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes.

Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of Knockout THP1 Cells.

Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor.

Gut Microbiota Predicts Healthy Late-Life Aging in Male Mice.

Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging.

Defining the structure of the NF-ĸB pathway in human immune cells using quantitative proteomic data.

The NF-ĸB transcription factor is a critical regulator of immune homeostasis and inflammatory responses and is a critical factor in the pathogenesis of inflammatory disease. The pathways to NF-ĸB activation are paradigms for signal-induced ubiquitination and proteasomal degradation, control of transcription factor function by subcellular localisation, and the control of gene transcription and physiological processes by signal transduction mechanisms. Despite the importance of NF-ĸB in disease, the NF-ĸB pathway remains unexploited for the treatment of inflammatory disease.

A statistical model for describing and simulating microbial community profiles.

Many methods have been developed for statistical analysis of microbial community profiles, but due to the complex nature of typical microbiome measurements (e.g. sparsity, zero-inflation, non-independence, and compositionality) and of the associated underlying biology, it is difficult to compare or evaluate such methods within a single systematic framework.

Host-microbial interactions in the metabolism of different dietary fats.

Although generally presumed to be isocaloric, dietary fats can differ in their energetic contributions and metabolic effects. Here, we show how an explicit consideration of the gut microbiome and its interactions with human physiology can enrich our understanding of dietary fat metabolism. We outline how variable human metabolic responses to different dietary fats, such as altered ileal digestibility or bile acid production, have downstream effects on the gut microbiome that differentially promote energy gain and inflammation.

Effects of domestication on the gut microbiota parallel those of human industrialization.

Domesticated animals experienced profound changes in diet, environment, and social interactions that likely shaped their gut microbiota and were potentially analogous to ecological changes experienced by humans during industrialization. Comparing the gut microbiota of wild and domesticated mammals plus chimpanzees and humans, we found a strong signal of domestication in overall gut microbial community composition and similar changes in composition with domestication and industrialization. Reciprocal diet switches within mouse and canid dyads demonstrated the critical role of diet in shaping the domesticated gut microbiota.

MR Imaging Characteristics of Intraocular Perfluoro-n-Octane.

We describe the unique MR imaging characteristics of intraocular perfluoro-n-octane, a liquid used for intraoperative and postoperative tamponade in the context of complex retinal detachment repair, and contrast it with other intraocular pathologies. Because trace amounts of perfluoro-n-octane may be left in the globe postoperatively, it may be confused for other abnormalities, such as foreign bodies or tumors.

Age Patterning in Wild Chimpanzee Gut Microbiota Diversity Reveals Differences from Humans in Early Life.

Survival in primates is facilitated by commensal gut microbes that ferment otherwise indigestible plant matter, resist colonization by pathogens, and train the developing immune system. However, humans are unique among primates in that we consume highly digestible foods, wean early, mature slowly, and exhibit high lifelong investments in maintenance. These adaptations suggest that lifetime trajectories of human-microbial relationships could differ from those of our closest living relatives.

The deubiquitinase USP7 uses a distinct ubiquitin-like domain to deubiquitinate NF-ĸB subunits.

The transcription factor NF-ĸB is a master regulator of the innate immune response and plays a central role in inflammatory diseases by mediating the expression of pro-inflammatory cytokines. Ubiquitination-triggered proteasomal degradation of DNA-bound NF-ĸB strongly limits the expression of its target genes. Conversely, USP7 (deubiquitinase ubiquitin-specific peptidase 7) opposes the activities of E3 ligases, stabilizes DNA-bound NF-ĸB, and thereby promotes NF-ĸB-mediated transcription.

Microbial transmission in animal social networks and the social microbiome.

Host-associated microbiomes play an increasingly appreciated role in animal metabolism, immunity and health. The microbes in turn depend on their host for resources and can be transmitted across the host's social network. In this Perspective, we describe how animal social interactions and networks may provide channels for microbial transmission.

CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis.

Chromosomal rearrangements of the mixed lineage leukaemia (, also known as ) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. rearrangements () are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells.

The role of the microbiome in the neurobiology of social behaviour.

Microbes colonise all multicellular life, and the gut microbiome has been shown to influence a range of host physiological and behavioural phenotypes. One of the most intriguing and least understood of these influences lies in the domain of the microbiome's interactions with host social behaviour, with new evidence revealing that the gut microbiome makes important contributions to animal sociality. However, little is known about the biological processes through which the microbiome might influence host social behaviour.

The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity.