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The importance of gut microbiota in gastrointestinal (GI) physiology was well described, but our ability to study gut microbial ecosystems in their entirety was limited by culture-based methods prior to the sequencing revolution. The advent of high-throughput sequencing opened new avenues, allowing us to study gut microbial communities as an aggregate, independent of our ability to culture individual microbes. Early studies focused on association of changes in gut microbiota with different disease states, which was necessary to identify a potential role for microbes and generate novel hypotheses. Over the past few years the field has moved beyond associations to better understand the mechanistic implications of the microbiome in the pathophysiology of complex diseases. This movement also has resulted in a shift in our focus toward therapeutic strategies, which rely on better understanding the mediators of gut microbiota–host cross-talk. It is not surprising the gut microbiome has been implicated in the pathogenesis of functional gastrointestinal disorders given its role in modulating physiological processes such as immune development, GI motility and secretion, epithelial barrier integrity, and brain–gut communication. In this review, we focus on the current state of knowledge and future directions in microbiome research as it pertains to functional gastrointestinal disorders. We summarize the factors that help shape the gut microbiome in human beings. We discuss data from animal models and human studies to highlight existing paradigms regarding the mechanisms underlying microbiota-mediated alterations in physiological processes and their relevance in human interventions. While translation of microbiome science is still in its infancy, the outlook is optimistic and we are advancing in the right direction toward precise mechanism-based microbiota therapies. [ABSTRACT FROM AUTHOR]

Activity-based anorexia (ABA) is a well-established animal model mimicking the eating disorder anorexia nervosa (AN). Since the pathophysiology of AN is yet poorly understood and specific drug treatments are lacking so far, animal models might be useful to further understand this disease. ABA consists of time-restricted access to food for 1.5 h/day and the possibility to exercise in a running wheel for 24 h/day. This combination leads to robust body weight loss as observed in AN. Here, we investigated the activation of brain corticotropin-releasing factor (CRF) neurons, a transmitter involved in the response to stress, emotional processes and also food intake. After development of ABA, rat brains were processed for c-Fos and CRF double immunohistochemistry. ABA increased the number of c-Fos/CRF double labeled neurons in the paraventricular nucleus (PVN) and the dorsomedial hypothalamic nucleus (DMH) compared to the ad libitum (AL, ad libitum fed, no running wheel) and activity (AC, ad libitum fed, running wheel, p  < 0.05) but not to the restricted feeding (RF, food for 1.5 h/day, no running wheel, p  > 0.05) group. Also the number of CRF neurons was increased in the DMH of ABA rats compared to AL and AC ( p  < 0.05). In the Edinger-Westphal nucleus (EW) the number of c-Fos positive neurons was increased in ABA and RF compared to AC ( p  < 0.05), while the number of double labeled neurons was not different ( p  > 0.05). Taken together, brain CRF activated under conditions of ABA might play a role in the development and maintenance of this animal model and possibly also in human AN. [ABSTRACT FROM AUTHOR]

Activity-based anorexia (ABA) is an established animal model for the eating disorder anorexia nervosa (AN). The pathophysiology of AN and the involvement of food intake-regulatory peptides is still poorly understood. Nesfatin-1, an anorexigenic peptide also involved in the mediation of stress, anxiety and depression might be a likely candidate involved in the pathogenesis of AN. Therefore, activation of nesfatin-1 immunoreactive (ir) brain nuclei was investigated under conditions of ABA. Female Sprague-Dawley rats were used and divided into four groups (n = 6/group): activity-based anorexia (ABA), restricted feeding (RF), activity (AC) and ad libitum fed (AL). After the 21-day experimental period and development of ABA, brains were processed for c-Fos/nesfatin-1 double labeling immunohistochemistry. ABA increased the number of nesfatin-1 immunopositive neurons in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, locus coeruleus and in the rostral part of the nucleus of the solitary tract compared to AL and AC groups ( p < 0.05) but not to RF rats ( p > 0.05). Moreover, we observed significantly more c-Fos and nesfatin-1 ir double-labeled cells in ABA rats compared to RF, AL and AC in the supraoptic nucleus ( p < 0.05) and compared to AL and AC in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, dorsal raphe nucleus and the rostral raphe pallidus ( p < 0.05). Since nesfatin-1 plays a role in the inhibition of food intake and the response to stress, we hypothesize that the observed changes of brain nesfatin-1 might play a role in the pathophysiology and symptomatology under conditions of ABA and potentially also in patients with AN. [ABSTRACT FROM AUTHOR]

Nesfatin-1 was discovered a decade ago and despite the fact that it represents just one of a multitude of food intake-inhibiting factors it received increasing attention. This led to a detailed characterization of NUCB2/nesfatin-1's physiological property to reduce food intake and also gave rise to an involvement in the long term regulation of body weight, especially under conditions of obesity. In addition, studies indicated the involvement of NUCB2/nesfatin-1 in other homeostatic functions as well: glucose homeostasis, water intake, gastrointestinal functions, temperature regulation, cardiovascular functions, puberty onset and sleep. These pleiotropic actions underline the physiological relevance of this peptide. Recently, the involvement of NUCB2/nesfatin-1 in psychiatric disorders such as anxiety has been investigated giving rise to the speculation that NUCB2/nesfatin-1 represents a peptidergic link between eating and anxiety/depression disorders. [ABSTRACT FROM AUTHOR]

Abstract: Nesfatin-1 is an 82 amino acid peptide recently discovered in the brain which is derived from nucleobindin2 (NUCB2), a protein that is highly conserved across mammalian species. Nesfatin-1 has received much attention over the past two years due to its reproducible food intake-reducing effect that is linked with recruitment of other hypothalamic peptides regulating feeding behavior. A growing amount of evidence also supports that various stressors activate fore- and hindbrain NUCB2/nesfatin-1 circuitries. In this review, we outline the central nervous system distribution of NUCB2/nesfatin-1, and recent developments on the peripheral expression of NUCB2/nesfatin-1, in particular its co-localization with ghrelin in gastric X/A-like cells and insulin in ß-cells of the endocrine pancreas. Functional studies related to the characteristics of nesfatin-1''s inhibitory effects on dark phase food intake are detailed as well as the central activation of NUCB2/nesfatin-1 immunopositive neurons in the response to psychological, immune and visceral stressors. Lastly, potential clinical implications of targeting NUCB2/nesfatin-1 signaling and existing gaps in knowledge to ascertain the role and mechanisms of action of nesfatin-1 are presented. [Copyright &y& Elsevier]

Abstract: The present study analyses the expression and distribution of neuronal nitric oxide synthase (nNOS) in the brainstem of animals pre-treated with Escherichia coli or Helicobacter pylori LPS, at doses that modulate gastric motor function. Systemic administration of H. pylori LPS prevented in a dose-dependent manner (5, 40 and 100 μg kg−1, i.v.) the increase in intragastric pressure induced by 2-deoxy-d-glucose (200 mg kg−1, i.v.) in urethane-anaesthetized rats. Quantitative analysis showed a significant increase in the amount of nNOS mRNA induced by E. coli or H. pylori LPS (2 h later), in a segment of the brainstem containing the dorsal vagal complex (DVC). Immunohistochemical studies showed nNOS presence in the DVC of vehicle-treated rats. Both E. coli (40 μg kg−1, i.p.) and H. pylori LPS (100 μg kg−1, i.p.) significantly increased (2 h later) the number of nNOS immunoreactive cells in this area, mainly at the most rostral level. The present study shows that systemic administration of E. coli or H. pylori LPS induces a transcriptional up-regulation of the nNOS in the DVC of the brainstem and suggests a role for NO synthesis in this area in the control of gastric motor function under endotoxemia. [Copyright &y& Elsevier]

• Restraint stress activates and induces a significant increase of phoenixin expression in several nuclei. • Phoenixin expression and activity are positively correlated in the RPa, DMN and mNTS. • Phoenixin possibly has a counter-balancing role in a negative feedback loop with nesfatin-1 to manage reactions to stress. Phoenixin is a recently discovered peptide, which has been associated with reproduction, anxiety and food intake. Based on a considerable co-localization it has been linked to nesfatin-1, with a possible antagonistic mode of action. Since nesfatin-1 is known to play a role in anxiety and the response to stress, this study aims to investigate the effects of a well-established psychological stress model, restraint stress, on phoenixin-expressing brain nuclei and phoenixin expression in rats. Male Sprague-Dawley rats were subjected to restraint stress (n = 8) or left undisturbed (control, n = 6) and the brains processed for c-Fos- and phoenixin immunohistochemistry. The number of c-Fos expressing cells was counted and phoenixin expression assessed semiquantitatively. Restraint stress significantly increased c-Fos expression in the dorsal motor nucleus of vagus nerve (DMN, 52-fold, p < 0.001), raphe pallidus (RPa, 15-fold, p < 0.001), medial part of the nucleus of the solitary tract (mNTS, 16-fold, p < 0.001), central amygdaloid nucleus, medial division (CeM, 9-fold, p = 0.01), supraoptic nucleus (SON, 9-fold, p < 0.001) and the arcuate nucleus (Arc, 2.5-fold, p < 0.03) compared to control animals. Also phoenixin expression significantly increased in the DMN (17-fold, p < 0.001), RPa (2-fold, p < 0.001) and mNTS (1.6-fold, p < 0.001) with positive correlations between c-Fos and phoenixin (r = 0.74–0.85; p < 0.01) in these nuclei. This pattern of activation suggests an involvement of phoenixin in response to restraint stress. Whether phoenixin mediates stress effects or is activated in a counterbalancing fashion will have to be further investigated. [ABSTRACT FROM AUTHOR]