Antibiotic-induced gut dysbiosis elicits gut-brain axis relevant multi-omic signatures and behavioral and neuroendocrine changes in a nonhuman primate model.

Emerging evidence indicates that antibiotic-induced dysbiosis can play an etiological role in the pathogenesis of neuropsychiatric disorders. However, most of this evidence comes from rodent models. The objective of this study was to evaluate if antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut-brain axis disruption in common marmosets (Callithrix jacchus) - a nonhuman primate model often used to study sociability and stress. We were able to successfully induce dysbiosis in marmosets using a custom antibiotic cocktail (vancomycin, enrofloxacin and neomycin) administered orally for 28 days. This gut dysbiosis altered gut metabolite profiles, behavior, and stress reactivity. Increase in gut Fusobacterium spp. post-antibiotic administration was a novel dysbiotic response and has not been observed in any rodent or human studies to date. There were significant changes in concentrations of several gut metabolites which are either neurotransmitters (e.g., GABA and serotonin) or have been found to be moderators of gut-brain axis communication in rodent models (e.g., short-chain fatty acids and bile acids). There was an increase in affiliative behavior and sociability in antibiotic-administered marmosets, which might be a coping mechanism in response to gut dysbiosis-induced stress. Increase in urinary cortisol levels after multiple stressors provides more definitive proof that this model of dysbiosis may cause disrupted communication between gut and brain in common marmosets. This study is a first attempt to establish common marmosets as a novel model to study the impact of severe gut dysbiosis on gut-brain axis cross-talk and behavior.

Biological and behavioral predictors of relative energy intake after acute exercise.

Energy intake in the post-exercise state is highly variable and compensatory eating - i.e., (over-) compensation of the expended energy via increased post-exercise energy intake - occurs in some individuals but not others. We aimed to identify predictors of post-exercise energy intake and compensation. In a randomized crossover design, 57 healthy participants (21.7 [SD = 2.5] years; 23.7 [SD = 2.3] kg/m2, 75% White, 54% female) completed two laboratory-based test-meals following (1) 45-min exercise and (2) 45-min rest (control). We assessed associations between biological (sex, body composition, appetite hormones) and behavioral (habitual exercise via prospective exercise log, eating behavior traits) characteristics at baseline and total energy intake, relative energy intake (intake - exercise expenditure), and the difference between post-exercise and post-rest intake. We found a differential impact of biological and behavioral characteristics on total post-exercise energy intake in men and women. In men, only fasting (baseline) concentrations of appetite-regulating hormones (peptide YY [PYY, ß = 0.88, P < 0.001] and adiponectin [ß = 0.66, P = 0.005] predicted total post-exercise energy intake, while in women, only habitual exercise (ß = -0.44, P = 0.017) predicted total post-exercise energy intake. Predictors of relative intake were almost identical to those of total intake. The difference in energy intake between exercise and rest was associated with VO2peak (ß = -0.45, P = 0.020), fasting PYY (ß = 0.53, P = 0.036), and fasting adiponectin (ß = 0.57, P = 0.021) in men but not women (all P > 0.51). Our results show that biological and behavioral characteristics differentially affect total and relative post-exercise energy intake in men and women. This may help identify individuals who are more likely to compensate for the energy expended in exercise. Targeted countermeasures to prevent compensatory energy intake after exercise should take the demonstrated sex differences into account.

An approach for studying the contributions of childhood sexual abuse and HPA axis dysregulation to substance use disorders.

An environmental risk factor for substance abuse and dependence is childhood sexual abuse (CSA). We piloted an approach we developed to test the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis dysregulation from the stress of CSA is a biological mediator. We based our hypothesis on the allostasis model. New admissions to residential treatment for substance use disorders (N = 41) were evaluated for CSA history and two HPA axis regulation measures at baseline, one month, and two months. The two HPA axis regulation measures were morning cortisol level and the dexamethasone suppression test. Five potential covariates were also measured to increase reliability of the findings. Feasibility outcomes were mostly favorable, and included rates of participation (57 %), attrition (46 % at one month and 71 % at two months), and compliance with data collection procedures (87 % for morning cortisol level and 84 % for the dexamethasone suppression test). High attrition rates at one and two months were entirely attributable to high rates of leaving treatment, an important consideration for future studies. Baseline correlations among variables showed a significant negative correlation between dexamethasone suppression and perceived stress, a potential covariate (rho = -0.458). This finding suggests that individuals with lower stress levels have better negative feedback regulation of the HPA axis, which results in the benefit of lower cortisol exposure-a finding congruent with the allostasis model.

Uneven but Conservative Pacing Is Associated With Performance During Uphill and Downhill Running.

PURPOSE: To investigate the relationship between pacing strategy and performance during uphill and downhill running-specifically, what distribution of energy corresponds to faster race finish times between and among participants. METHODS: Eighteen years of race data from a 10.2-mile running race with an uphill first half and a downhill second half were analyzed to identify relationships between pacing and performance. A pacing coefficient (PC), equal to a participant's ascent time divided by finishing time (FT), was used to define each participant's pacing strategy. The American College of Sports Medicine metabolic running equation was used to estimate energy expenditure during the ascent, descent, and total race. Statistical analyses compared participants' PC to their FT and finishing place within their age and gender category. Additionally, FT and finishing place were compared between groups of participants who exhibited similar pacing strategies. RESULTS: PCs were positively associated with faster FTs (r2 = .120, P < .001) and better finishing positions (r2 = .104, P < .001). PCs above .600 were associated with the fastest average FTs and best average finishing position within age and gender categories (all P ≤ .047). CONCLUSIONS: Participants performed the best when energy expenditure increased no more than 10.4% during the uphill portion compared to their overall average. It is not possible to state that overly aggressive uphill efforts resulted in premature fatigue and thus slower decent times and worse race performance. However, participants should still avoid overly aggressive uphill pacing, as performance was associated with larger PCs.

Social Support Buffers the Effects of Prenatal Depressed Mood: A Mixed-Methods Study.

BACKGROUND: Women use various coping strategies to deal with stress and depression. These strategies are shaped by social contexts over the life course and may attenuate and/or exacerbate the physiologic effects of depression. AIMS: The purpose of this study was to determine whether coping strategies (active, disengaged, or social support coping) moderate depression-related diurnal cortisol dysregulation and to explore how social context influences women's use of coping. METHODS: This was a mixed-methods study of pregnant women (N = 65) during mid-pregnancy. Cortisol was measured in saliva collected during the waking hours of the day. Participants completed the Edinburgh Depression Scale and the Brief COPE. A subset of the sample participated in semistructured qualitative interviews (n = 20). RESULTS: Social support coping, but not active or disengaged coping, moderated end-of-day cortisol levels. Among depressed women, higher use of social support was associated with lower and more dynamic (i.e., less flat) diurnal cortisol rhythms. The qualitative findings revealed how complex social dynamics related to financial insecurity, lack of mutuality, and social identity affected women's use of and access to social support. CONCLUSION: These findings support theories of the stress-buffering effects of social support. Future research is needed to examine how social determinants affect access to social support, and how early life social experiences condition women's adaptive formation of social support coping strategies over the life course. Clinically, these findings underscore the value of relationship-centered nursing care for depressed women.

Captive Common Marmosets (Callithrix jacchus) Are Colonized throughout Their Lives by a Community of Bifidobacterium Species with Species-Specific Genomic Content That Can Support Adaptation to Distinct Metabolic Niches.

The common marmoset (Callithrix jacchus) is an omnivorous New World primate whose diet in the wild includes large amounts of fruit, seeds, flowers, and a variety of lizards and invertebrates. Marmosets also feed heavily on tree gums and exudates, and they have evolved unique morphological and anatomical characteristics to facilitate gum feeding (gummivory). In this study, we characterized the fecal microbiomes of adult and infant animals from a captive population of common marmosets at the Callitrichid Research Center at the University of Nebraska at Omaha under their normal dietary and environmental conditions. The microbiomes of adult animals were dominated by species of Bifidobacterium, Bacteroides, Prevotella, Phascolarctobacterium, Megamonas, and Megasphaera. Culturing and genomic analysis of the Bifidobacterium populations from adult animals identified four known marmoset-associated species (B. reuteri, B. aesculapii, B. myosotis, and B. hapali) and three unclassified taxa of Bifidobacterium that are phylogenetically distinct. Species-specific quantitative PCR (qPCR) confirmed that these same species of Bifidobacterium are abundant members of the microbiome throughout the lives of the animals. Genomic loci in each Bifidobacterium species encode enzymes to support growth and major marmoset milk oligosaccharides during breastfeeding; however, metabolic islands that can support growth on complex polysaccharide substrates in the diets of captive adults (pectin, xyloglucan, and xylan), including loci in B. aesculapii that can support its unique ability to grow on arabinogalactan-rich tree gums, were species-specific. IMPORTANCEBifidobacterium species are recognized as important, beneficial microbes in the human gut microbiome, and their ability colonize individuals at different stages of life is influenced by host, dietary, environmental, and ecological factors, which is poorly understood. The common marmoset is an emerging nonhuman primate model with a short maturation period, making this model amenable to study the microbiome throughout a life history. Features of the microbiome in captive marmosets are also shared with human gut microbiomes, including abundant populations of Bifidobacterium species. Our studies show that several species of Bifidobacterium are dominant members of the captive marmoset microbiome throughout their life history. Metabolic capacities in genomes of the marmoset Bifidobacterium species suggest species-specific adaptations to different components of the captive marmoset diet, including the unique capacity in B. aesculapii for degradation of gum arabic, suggesting that regular dietary exposure in captivity may be important for preserving gum-degrading species in the microbiome.

Fecal Short-Chain Fatty Acid Concentrations Increase in Newly Paired Male Marmosets (Callithrix jacchus).

The role by which the gut microbiome influences host health (e.g., energy equilibrium and immune system) may be partly mediated by short-chain fatty acids, which are bacterial fermentation products from the dietary fibers. However, little is known about longitudinal changes in gut microbiome metabolites during cohabitation alongside social contact. In common marmosets (Callithrix jacchus), the gut microbiome community is influenced by social contact, as newly paired males and females develop convergent microbial profiles. Here, we monitored the dynamics of short-chain fatty acid concentrations in common marmoset feces from the prepairing (PRE) to postpairing (POST) stages. In males, we observed that the concentrations of acetate, propionate, isobutyrate, and isovalerate significantly increased in the POST stage compared to the PRE stage. However, no significant changes were found in females. We further found that the propionate concentration was significantly positively correlated with the abundance of Phascolarctobacterium in the male feces. Thus, the sex difference in the changes in the concentrations of short-chain fatty acids might be related to sex-biased gut microbiome transmission after pairing. We suggest that the significant changes in the gut microbiomes and some short-chain fatty acids of the common marmoset during cohabitation may contribute to physiological homeostasis during pairing.IMPORTANCE This study addressed a knowledge gap about longitudinal changes in the gut microbiome metabolites during animal pairing. This research in the laboratory common marmoset can control for the confounding factors such as diet and other environmental conditions. Phascolarctobacterium showed the highest contribution to the sex-biased transmission of the female to the male after pairing. Here, we observed the sex difference in the increase in short-chain fatty acid concentration in the feces of newly paired marmosets, which may be caused by the sex-biased gut microbiome transmission after pairing.

Sex Bias in Gut Microbiome Transmission in Newly Paired Marmosets (Callithrix jacchus).

Social behavior can alter the microbiome composition via transmission among social partners, but there have been few controlled experimental studies of gut microbiome transmission among social partners in primates. We collected longitudinal fecal samples from eight unrelated male-female pairs of marmoset monkeys prior to pairing and for 8 weeks following pairing. We then sequenced 16S rRNA to characterize the changes in the gut microbiome that resulted from the pairing. Marmoset pairs had a higher similarity in gut microbiome communities after pairing than before pairing. We discovered sex differences in the degrees of change in gut microbiome communities following pairing. Specifically, the gut microbiome communities in males exhibited greater dissimilarity from the prepairing stage (baseline) than the gut microbiome communities in females. Conversely, females showed a gradual stabilization in the rate of the gut microbiome community turnover. Importantly, we found that the male fecal samples harbored more female-source gut microbes after pairing, especially early in pairing (paired test, P < 0.05), possibly linked to sex bias in the frequencies of social behavior. From this controlled study, we report for the first time that pair-living primates undergo significant changes in gut microbiome during pairing and that females transmit more microbes to their partners than males do. The potential biases influencing which microbes are transmitted on the basis of sex and whether they are due to sex biases in other behavioral or physiological features need to be widely investigated in other nonhuman primates and humans in the future.IMPORTANCE In this controlled study, we collected longitudinal fecal samples from 16 male and female marmoset monkeys for 2 weeks prior to and for 8 weeks after pairing in male-female dyads. We report for the first time that marmoset monkeys undergo significant changes to the gut microbiome following pairing and that these changes are sex-biased; i.e., females transmit more microbes to their social partners than males do. Marmosets exhibit pair bonding behavior such as spatial proximity, physical contact, and grooming, and sex biases in these behavioral patterns may contribute to the observed sex bias in social transmission of gut microbiomes.

Comparison of the pharmacological profiles of arginine vasopressin and oxytocin analogs at marmoset, macaque, and human vasopressin 1a receptor.

Arginine vasopressin (AVP) and oxytocin (OT) are nonapeptides that bind to G-protein coupled receptors and influence social behaviors. Consensus mammalian AVP and OT (Leu8-OT) sequences are highly conserved. In marmosets, an amino acid change in the 8th position of the peptide (Pro8-OT) exhibits unique structural and functional properties. There is ∼85 % structural homology between the OT receptor (OTR) and vasopressin 1a receptor (V1aR) resulting in significant cross-reactivity between the ligands and receptors. Chinese hamster ovary (CHO) cells expressing marmoset (mV1aR), macaque (qV1aR), or human vasopressin receptor 1a (hV1aR) were used to assess AVP, Leu8-OT and Pro8-OT pharmacological profiles. To assess activation of Gq, functional assays were performed using Fluo-3 to measure ligand-induced Ca2+ mobilization. In all three V1aR-expressing cell lines, AVP was more potent than the OT ligands. To assess ligand-induced hyperpolarization, FLIPR Membrane Potential (FMP) assays were performed. In all three V1aR lines, AVP was more potent than the OT analogs. The distinctive U-shaped concentration-response curve displayed by AVP may reflect enhanced desensitization of the mV1aR and hV1aR, which is not observed with qV1aR. Evaluation of Ca2+-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Taken together, these data suggest differences in ligand-receptor signaling that may underlie differences in social behavior. Integrative studies of behavior, genetics and ligand-receptor interaction will help elucidate the connection between receptor pharmacology and social behaviors.

Quantifying snowfall from orographic cloud seeding.

Climate change and population growth have increased demand for water in arid regions. For over half a century, cloud seeding has been evaluated as a technology to increase water supply; statistical approaches have compared seeded to nonseeded events through precipitation gauge analyses. Here, a physically based approach to quantify snowfall from cloud seeding in mountain cloud systems is presented. Areas of precipitation unambiguously attributed to cloud seeding are isolated from natural precipitation (<1 mm h-1). Spatial and temporal evolution of precipitation generated by cloud seeding is then quantified using radar observations and snow gauge measurements. This study uses the approach of combining radar technology and precipitation gauge measurements to quantify the spatial and temporal evolution of snowfall generated from glaciogenic cloud seeding of winter mountain cloud systems and its spatial and temporal evolution. The results represent a critical step toward quantifying cloud seeding impact. For the cases presented, precipitation gauges measured increases between 0.05 and 0.3 mm as precipitation generated by cloud seeding passed over the instruments. The total amount of water generated by cloud seeding ranged from 1.2 × 105 m3 (100 ac ft) for 20 min of cloud seeding, 2.4 × 105 m3 (196 ac ft) for 86 min of seeding to 3.4 x 105 m3 (275 ac ft) for 24 min of cloud seeding.