Biology subjects

Carmody, R. N.

Publications and source records attributed to Carmody, R. N..

9 recordsLinked to original sources

bioRxiv2026

Evolutionary trade-offs between growth and reproduction under obesogenic conditions: sex-biased skeletal and gonadal maturation in mice

Adolescence is a brief period during which finite energy resources are reallocated from linear growth toward reproductive maturation. Rising childhood obesity and earlier onset of puberty suggest that modern, energy rich diets may distort these evolved energy allocation rules, but causal mechanisms remain unclear. Here, we expose male and female wild-type and leptin receptor deficient (Db/Db) to either high fat or normal chow diets. We longitudinally analyze metabolic, skeletal, gonadal, endocrine and insulin-receptor phenotypes from 4-10 weeks of age (sexual maturation window in mice). In WT males, HFDs increased adiposity and impaired glucose tolerance, and selectively remodeled joint morphology, advanced gonadal maturation, and shifted insulin receptor expression from growth plates to testes. Together, these changes indicate a rebalancing of energy use toward reproduction at the expense of skeletal and metabolic health. WT females showed subtler systemic metabolic disruption but clear diet-responsive changes in growth plate and ovarian maturation. Our findings indicate that energy-rich diets during adolescence shift evolved allocation rules to prioritize reproductive readiness over skeletal robustness in a sex-dependent manner, with potential consequences for precocious puberty and bone health in humans.

evolutionary biology↗

bioRxiv2026

Fasting and re-feeding independently alter mouse gut microbiota during intermittent fasting

Intermittent fasting (IF) elicits metabolic benefits that are partially driven by the gut microbiome. Studies have focused on endpoint IF-induced changes in the gut microbiome but have not explored whether the oscillating nature of IF elicits day-to-day microbiome changes that could independently affect health. To discriminate the long-term and short-term effects of IF on the gut microbiota, we fasted mice every other day (IF1:1) or every two days (IF1:2), measuring daily changes in body mass and composition, food intake, and gut microbiota composition. We show that short-term effects of fasting and re-feeding on gut microbiota composition outweigh longer-term effects of IF treatment, with composition responding differently to re-feeding and fasting. Re-feeding specifically promoted rapid expansion of Lactobacillus, a bacterial genus linked mechanistically to the metabolic benefits of IF. Our results highlight the plasticity of the gut microbiota, especially re-feeding effects, as a potential contributor to microbiome-mediated metabolic benefits of IF.

microbiology↗

bioRxiv2025

Early-life microbiota disruption by antibiotics elicits fitness trade-offs that differ by sex

Exposure to early-life antibiotics (ELA) promotes adult obesity across diverse species, often more strongly in males than females1-3. However, the physiological and evolutionary mechanisms driving ELA-mediated developmental plasticity and their consequences for fitness remain unclear3. Here, treating young mice with high- or low-dose ampicillin altered the gut microbiome and elicited reduced lean mass and energy expenditure in males to promote increased adult visceral adiposity. High-dose ELA constrained energy availability during treatment, evidenced by reduced growth and cecal short-chain fatty acids, raising the possibility that developmental plasticity under ELA could be adaptive in energy-limited environments. Adult ELA-treated males had reduced fitness under free-fed conditions -- driven by smaller body size, fat stores, and impaired immunity -- but were buffered against fitness reductions under caloric restriction, consistent with predictive adaptive response models of development4,5. Strikingly, ELA-treated females exhibited none of the proximate metabolic responses observed in males, with adult body size and composition indistinguishable from controls. In the absence of similar developmental plasticity, ELA-treated females exhibited exacerbated fitness reductions under caloric restriction, including lower energetic investments in reproduction and immunity. Our results suggest that ELA exposure elicits sexually dimorphic developmental responses that engender long-term health and fitness consequences dependent on adult nutritional conditions.

evolutionary biology↗

bioRxiv2025

Polyunsaturated fatty acids promote appetite via the microbiome-gut-brain axis

Appetite is regulated by nutrient-sensing systems that integrate long-term signals from energy stores and short-term cues from dietary intake, yet this regulation is increasingly disrupted by industrialized diets. Although the physiological effects of industrialized diets are well documented, the continued rise in metabolic and eating disorders underscores a critical gap in our understanding of how these diets shape neural regulation of eating behavior. Here, we tested how distinct properties of industrialized diets alter brain neurochemistry and change appetite. We probed the properties of an industrialized diet through contrasts targeting the overall diet pattern (Western vs. control), enriched macronutrients (fat vs. sugar), and isocaloric trade-offs of macronutrient variants (saturated fatty acids vs. polyunsaturated fatty acids [PUFA]). The most salient effects emerged from the finest-grained contrast: PUFA conditioning increased appetite through a mechanism involving elevated brain 5-hydroxyindoleacetic acid (5-HIAA), a primary serotonin catabolite associated with the gut microbiome. Fecal microbiota transplants into germ-free mice confirmed that the PUFA-conditioned gut microbiota carries an appetite-enhancing signature. Together, our findings delineate a diet-microbiome-gut-brain axis through which dietary components of industrialized diets can modulate appetite and contribute to altered eating behavior. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/667447v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@650141org.highwire.dtl.DTLVardef@1358b06org.highwire.dtl.DTLVardef@3a4c0corg.highwire.dtl.DTLVardef@156e685_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryDietary polyunsaturated fatty acids enhance appetite via a gut microbiome-serotonergic pathway.

microbiology↗

bioRxiv2024

Dietary preservatives alter the gut microbiota in vitro and in vivo with sex-specific consequences for host metabolic development

Antibiotics in early life can promote adiposity via interactions with the gut microbiota. However, antibiotics represent only one possible route of antimicrobial exposure. Dietary preservatives exhibit antimicrobial activity, contain chemical structures accessible to microbial enzymes, and alter environmental conditions favoring specific microbial taxa. Therefore, preservatives that retain bioactivity in the gut might likewise alter the gut microbiota and host metabolism. Here we conduct in vitro, ex vivo, and in vivo experiments in mice to test the effects of preservatives on the gut microbiota and host physiology. We screened common dietary preservatives against a panel of human gut isolates and whole fecal communities, finding that preservatives strongly altered microbial growth and community structure. We exposed mice to diet-relevant doses of 4 preservatives [acetic acid, BHA (butylated hydroxyanisole), EDTA (ethylenediaminetetraacetic acid) and sodium sulfite], which each induced compound-specific changes in gut microbiota composition. Finally, we compared the long-term effects of early-life EDTA and low-dose antibiotic (ampicillin) exposure. EDTA exposure modestly reduced nutrient absorption and cecal acetate in both sexes, resulting in lower adiposity in females despite greater food intake. Females exposed to ampicillin also exhibited lower adiposity, along with larger brains and smaller livers. By contrast, in males, ampicillin exposure generally increased energy harvest and decreased energy expenditure, resulting in higher adiposity. Our results highlight the potential for everyday doses of common dietary preservatives to affect the gut microbiota and impact metabolism differently in males and females. Thus, despite their generally-regarded-as-safe designation, preservatives could have unintended consequences for consumer health. SIGNIFICANCEEarly-life exposure to antibiotics can alter the gut microbiota and shape adult metabolic health. Here we show that dietary preservatives can have analogous effects. Common dietary preservatives altered gut microbiota composition in vitro, ex vivo and in vivo. Early-life EDTA exposure had long-term, sex-specific consequences for energy metabolism. Simultaneously, we deliver new mechanistic understanding of early-life antimicrobial-induced effects on adiposity via evidence that low-dose ampicillin treatment increases energy harvest while conserving energy expenditure in males, promoting adiposity, while EDTA treatment dampens energy harvest, promoting leanness in females. Overall, our results emphasize that early-life gut microbiome disruptions can be triggered by diverse antimicrobial exposures, with previously unappreciated metabolic consequences that differ for males and females.

physiology↗

bioRxiv2021

Common proanthocyanidin-rich foods modulate gastrointestinal blooms of Akkermansia muciniphila in a diet-dependent manner

Developing methods to modulate growth of the mucin-degrading gut bacterium Akkermansia muciniphila could benefit patients with different health needs, as A. muciniphila has been associated with both positive metabolic health outcomes and detrimental neurodegenerative outcomes. Growth of A. muciniphila is sensitive to plant-derived polyphenols, and particularly proanthocyanidins (PACs), when administered in isolated form at supraphysiological doses. However, it remains unclear whether doses sufficient for these effects are achievable via diet. Here, we explore the extent to which nutritionally relevant doses of common polyphenol-rich foods - berries, wine, and coffee - influence A. muciniphila abundance in C57BL/6J mice under varying dietary conditions. By administering polyphenol-rich whole foods, comparing polyphenol-depleted and PAC-rich versus PAC-poor food supplements, and through gradient PAC-dosing experiments, we show that PAC-rich foods uniquely induce A. muciniphila growth at doses that are feasibly achieved through routine diet. Notably, the effects of PAC supplementation were detected against a high-fat diet but not a low-fat control diet background, highlighting the importance of habitual diet strategies in either amplifying or mitigating the prebiotic effects of PAC-rich food consumption. Ultimately, our work suggests that both PACs and diet influence A. muciniphila abundance with downstream impacts for human health.

microbiology↗

bioRxiv2021

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. Here we report findings from a small longitudinal study of male C57BL/6 mice maintained on either ad libitum or mild (15%) CR diets from 21 months of age and tracked until natural death. We demonstrate that CR results in a significant reduction in frailty index (FI), a well-established indicator of aging. We observed significant alterations in bacterial load, diversity, and compositional patterns of the mouse gut microbiota during the aging process. Interrogating the FI-related microbial features using machine learning techniques, we show that gut microbial signatures from 21-month-old mice can predict the healthy aging of 30-month-old mice with reasonable accuracy. This study deepens our understanding of the links between CR, gut microbiota, and frailty in the aging process of mice.

microbiology↗

bioRxiv2021

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, nonindependence, and compositionality) and of the associated underlying biology, it is difficult to compare or evaluate such methods within a single systematic framework. To address this challenge, we developed SparseDOSSA (Sparse Data Observations for the Simulation of Synthetic Abundances): a statistical model of microbial ecological population structure, which can be used to parameterize real-world microbial community profiles and to simulate new, realistic profiles of known structure for methods evaluation. Specifically, SparseDOSSAs model captures marginal microbial feature abundances as a zero-inflated log-normal distribution, with additional model components for absolute cell counts and the sequence read generation process, microbemicrobe, and microbe-environment interactions. Together, these allow fully known covariance structure between synthetic features (i.e. "taxa") or between features and "phenotypes" to be simulated for method benchmarking. Here, we demonstrate SparseDOSSAs performance for 1) accurately modeling human-associated microbial population profiles; 2) generating synthetic communities with controlled population and ecological structures; 3) spiking-in true positive synthetic associations to benchmark analysis methods; and 4) recapitulating an end-to-end mouse microbiome feeding experiment. Together, these represent the most common analysis types in assessment of real microbial community environmental and epidemiological statistics, thus demonstrating SparseDOSSAs utility as a general-purpose aid for modeling communities and evaluating quantitative methods. An open-source implementation is available at http://huttenhower.sph.harvard.edu/sparsedossa2.

bioinformatics↗

bioRxiv2019

Parallel signatures of mammalian domestication and human industrialization in the gut microbiota

Domestication may have had convergent effects on the microbiota of domesticates and humans through analogous ecological shifts. Comparing the gut microbiota of domestic and related wild mammals plus humans and chimpanzees, we found consistent shifts in composition in domestic animals and in humans from industrialized but not traditional societies. Reciprocal diet switches in mice and canids demonstrated that diet played a dominant role in shaping the domestic gut microbiota, with stronger responses in the member of the wild-domestic pair with higher dietary and microbial diversity. Laboratory mice recovered wild-like microbial diversity and responsiveness with experimental colonization. We conclude that domestication and industrialization have similarly impacted the gut microbiota, emphasizing the utility of domestic animal models and diets for understanding host-microbial interactions in rapidly changing environments.

microbiology↗