Comprehensive elucidation of resting-state functional connectivity in anorexia nervosa by a multicenter cross-sectional study.

BACKGROUND: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs). METHODS: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons. RESULTS: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction). CONCLUSION: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Dietary supplementation with 1-kestose induces altered locomotor activity and increased striatal dopamine levels with a change in gut microbiota in male mice.

1-Kestose (KES), a dietary fiber and prebiotic carbohydrate, benefits various physiological functions. This study aimed to examine whether diets supplemented with KES over three consecutive generations could significantly affect some host physiological aspects, including behavioral phenotypes and gut microbial ecology. Mice that received KES-supplemented diets for three generations demonstrated increased activity compared with those fed diets lacking KES. Furthermore, the KES group showed increased striatal dopamine (DA) and serotonin (5-HT) levels. The observed increase in DA levels within the striatum was positively correlated with locomotor activity in the KES group but not in the control (CON) group. The α-diversities were significantly lower in the KES group compared to the CON group. The three-dimensional principal coordinate analysis revealed a substantial distinction between the KES and CON groups across each generation. At the genus level, most gut microbiota genera exhibited lower abundances in the KES group than in the CON group, except for Bifidobacteria and Akkermansia. Spearman's rank-order analysis indicated significant negative correlations between the striatal DA levels and α-diversity values. These findings suggest that prolonged supplementation with KES may stimulate increased locomotor activity along with elevated striatal DA levels, which are potentially associated with KES-induced alterations in the gut microbiota.

Persistence of gut dysbiosis in individuals with anorexia nervosa.

Recent evidence suggests a crucial role of the gut microbiota in the pathogenesis of anorexia nervosa (AN). In this study, we carried out a series of multiple analyses of the gut microbiota of hospitalized individuals with AN over three months using 16S or 23S rRNA-targeted reverse transcription-quantitative polymerase chain reaction (PCR) technology (YIF-SCAN®), which is highly sensitive and enables the precise quantification of viable microorganisms. Despite the weight gain and improvements in psychological features observed during treatment, individuals with AN exhibited persistent gut microbial dysbiosis over the three-month duration. Principal component analysis further underscored the distinct microbial profile of individuals with AN, compared with that of age-matched healthy women at all time points. Regarding the kinetics of bacterial detection, the detection rate of Lactiplantibacillus spp. significantly increased after inpatient treatment. Additionally, the elevation in the Bifidobacterium counts during inpatient treatment was significantly correlated with the subsequent body weight gain after one year. Collectively, these findings suggest that gut dysbiosis in individuals with AN may not be easily restored solely through weight gain, highlighting the potential of therapeutic interventions targeting microbiota via dietary modifications or live biotherapeutics.

Psychological characteristics associated with the brain volume of patients with fibromyalgia.

Fibromyalgia (FM) is a disease characterized by chronic widespread pain concomitant with psychiatric symptoms such as anxiety and depression. It has been reported that FM patients engage in pain catastrophizing. In this study, we investigated characteristics of the brain volume of female FM patients and the association between psychological indices and brain volume. Thirty-nine female FM patients and 25 female healthy controls (HCs) were recruited for the study, and five FM patients were excluded due to white matter lesions. The following analyses were performed: (1) T1-weighted MRI were acquired for 34 FM patients (age 41.6 ± 7.4) and 25 HCs (age 39.5 ± 7.4). SPM12 was used to compare their gray and white matter volumes. (2) Data from anxiety and depression questionnaires (State-Trait Anxiety Inventory and Hospital Anxiety and Depression Scale), the Pain Catastrophizing Scale (subscales rumination, helplessness, magnification), and MRI were acquired for 34 FM patients (age 41.6 ± 7.4). Correlation analysis was done of the psychological indices and brain volume. We found that (1) The white matter volume of the temporal pole was larger in the FM patient group than in the HC group. (2) Correlation analysis of the psychological indices and gray matter volume showed a negative correlation between trait anxiety and the amygdala. For the white matter volume, positive correlations were found between depression and the brainstem and between magnification and the postcentral gyrus. Changes in the brain volume of female FM patients may be related to anxiety, depression, and pain catastrophizing.

Alexithymia characteristics are associated with salience network activity in healthy participants: an arterial spin labeling study.

BACKGROUND: Alexithymia, a personality trait characterized by difficulties in identifying and expressing their emotions despite having a range of emotional experiences, can impact individuals' stress coping mechanisms. While many studies have investigated brain functions associated with specific tasks in relation to emotion processing, research focusing on resting-state brain functions has been limited. Thus, the aim of this study was to investigate the relationship between alexithymia and brain function by analyzing arterial spin labeling (ASL) data obtained during the resting state. METHODS: A brain structural and functional imaging study was conducted on 42 healthy adult men and women using ASL and the 20-item Toronto Alexithymia Scale (TAS-20) questionnaire survey. Cerebral blood flow and functional connectivity values were calculated for regions of interest in the default mode network, saliency network, and central executive network from the ASL data. Correlation analysis was performed with TAS20 scores, and partial correlation analysis was conducted to control for anxiety and depression. RESULTS: The functional connectivity analysis revealed a negative correlation between the functional connectivity of the right insular cortex and left anterior cingulate cortex and the total score of TAS, as well as difficulty identifying feelings and difficulty describing feeling subscores, indicating that the higher the scores, the weaker the functional connectivity between these regions (T = -3.830, p = 0.0013, R = -0.5180). This correlation remained significant even after controlling for anxiety and depression using partial correlation analysis. CONCLUSION: The present study revealed differences in the activity of the Saliency Network at rest as measured by ASL, which were independent of anxiety and depression, and varied depending on the severity of alexithymia. This functional change may underlie the neural basis of decreased emotional processing observed in alexithymia. These findings may contribute to the elucidation of the neural mechanisms of alexithymia, which can lead to social impairments, and suggest the usefulness of ASL measurement as a biomarker of alexithymia.

Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging study.

The psychopathology of patients with anorexia nervosa has been hypothesized to involve inappropriate self-referential processing, disturbed interoceptive awareness, and excessive cognitive control, including distorted self-concern, disregard of their own starvation state, and extreme weight-control behavior. We hypothesized that the resting-state brain networks, including the default mode, salience and frontal-parietal networks, might be altered in such patients, and that treatment might normalize neural functional connectivity, with improvement of inappropriate self-cognition. We measured resting-state functional magnetic resonance images from 18 patients with anorexia nervosa and 18 healthy subjects before and after integrated hospital treatment (nourishment and psychological therapy). The default mode, salience, and frontal-parietal networks were examined using independent component analysis. Body mass index and psychometric measurements significantly improved after treatment. Before treatment, default mode network functional connectivity in the retrosplenial cortex and salience network functional connectivity in the ventral anterior insula and rostral anterior cingulate cortex were decreased in anorexia nervosa patients compared with those in controls. Interpersonal distrust was negatively correlated with salience network functional connectivity in the rostral anterior cingulate cortex. Default mode network functional connectivity in the posterior insula and frontal-parietal network functional connectivity in the angular gyrus were increased in anorexia nervosa patients compared with those in controls. Comparison between pre- and post-treatment images from patients with anorexia nervosa exhibited significant increases in default mode network functional connectivity in the hippocampus and retrosplenial cortex, and salience network functional connectivity in the dorsal anterior insula following treatment. Frontal-parietal network functional connectivity in the angular cortex showed no significant changes. The findings revealed that treatment altered the functional connectivity in several parts of default mode and salience networks in patients with anorexia nervosa. These alterations of neural function might be associated with improvement of self-referential processing and coping with sensations of discomfort following treatment for anorexia nervosa.

Differences in the presentation of COVID-19-related psychosocial stress and general psychological distress and the relation between the number of care days and these symptoms among Japanese ward staff working exclusively with COVID-19 and support staff.

BACKGROUND: Psychological distress has been frequently observed in frontline healthcare workers under stress during the coronavirus disease 2019 (COVID-19) epidemic; however, it is unclear if there are differences in the stress and symptoms experienced by staff members who work exclusively in a COVID-19 ward and support staff temporarily deployed to a COVID-19 ward. The present study investigated psychosocial stress specific to the care for patients with COVID-19 and psychological distress among ward staff working exclusively with COVID-19 and temporary support staff. METHODS: The participants were full-time nurses and doctors working in COVID-19 wards or the ICU who provided face-to-face care to patients with COVID-19 during the COVID-19 outbreak in February of 2021. The data of 67 staff members (21 exclusively working with Covid-19 patients (group A) and 46 in the temporary support group (group B)) was available for study. Psychosocial stress specific to healthcare professionals during this COVID-19 outbreak (Tokyo Metropolitan Distress Scale for Pandemic [TMDP]) and general psychological distress (K6) were assessed. RESULTS: The K6 score was significantly lower in group B than in group A (p = .006), but no significant difference was found in the total score of TMDP or its subscales. Positive correlations were found between TMDP and K6 for group B (p = .011), as was the number of days of care on TMDP-social (rs = .456, p = .001). CONCLUSION: Even though support staff members experienced lower psychological distress than staff working exclusively with COVID-19, COVID-19-related psychosocial stress specific to HCWs was comparable. The support staff also presented psychological distress associated with psychosocial stress specific to healthcare professionals during this COVID-19 outbreak, and the COVID-19-related social stress was enhanced as the number of working days increased. Our results show that all staff, not only those working exclusively with COVID-19 patients but also other support staff should be provided with care focusing on COVID-19-related psychosocial occupational stress.

Occupational stress, psychological distress, physical symptoms, and their interrelationships among frontline nurses caring for COVID-19 patients in Japan.

This study aimed to identify occupational stress, psychosomatic symptoms, psychological distress, and their correlations among frontline nurses during and after the first peak of the coronavirus disease 2019 (COVID-19) outbreak in Japan. Sixteen frontline nurses, aged 25 to 52 years, working in a ward with COVID-19 patients participated in this study. Two months after the peak of the first wave of the COVID-19 outbreak in Japan, the COVID-19-related occupational stress scale (COS; questionnaire items: fear of infection and increased workload) and physical symptom scale (PS; questionnaire items: gastrointestinal symptoms, pain, appetite loss, and insomnia) were assessed. The degree of general psychological distress was evaluated using the 6-item Kessler Scale (K6). Simultaneously, participants were asked to recall their condition during the peak period of the first wave and rate it using the same scale. K6 was positively correlated with COS and PS during the peak period (rs = 0.574, P = .020 and rs = 0.587, P = .017, respectively). Increased workload was positively correlated with the K6 score both during and after the peak period (rs = 0.869, P < .001 and rs = 0.732, P = <.001, respectively) and was positively correlated with insomnia during the peak period (rs = 0.498, P < .05). The COS, PS, and K6 scores during the peak period were significantly higher than those after the peak period. Psychological distress at the peak was associated with PS and occupational stress. An increased workload during peak periods can cause psychological distress and insomnia. The occupational stress, PS, and psychological distress of nurses working in COVID-19 wards improved after the peak of COVID-19.

Association Between Diabetes and Gray Matter Atrophy Patterns in a General Older Japanese Population: The Hisayama Study.

OBJECTIVE: To examine the association between diabetes and gray matter atrophy patterns in a general older Japanese population. RESEARCH DESIGN AND METHODS: In 2012, a total of 1,189 community-dwelling Japanese aged ≥65 years underwent brain MRI scans. Regional gray matter volumes (GMV) and intracranial volume (ICV) were measured by applying voxel-based morphometry (VBM) methods. The associations of diabetes and related parameters with the regional GMV/ICV were examined using an ANCOVA. The regional gray matter atrophy patterns in the subjects with diabetes or elevated fasting plasma glucose (FPG) or 2-h postload glucose (2hPG) levels were investigated using VBM. RESULTS: Subjects with diabetes had significantly lower mean values of GMV/ICV in the frontal lobe, temporal lobe, insula, deep gray matter structures, and cerebellum than subjects without diabetes after adjusting for potential confounders. A longer duration of diabetes was also significantly associated with lower mean values of GMV/ICV in these brain regions. The multivariable-adjusted mean values of the temporal, insular, and deep GMV/ICV decreased significantly with elevating 2hPG levels, whereas higher FPG levels were not significantly associated with GMV/ICV of any brain regions. In the VBM analysis, diabetes was associated with gray matter atrophy in the bilateral superior temporal gyri, right middle temporal gyrus, left inferior temporal gyrus, right middle frontal gyrus, bilateral thalami, right caudate, and right cerebellum. CONCLUSIONS: The current study suggests that a longer duration of diabetes and elevated 2hPG levels are significant risk factors for gray matter atrophy in various brain regions.

Dietary tryptophan, tyrosine, and phenylalanine depletion induce reduced food intake and behavioral alterations in mice.

Important precursors of monoaminergic neurotransmitters, dietary tryptophan (TRP), tyrosine, and phenylalanine (all referred to as TTP), play crucial roles in a wide range of behavioral and emotional functions. In the current study, we investigated whether diets devoid of TTP or diets deficient in TRP alone can affect body weight, behavioral characteristics, and gut microbiota, by comparing mice fed on these amino acids-depleted diets to mice fed on diets containing regular levels of amino acids. Both dietary TTP- and TRP-deprived animals showed a reduction in food intake and body weight. In behavioral analyses, the mice fed TTP-deprived diets were more active than mice fed diets containing regular levels of amino acids. The TRP-deprived group exhibited a reduction in serum TRP levels, concomitant with a decrease in serotonin and 5-hydroxyindoleacetic acid levels in some regions of the brain. The TTP-deprived group showed a reduction in TTP levels in the serum, concomitant with decreases in both phenylalanine and tyrosine levels in the hippocampus, as well as serotonin, norepinephrine, and dopamine concentrations in some regions of the brain. Regarding the effects of TRP or TTP deprivation on gut microbial ecology, the relative abundance of genus Roseburia was significantly reduced in the TTP-deprived group than in the dietary restriction control group. Interestingly, TTP was found even in the feces of mice fed TTP- and TRP-deficient diets, suggesting that TTP is produced by microbial or enzymatic digestion of the host-derived proteins. However, microbe generated TTP did not compensate for the systemic TTP deficiency induced by the lack of dietary TTP intake. Collectively, these results indicate that chronic dietary TTP deprivation induces decreased monoamines and their metabolites in a brain region-specific manner. The altered activities of the monoaminergic systems may contribute to increased locomotor activity.

Role of Gut Microbiota in the Pathophysiology of Stress-Related Disorders: Evidence from Neuroimaging Studies.

BACKGROUND: The brain and gut communicate bidirectionally via immune, neurological, and endocrine pathways, which is termed the "brain-gut interaction." Recent studies of gut microbiota as a mediator of this interaction have provided a growing body of scientific evidence that suggests that the gut microbiota influences stress and emotional responses and stress-related disorders. SUMMARY: Major advances in analytical methods have led to an increased number of studies that combine gut microbiota and neuroimaging, mainly magnetic resonance imaging, to elucidate the mechanisms. Observational studies have been done to examine brain characteristics related to gut microbiota profiles, and intervention studies have examined brain changes related to probiotic intake. Studies of healthy subjects using negative emotional stimuli have shown that the pattern of emotional response differs depending on the gut microbiota profile and that probiotic intervention can modulate emotional response and be a buffer against the negative effects of stress. In studies on irritable bowel syndrome (IBS), a typical psychosomatic disorder, IBS-specific gut microbiota were reported to contribute to visceral irritability and pain by affecting the subcortical regions. Studies on psychiatric disorders revealed that a relative abundance of Bacteroides that produce γ-aminobutyric acid in feces was associated with a change in brain function specific to depression and that gut microbiota have an influence on abnormalities in the reward system of attention-deficit/hyperactivity disorder.

Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive-behavioural therapy for eating disorders.

INTRODUCTION: Anorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality ratio of bulimia nervosa is 1.49; however, it is characterised by suicidality resulting in a shorter time to death. While there is no current validated drug treatment for eating disorders in Japan, cognitive-behavioural therapy (CBT) is a well-established and commonly used treatment. CBT is also recommended in the Japanese Guidelines for the Treatment of Eating Disorders (2012) and has been covered by insurance since 2018. However, the neural mechanisms responsible for the effect of CBT have not been elucidated, and the use of biomarkers such as neuroimaging data would be beneficial. METHODS AND ANALYSIS: The Eating Disorder Neuroimaging Initiative is a multisite prospective cohort study. We will longitudinally collect data from 72 patients with eating disorders (anorexia nervosa and bulimia nervosa) and 70 controls. Data will be collected at baseline, after 21-41 sessions of CBT and 12 months later. We will assess longitudinal changes in neural circuit function, clinical data, gene expression and psychological measures by therapeutic intervention and analyse the relationship among them using machine learning methods. ETHICS AND DISSEMINATION: The study was approved by The Ethical Committee of the National Center of Neurology and Psychiatry (A2019-072). We will obtain written informed consent from all patients who participate in the study after they had been fully informed about the study protocol. All imaging, demographic and clinical data are shared between the participating sites and will be made publicly available in 2024. TRIAL REGISTRATION NUMBER: UMIN000039841.

Metabolomics profile of Japanese female patients with restricting-type anorexia nervosa.

In this study, the serum metabolic profiles of 10 female patients with restricting type anorexia nervosa (ANR) were compared to those of 10 age-matched healthy female controls. While the levels of amino acids were lower among the patients than among the controls, the levels of uremic toxins, including p-cresyl sulfate (PCS), indole-3-acetic acid, and phenyl sulfate, were higher in ANR patients. The serum PCS levels correlated positively with the abundance of the Clostridium coccoides group or the C. leptum subgroup in the feces of patients, but not in those of controls. Collectively, these results indicate that the serum metabolic profiles of patients with ANR differ from those of healthy women in terms of both decreased amino acid levels and increased uremic toxins. Gut microbes including C. coccoides or C. leptum may be involved in such an increase in uremic toxins.

Dietary delivery of acetate to the colon using acylated starches as a carrier exerts anxiolytic effects in mice.

Recently, short-chain fatty acids (SCFA) have been shown to play an important role in mediating the gut-brain interaction and thereby participate in the patho-physiological process of stress-related disorders. In the current study, we examined whether SCFA generated in the lower gut affects host metabolic and behavioral characteristics. To determine this, we used special diets containing acylated starches that can reach the colon without being absorbed in the upper gastrointestinal tract of male mice. The delivery of SCFA to the colon using this method induced a substantial increase in acetate, butyrate, and propionate in the cecum. Moreover, the diets containing acylated starches also decreased microbial diversity in the cecum, concomitant with a significant impact on microbial composition. In marble-burying (MB) tests, the mice that consumed diets containing acetylated starches showed a decrease in anxiety-like behavior compared with the mice that consumed diets containing either butyrylated or propionylated starches. Cecal acetate contents were significantly associated with anxiety-like behaviors when evaluated by elevated plus-maze and MB tests. Collectively, these results indicate that gut acetate elevation of a dietary origin may exert anxiolytic effects on behavioral phenotypes of the host.

The Gut Microbiome Derived From Anorexia Nervosa Patients Impairs Weight Gain and Behavioral Performance in Female Mice.

Anorexia nervosa (AN) results in gut dysbiosis, but whether the dysbiosis contributes to AN-specific pathologies such as poor weight gain and neuropsychiatric abnormalities remains unclear. To address this, germ-free mice were reconstituted with the microbiota of four patients with restricting-type AN (gAN mice) and four healthy control individuals (gHC mice). The effects of gut microbes on weight gain and behavioral characteristics were examined. Fecal microbial profiles in recipient gnotobiotic mice were clustered with those of the human donors. Compared with gHC mice, gAN mice showed a decrease in body weight gain, concomitant with reduced food intake. Food efficiency ratio (body weight gain/food intake) was also significantly lower in gAN mice than in gHC mice, suggesting that decreased appetite as well as the capacity to convert ingested food to unit of body substance may contribute to poor weight gain. Both anxiety-related behavior measured by open-field tests and compulsive behavior measured by a marble-burying test were increased only in gAN mice but not in gHC mice. Serotonin levels in the brain stem of gAN mice were lower than those in the brain stem of gHC mice. Moreover, the genus Bacteroides showed the highest correlation with the number of buried marbles among all genera identified. Administration of Bacteroides vulgatus reversed compulsive behavior but failed to exert any substantial effect on body weight. Collectively, these results indicate that AN-specific dysbiosis may contribute to both poor weight gain and mental disorders in patients with AN.

Role of the right anterior insular cortex in joint attention-related identification with a partner.

Understanding others as intentional agents is critical in social interactions. We perceive others' intentions through identification, a categorical judgment that others should work like oneself. The most primitive form of understanding others' intentions is joint attention (JA). During JA, an initiator selects a shared object through gaze (initiative joint attention, IJA), and the responder follows the direction of the initiator's gaze (reactive joint attention, RJA). Therefore, both participants share the intention of object selection. However, the neural underpinning of shared intention through JA remains unknown. In this study, we hypothesized that JA is represented by inter-individual neural synchronization of the intention-related activity. Additionally, JA requires eye contact that activates the limbic mirror system; therefore, we hypothesized that this system is involved in shared attention through JA. To test these hypotheses, participants underwent hyperscanning fMRI while performing JA tasks. We found that IJA-related activation of the right anterior insular cortex of participants was positively correlated with RJA-related activation of homologous regions in their partners. This area was activated by volitional selection of the target during IJA. Therefore, identification with others by JA is likely accomplished by the shared intentionality of target selection represented by inter-individual synchronization of the right anterior insular cortex.

Regulation of gut luminal serotonin by commensal microbiota in mice.

Gut lumen serotonin (5-hydroxytryptamine: 5-HT) contributes to several gastrointestinal functions such as peristaltic reflexes. 5-HT is released from enterochromaffin (EC) cells in response to a number of stimuli, including signals from the gut microbiota. However, the specific mechanism by which the gut microbiota regulates 5-HT levels in the gut lumen has not yet been clarified. Our previous work with gnotobiotic mice showed that free catecholamines can be produced by the deconjugation of conjugated catecholamines; hence, we speculated that deconjugation by bacterial enzymes may be one of the mechanisms whereby gut microbes can produce free 5-HT in the gut lumen. In this study, we tested this hypothesis using germ-free (GF) mice and gnotobiotic mice recolonized with specific pathogen-free (SPF) fecal flora (EX-GF). The 5-HT levels in the lumens of the cecum and colon were significantly lower in the GF mice than in the EX-GF mice. Moreover, these levels were rapidly increased, within only 3 days after exposure to SPF microbiota. The majority of 5-HT was in an unconjugated, free form in the EX-GF mice, whereas approximately 50% of the 5-HT was found in the conjugated form in the GF mice. These results further support the current view that the gut microbiota plays a crucial role in promoting the production of biologically active, free 5-HT. The deconjugation of glucuronide-conjugated 5-HT by bacterial enzymes is likely one of the mechanisms contributing to free 5-HT production in the gut lumen.

QseC inhibition as an antivirulence approach for colitis-associated bacteria.

Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/-Rag2-/- IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.