STEERING THE MICROBIOTA-GUT-BRAIN AXIS BY ANTIBIOTICS TO MODEL NEURO-IMMUNE-ENDOCRINE DISORDERS.

BACKGROUND: Over the last century, animal models have been employed to study the gut-brain axis and its relationship with physiological processes, including those necessary for survival, such as food intake regulation and thermoregulation; those involved in diseases, ranging from inflammation to obesity; and those concerned to the development of neurodegenerative diseases and neuropsychiatric disorders, such as Alzheimer's disease and autism spectrum disorder, respectively. SUMMARY: The gut microbiota has been recognized in the last decade as an essential functional component of this axis. Many reports demonstrate that the gut microbiota influences the development of a vast array of physiological processes. Experiments that use animal models to assess the effect of the gut microbiota on the brain and behavior may involve the acute or chronic administration of wide-spectrum antibiotics. KEY MESSAGES: This narrative review summarizes the beneficial or detrimental effects of antibiotics administered prenatally or postnatally to rodents during acute or chronic periods in a wide range of protocols. These include animal models of disease and behavioral paradigms of learning and memory, anxiety, obsessive-compulsive disorder, and autism spectrum disorder. Biomarkers and behavioral assays associated with antibiotic exposure are also included in this review.

Assessing the effects of oxytocin in changes of core body temperature during LPS-induced endotoxemia: A novel approach using Extended Poincaré Plot Analysis.

Oxytocin has shown cardioprotective effects during inflammation and may modify the core body temperature changes in LPS-induced endotoxemia. Notably, the time series analysis of core body temperature fluctuations may indicate thermoregulation alterations. This study aims to assess the effects of oxytocin on changes in the core body temperature by analyzing the fluctuations of the temperature time series of endotoxemic rats. Twelve hours of continuous core body temperature fluctuations time series were obtained from adult male Dark Agouti rats implanted with a telemetric transmitter under the following treatment: lipopolysaccharide (LPS); oxytocin (O); lipopolysaccharide + oxytocin (LPS + O), and vehicle or control (C). The temperature fluctuations time series were analyzed using the Extended Poincaré Plot Analysis (EPPA), a novel approach for measuring nonlinear features, to compute the autocorrelation by Pearson's correlation coefficient r, the standard deviation perpendicular to the line of identity (SD1), and the standard deviation parallel to the line of identity (SD2). The autocorrelation of the temperature fluctuations assessed by Pearson's coefficient was significantly higher in the LPS group compared to control rats (C). Likewise, the co-administration of oxytocin during endotoxemia (LPS + O) significantly reduced the autocorrelation and increased the short-term variability (SD1) of temperature fluctuations compared to those recorded with a single dose of LPS. Thus, we concluded that oxytocin may introduce thermoregulatory changes under LPS-induced endotoxemia. The EPPA is a simple and powerful approach to assess physiological variability that can provide valuable insights into changes in thermoregulation.

Dedicated odor-taste stimulation design for fMRI flavor studies.

BACKGROUND: Flavor is a mental representation that results from the brain's integration of at least odor and taste, and fMRI can highlight brain-related areas. However, delivering stimuli during fMRI can be challenging especially when administrating liquid stimuli in supine position. It remains unclear how and when odorants are released in the nose and how to improve odorant release. NEW METHOD: We used a proton transfer reaction mass spectrometer (PTR-MS) to monitor the in vivo release of odorants via the retronasal pathway during retronasal odor-taste stimulation in a supine position. We tested techniques to improve odorant release, including avoiding or delaying swallowing and velum open training (VOT). RESULTS: Odorant release was observed during retronasal stimulation, before swallowing, and in a supine position. VOT did not improve odorant release. Odorant release during stimulation had a latency more optimal for fitting with BOLD timing than after swallowing. COMPARISON WITH EXISTING METHOD(S): Previous in vivo measurements of odorant release under fMRI-like conditions showed that odorant release occurred only after swallowing. On the contrary, a second study found that aroma release could occur before swallowing, but participants were sitting. CONCLUSION: Our method shows optimal odorant release during the stimulation phase, meeting the criteria for high-quality brain imaging of flavor processing without swallowing-related motion artifacts. These findings provide an important advancement in understanding the mechanisms underlying flavor processing in the brain.

Adiposity affects emotional information processing.

Obesity is a worldwide epidemic associated with severe health and psychological wellbeing impairments expressed by an increased prevalence of affective disorders. Emotional dysfunction is important due to its effect on social performance. The aim of the present narrative review is to provide a general overview of human research exploring emotional information processing in overweight and obese people. Evidence suggests that obesity is associated with an attenuation of emotional experience, contradictory findings about emotion recognition, and scarce research about automatic emotional information processing. Finally, we made some concluding considerations for future research on emotional information processing in overweight and obese people.

Social complexity as a driving force of gut microbiota exchange among conspecific hosts in non-human primates.

The emergent concept of the social microbiome implies a view of a highly connected biological world, in which microbial interchange across organisms may be influenced by social and ecological connections occurring at different levels of biological organization. We explore this idea reviewing evidence of whether increasing social complexity in primate societies is associated with both higher diversity and greater similarity in the composition of the gut microbiota. By proposing a series of predictions regarding such relationship, we evaluate the existence of a link between gut microbiota and primate social behavior. Overall, we find that enough empirical evidence already supports these predictions. Nonetheless, we conclude that studies with the necessary, sufficient, explicit, and available evidence are still scarce. Therefore, we reflect on the benefit of founding future analyses on the utility of social complexity as a theoretical framework.

Chronic-Antibiotics Induced Gut Microbiota Dysbiosis Rescues Memory Impairment and Reduces ß-Amyloid Aggregation in a Preclinical Alzheimer's Disease Model.

Alzheimer's disease (AD) is a multifactorial pathology characterized by ß-amyloid (Aß) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aß and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aß deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.

Voluntary physical activity improves spatial and recognition memory deficits induced by post-weaning chronic exposure to a high-fat diet.

Childhood and adolescent exposure to obesogenic environments has contributed to the development of several health disorders, including neurocognitive impairment. Adolescence is a critical neurodevelopmental window highly influenced by environmental factors that affect brain function until adulthood. Post-weaning chronic exposure to a high-fat diet (HFD) adversely affects memory performance; physical activity is one approach to coping with these dysfunctions. Previous studies indicate that voluntary exercise prevents HFD's detrimental effects on memory; however, it remains to evaluate whether it has a remedial/therapeutical effect when introduced after a long-term HFD exposure. This study was conducted on a diet-induced obesity mice model over six months. After three months of HFD exposure (without interrupting the diet) access to voluntary physical activity was provided. HFD produced weight gain, increased adiposity, and impaired glucose tolerance. Voluntary physical exercise ameliorated glucose tolerance and halted weight gain and fat accumulation. Additionally, physical activity mitigated HFD-induced spatial and recognition memory impairments. Our data indicate that voluntary physical exercise starting after several months of periadolescent HFD exposure reverses metabolic and cognitive alterations demonstrating that voluntary exercise, in addition to its known preventive effect, also has a restorative impact on metabolism and cognition dysfunctions associated with obesity.

Vaginal Microbiota Is Stable and Mainly Dominated by Lactobacillus at Third Trimester of Pregnancy and Active Childbirth: A Longitudinal Study of Ten Mexican Women.

In healthy women at reproductive age, the vaginal microbiota is mainly dominated by Lactobacillus bacteria during pregnancy and non-pregnancy stages. However, little is known about longitudinal changes within the vaginal microbiota composition from the third trimester of pregnancy to childbirth in healthy women. Thus, we conducted an exploratory longitudinal study of vaginal microbiota composition of 10 Mexican pregnant women, sampling from the same volunteer at two-time points: third trimester of pregnancy and active childbirth. Vaginal bacterial microbiota was characterized by V3-16S rDNA libraries by high-throughput sequencing and bioinformatics methods. Out of ten, vaginal microbiota from eight women was dominated by the Lactobacillus genus at both time points, whereas the other two women showed vaginal microbiota composition with high abundance of genera Gardnerella, Prevotella, and members of the Atopobiaceae family, without any preterm birth correlation. Importantly, we found no statistically significant differences in relative abundances, absolute reads count, alpha and beta diversity between the third trimester of pregnancy, and active childbirth time points. However, compared to the third trimester of pregnancy, we observed a trend with higher absolute reads counts for Gardnerella, Faecalibaculum, Ileibacterium, and Lactococcus genus at active childbirth and lower absolute reads count of Lactobacillus genus. Our results suggest that the vaginal microbiota composition is stable, and Lactobacillus genus is the dominant taxa in Mexican women's vagina at the third trimester of pregnancy and childbirth.

Postnatal exposure to lipopolysaccharide combined with high-fat diet consumption induces immune tolerance without prevention in spatial working memory impairment.

High-fat diet (HFD) consumption has been related to metabolic alterations, such as obesity and cardiovascular problems, and has pronounced effects on brain plasticity and memory impairment. HFD exposure has a pro-inflammatory effect associated with microglial cell modifications in the hippocampus, a region involved in the working memory process. Immune tolerance can protect from inflammation in periphery induced by HFD consumption, when the immune response is desensitized in development period with lipopolysaccharide (LPS) exposure, maybe this previously state can change the course of the diseases associated to HFDs but is not known if can protect the hippocampus's inflammatory response. In the present study, male mice were injected with LPS (100 µg.kg-1 body weight) on postnatal day 3 and fed with HFD for 16 weeks after weaning. Ours results indicated that postnatal exposure to LPS in the early postnatal developmental stage combined with HFD consumption prevented glycemia, insulin, HOMA-IR, microglial process, and increased pro-inflammatory cytokines mRNA expression, without changes in body weight gain and spatial working memory with respect vehicle + HFD group. These findings suggest that HFD consumption after postnatal LPS exposure induces hippocampal immune tolerance, without prevention in spatial working memory impairment on male mice.

Spatial Memory and Gut Microbiota Alterations Are Already Present in Early Adulthood in a Pre-clinical Transgenic Model of Alzheimer's Disease.

The irreversible and progressive neurodegenerative Alzheimer's disease (AD) is characterized by cognitive decline, extracellular ß-amyloid peptide accumulation, and tau neurofibrillary tangles in the cortex and hippocampus. The triple-transgenic (3xTg) mouse model of AD presents memory impairment in several behavioral paradigms and histopathological alterations from 6 to 16 months old. Additionally, it seems that dysbiotic gut microbiota is present in both mouse models and patients of AD at the cognitive symptomatic stage. The present study aimed to assess spatial learning, memory retention, and gut microbiota alterations in an early adult stage of the 3xTg-AD mice as well as to explore its sexual dimorphism. We evaluated motor activity, novel-object localization training, and retention test as well as collected fecal samples to characterize relative abundance, alpha- and beta-diversity, and linear discriminant analysis (LDA) effect size (LEfSe) analysis in gut microbiota in both female and male 3xTg-AD mice, and controls [non-transgenic mice (NoTg)], at 3 and 5 months old. We found spatial memory deficits in female and male 3xTg-AD but no alteration neither during training nor in motor activity. Importantly, already at 3 months old, we observed decreased relative abundances of Actinobacteria and TM7 in 3xTg-AD compared to NoTg mice, while the beta diversity of gut microbiota was different in female and male 3xTg-AD mice in comparison to NoTg. Our results suggest that gut microbiota modifications in 3xTg-AD mice anticipate and thus could be causally related to cognitive decline already at the early adult age of AD. We propose that microbiota alterations may be used as an early and non-invasive diagnostic biomarker of AD.

A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway.

The emergent Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could produce a maternal immune activation (MIA) via the inflammatory response during gestation that may impair fetal neurodevelopment and lead to postnatal and adulthood mental illness and behavioral dysfunctions. However, so far, limited evidence exists regarding long-term physiological, immunological, and neurodevelopmental modifications produced by the SARS-CoV-2 in the human maternal-fetal binomial and, particularly, in the offspring. Relevant findings derived from epidemiological and preclinical models show that a MIA is indeed linked to an increased risk of neurodevelopmental disorders in the offspring. We hypothesize that a gestational infection triggered by SARS-CoV-2 increases the risks leading to neurodevelopmental disorders of the newborn, which can affect childhood and the long-term quality of life. In particular, disruption of either the maternal or the fetal cholinergic anti-inflammatory pathway (CAP) could cause or exacerbate the severity of COVID-19 in the maternal-fetal binomial. From a translational perspective, in this paper, we discuss the possible manifestation of a MIA by SARS-CoV-2 and the subsequent neurodevelopmental disorders considering the role of the fetal-maternal cytokine cross-talk and the CAP. Specifically, we highlight the urgent need of preclinical studies as well as multicenter and international databanks of maternal-fetal psychophysiological data obtained pre-, during, and post-infection by SARS-CoV-2 from pregnant women and their offspring.

Food anticipatory hormonal responses: A systematic review of animal and human studies.

Food anticipatory hormonal responses (cephalic responses) are proactive physiological processes, that allow animals to prepare for food ingestion by modulating their hormonal levels in response to food cues. This process is important for digesting food, metabolizing nutrients and maintaining glucose levels within homeostasis. In this systematic review, we summarize the evidence from animal and human research on cephalic responses. Thirty-six animal and fifty-three human studies were included. The majority (88 %) of studies demonstrated that hormonal levels are changed in response to cues previously associated with food intake, such as feeding time, smell, and sight of food. Most evidence comes from studies on insulin, ghrelin, pancreatic polypeptide, glucagon, and c-peptide. Moreover, impaired cephalic responses were found in disorders related to metabolism and food intake such as diabetes, pancreatic insufficiency, obesity, and eating disorders, which opens discussions about the etiological mechanisms of these disorders as well as on potential therapeutic opportunities.

Chemogenetic silencing of hippocampus and amygdala reveals a double dissociation in periadolescent obesogenic diet-induced memory alterations.

In addition to numerous metabolic comorbidities, obesity is associated with several adverse neurobiological outcomes, especially learning and memory alterations. Obesity prevalence is rising dramatically in youth and is persisting in adulthood. This is especially worrying since adolescence is a crucial period for the maturation of certain brain regions playing a central role in memory processes such as the hippocampus and the amygdala. We previously showed that periadolescent, but not adult, exposure to obesogenic high-fat diet (HFD) had opposite effects on hippocampus- and amygdala-dependent memory, impairing the former and enhancing the latter. However, the causal role of these two brain regions in periadolescent HFD-induced memory alterations remains unclear. Here, we first showed that periadolescent HFD induced long-term, but not short-term, object recognition memory deficits, specifically when rats were exposed to a novel context. Using chemogenetic approaches to inhibit targeted brain regions, we then demonstrated that recognition memory deficits are dependent on the activity of the ventral hippocampus, but not the basolateral amygdala. On the contrary, the HFD- induced enhancement of conditioned odor aversion specifically requires amygdala activity. Taken together, these findings suggest that HFD consumption throughout adolescence impairs long-term object recognition memory through alterations of ventral hippocampal activity during memory acquisition. Moreover, these results further highlight the bidirectional effects of adolescent HFD on hippocampal and amygdala functions.

Phase Entropy Analysis of Electrohysterographic Data at the Third Trimester of Human Pregnancy and Active Parturition.

Phase Entropy (PhEn) was recently introduced for evaluating the nonlinear features of physiological time series. PhEn has been demonstrated to be a robust approach in comparison to other entropy-based methods to achieve this goal. In this context, the present study aimed to analyze the nonlinear features of raw electrohysterogram (EHG) time series collected from women at the third trimester of pregnancy (TT) and later during term active parturition (P) by PhEn. We collected 10-min longitudinal transabdominal recordings of 24 low-risk pregnant women at TT (from 35 to 38 weeks of pregnancy) and P (>39 weeks of pregnancy). We computed the second-order difference plots (SODPs) for the TT and P stages, and we evaluated the PhEn by modifying the k value, a coarse-graining parameter. Our results pointed out that PhEn in TT is characterized by a higher likelihood of manifesting nonlinear dynamics compared to the P condition. However, both conditions maintain percentages of nonlinear series higher than 66%. We conclude that the nonlinear features appear to be retained for both stages of pregnancy despite the uterine and cervical reorganization process that occurs in the transition from the third trimester to parturition.

Analysis of the fetal cardio-electrohysterographic coupling at the third trimester of gestation in healthy women by Bivariate Phase-Rectified Signal Averaging.

INTRODUCTION: The fetal cardio-electrohysterographic coupling (FCEC) is defined as the influence of the uterine electrical activity on fetal heart rate. FCEC has been mainly evaluated by visual analysis of cardiotocographic data during labor; however, this physiological phenomenon is poorly explored during the antenatal period. Here we propose an approach known as Bivariate Phase-Rectified Signal Averaging analysis (BPRSA) to assess such FCEC in the late third trimester of low-risk pregnancies. We hypothesized that BPRSA is a more reliable measure of FCEC than visual analysis and conventional measures such as cross-correlation, coherence, and cross-sample entropy. Additionally, by using BPRSA it is possible to detect FCEC even from the third trimester of pregnancy. MATERIAL AND METHODS: Healthy pregnant women in the last third trimester of pregnancy (36.6 ± 1.8 gestational weeks) without any clinical manifestation of labor were enrolled in the Maternal and Childhood Research Center (CIMIGen), Mexico City (n = 37). Ten minutes of maternal electrohysterogram (EHG) and fetal heart rate (FHR) data were collected by a transabdominal non-invasive device. The FCEC was quantified by the coefficient of coherence, the maximum normalized cross-correlation, and the cross-sample entropy obtained either from the EHG and FHR raw signals or from the corresponding BPRSA graphs. RESULTS: We found that by using BPRSA, the FCEC was detected in 92% cases (34/37) compared to 48% cases (18/37) using the coefficient of coherence between the EHG and FHR raw signals. Also, BPRSA indicated FCEC in 82% cases (30/37) compared to 30% cases (11/37) using the maximum normalized cross-correlation. By comparing the analyses, the BPRSA evidenced higher FCEC in comparison to the coupling estimated from the raw EHG and FHR signals. CONCLUSIONS: Our results support the consideration that in the third trimester of pregnancy, the fetal heart rate is also influenced by uterine activity despite the emerging manifestation of this activity before labor. To quantify FCEC, the BPRSA can be applied to FHR and EHG transabdominal signals acquired in the third trimester of pregnancy.

Placebo and nocebo effects for itch and itch-related immune outcomes: A systematic review of animal and human studies.

Placebo and nocebo effects can influence somatic symptoms such as pain. For itch and other dermatological symptoms these effects have been far less investigated. This review systematically integrates evidence from both animal (mainly rodents) and human trials on placebo and nocebo effects in itch, itch-related symptoms and conditions of the skin and mucous membranes, and related immune outcomes (e.g., histamine). Thirty-one animal studies, and fifty-five human studies (k = 21 healthy participants, k = 34 patients) were included. Overall, studies consistently show that placebo and nocebo effects can be induced by various methods (e.g., suggestions, conditioning and social cues), despite high heterogeneity across studies. Effects of suggestions were found consistently across subjective and behavioral parameters (e.g., itch and scratching in humans), whereas conditioning was likely to impact physiological parameters under certain conditions (e.g., conditioning of histamine levels in stressed rodents). Brain areas responsible for itch processing were associated with nocebo effects. Future research may investigate how variations in methods impact placebo and nocebo effects, and whether all symptoms and conditions can be influenced equally.

Comparison of fetal heart rate variability by symbolic dynamics at the third trimester of pregnancy and low-risk parturition.

Fetal heart rate variability (fHRV) is an essential source of information to monitor fetal well-being during pregnancy. This study aimed to apply a nonlinear approach, known as symbolic dynamics (SD), for comparing human fHRV in the third trimester of pregnancy during active fetal state (TT) and active labor at term (P). We performed a longitudinal, prospective, descriptive, and comparative study composed of 42 longitudinal recordings of 5-minutes of fetal heartbeat interval series. Recordings were collected from 21 low-risk, healthy, pregnant women attending the Maternal and Child Research Center (CIMIGen), Mexico City. We calculated relevant linear parameters of fHRV between TT and P stages, such as the percentage of differences between adjacent RR intervals >5 ms (PRR5, related to vagal modulations) and other SD parameters such as the percentage of no variations between three successive symbols (%0V, reflects sympathetic modulations) and the probability of low variability with a threshold of 4 ms (POLVAR4, associated with a low variability). We identified statistical differences for PRR5 between TT and P (37.13% [28.47-47.60%] vs. 28.84% [19.36-36.76%], p = 0.03), respectively. Also, for 0V% (65.66% [59.01-71.80%] vs. 71.14% [65.94-75.87%], p = 0.03) and for POLVAR4 values (0.06 [0.04-0.11] vs. 0.15 [0.09-0.24], p = 0.002), respectively. Our results indicate that during parturition, the short-term fetal fHRV is decreased, showing a decreased vagal modulations and higher adrenergic response of the heart. These autonomic modifications may result from the fetal response to the stressful inflammatory challenge of labor. We thus confirmed that the analysis of the SD applied to fHRV time series could be a potential clinical biomarker to differentiate the fetal autonomic cardiac condition at different stages of pregnancy.

Food Disgust Scale: Spanish Version.

INTRODUCTION: The Food Disgust Scale (FDS) was recently developed and validated in Swiss adult population. This study aims to: (1) validate the FDS for the first time in a Spanish-speaking Mexican population, (2) correlate food disgust sensitivity with picky eating measures, and (3) explore the association between food disgust sensitivity and body mass index (BMI). MATERIALS AND METHODS: A Spanish version of the FDS (FDS-Sp) and its short version (FDS-Sp short) were tested with confirmatory factor analysis (CFA) in order to test the original item/factor structure. Bivariate correlations were performed to determine the association between FDS-Sp/FDS-Sp short scores and picky eating. Lastly, hierarchical linear regression analysis was carried out to determine the relationship between food disgust sensitivity and BMI. RESULTS: The factor structure of the FDS was replicated and acceptable internal consistency values were observed for FDS-Sp subscales (α varied between 0.781 and 0.955). Moreover, FDS-Sp subscales and FDS-Sp short were correlated with picky eating. Higher score in VEGI subscale of the FDS-Sp was a significant predictor for higher BMI, explaining 4% of the variance. CONCLUSION: FDS-Sp is a useful, reliable and robust psychometric instrument to measure the sensitivity to unpleasant food situations in a Mexican adult Spanish-speaking population. A relationship between food disgust sensitivity and picky eating, selective eating behaviors and neophobia in Mexicans was confirmed. BMI is multifactorial and only one subscale of FDS-Sp is a significant predictor for BMI status. These results are helpful to continue exploring food disgust in diverse populations.