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Serotonin, also known as 5-hydroxytryptamine (5-HT), is an evolutionarily ancient and phylogenetically conserved monoamine that regulates multifaceted physiological functions in mammals. 5-HT was, at one time, most extensively studied as a neurotransmitter within the central nervous system but is now known to regulate nonneuronal functions including immune responses in an autocrine-paracrine-endocrine manner. Compelling evidence from intervention studies using germ-free mice or antibiotic-associated microbiota perturbation suggests that novel interactions between 5-HT and the gut microbiota are essential in maintaining intestinal homeostasis. Importantly, recent studies reveal that bidirectional host-microbial interactions mediated by the host serotonergic system can promote distinct changes within the gut microbiota. These changes may potentially lead to a state known as “dysbiosis” that has been strongly associated with various gut pathologies including inflammatory bowel disease (IBD). In this review, we update the current understanding of host-microbiota interaction by focusing on the impact of peripheral 5-HT signaling within this dynamic. We also briefly highlight key environmental risk factors for IBD, such as the Western diet, and draw attention to the interaction of synthetic food colorants with 5-HT signaling that may facilitate future research.

Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.

Description, Elevated gut serotonin inhibits autophagy via mTOR promoting a disrupted microbiota and enhanced susceptibility to colitis., Autophagy, an essential intracellular recycling process, is linked to the pathogenesis of various diseases including Crohn’s disease (CD). Factors that lead to the development of impaired autophagy during intestinal inflammation remain largely unexplored. Here, we report the impact of the interaction between serotonin [5-hydroxytryptamine;(5-HT)] and autophagy in colitis in mouse and human studies. In mice, increased gut 5-HT inhibited autophagy and led to enhanced colitis susceptibility. Reciprocally, mice with reduced 5-HT exhibited up-regulated autophagy via the mammalian target of rapamycin pathway, which resulted in significantly decreased colitis. Deletion of autophagy gene, Atg7, in an epithelial-specific manner, in concert with reduced 5-HT, promoted the development of a colitogenic microbiota and abolished the protective effects conferred by reduced 5-HT. Notably, in control and patient peripheral blood mononuclear cells, we uncovered that 5-HT treatment inhibited autophagy. Our findings suggest 5-HT as a previously unidentified therapeutic target in intestinal inflammatory disorders such as CD that exhibits dysregulated autophagy.

Chemicals in food are widely used leading to significant human exposure. Allura Red AC (AR) is a highly common synthetic colorant; however, little is known about its impact on colitis. Here, we show chronic exposure of AR at a dose found in commonly consumed dietary products exacerbates experimental models of colitis in mice. While intermittent exposure is more akin to a typical human exposure, intermittent exposure to AR in mice for 12 weeks, does not influence susceptibility to colitis. However, exposure to AR during early life primes mice to heightened susceptibility to colitis. In addition, chronic exposure to AR induces mild colitis, which is associated with elevated colonic serotonin (5-hydroxytryptamine; 5-HT) levels and impairment of the epithelial barrier function via myosin light chain kinase (MLCK). Importantly, chronic exposure to AR does not influence colitis susceptibility in mice lacking tryptophan hydroxylase 1 (TPH1), the rate limiting enzyme for 5-HT biosynthesis. Cecal transfer of the perturbed gut microbiota by AR exposure worsens colitis severity in the recipient germ-free (GF) mice. Furthermore, chronic AR exposure elevates colonic 5-HT levels in naïve GF mice. Though it remains unknown whether AR has similar effects in humans, our study reveals that chronic long-term exposure to a common synthetic colorant promotes experimental colitis via colonic 5-HT in gut microbiota-dependent and -independent pathway in mice.

Several parasites have evolved to survive in the human intestinal tract and over 1 billion people around the world, specifically in developing countries, are infected with enteric helminths. Trichuris trichiura is one of the world’s most common intestinal parasites that causes human parasitic infections. Trichuris muris, as an immunologically well-defined mouse model of T. trichiura, is extensively used to study different aspects of the innate and adaptive components of the immune system. Studies on T. muris model offer insights into understanding host immunity, since this parasite generates two distinct immune responses in resistant and susceptible strains of mouse. Apart from the immune cells, T. muris infection also influences various components of the intestinal tract, especially the gut microbiota, mucus layer, epithelial cells and smooth muscle cells. Here, we reviewed the different immune responses generated by innate and adaptive immune components during acute and chronic T. muris infections. Furthermore, we discussed the importance of studying T. muris model in understanding host–parasite interaction in the context of alteration in the host’s microbiota, intestinal barrier, inflammation, and host defense, and in parasite infection-mediated modulation of other immune and inflammatory diseases.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray–Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.

BackgroundInflammatory bowel diseases are the most common chronic intestinal inflammatory conditions, and their incidence has shown a dramatic increase in recent decades. Limited efficacy and questionable safety profiles with existing therapies suggest the need for better targeting of therapeutic strategies. Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular metabolism and has been implicated in intestinal inflammation. Macrophages execute an important role in the generation of intestinal inflammation. Impaired AMPK in macrophages has been shown to be associated with higher production of proinflammatory cytokines; however, the role of macrophage AMPK in intestinal inflammation and the mechanism by which it regulates inflammation remain to be determined. In this study, we investigated the role of AMPK with a specific focus on macrophages in the pathogenesis of intestinal inflammation.MethodsA dextran sodium sulfate-induced colitis model was used to assess the disease activity index, histological scores, macroscopic scores, and myeloperoxidase level. Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β were measured by enzyme-linked immunosorbent assay. Transient transfection of AMPKβ1 and LC3-II siRNA in RAW 264.7 cells was performed to elucidate the regulation of autophagy by AMPK. The expression of p-AMPK, AMPK, and autophagy markers (eg, LC3-II, p62, Beclin-1, and Atg-12) was analyzed by Western blot.ResultsGenetic deletion of AMPKβ1 in macrophages upregulated the production of proinflammatory cytokines, aggravated the severity of dextran sodium sulfate-induced colitis in mice, which was associated with an increased nuclear translocation of nuclear factor-κB, and impaired autophagy both in vitro and in vivo. Notably, the commonly used anti-inflammatory 5-aminosalicylic acid (ie, mesalazine) and sodium salicylate ameliorated dextran sodium sulfate-induced colitis through the activation of macrophage AMPK targeting the β1 subunit.ConclusionsTogether, these data suggest that the development of therapeutic agents targeting AMPKβ1 may be effective in the treatment of intestinal inflammatory conditions including inflammatory bowel disease.

Background & Aims Serotonin (5-hydroxytryptamine [5-HT]) is synthesized mainly within enterochromaffin (EC) cells in the gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme for 5-HT synthesis in EC cells. Accumulating evidence suggests the importance of gut microbiota in intestinal inflammation. Considering the close proximity of EC cells and the microbes, we investigated the influence of gut-derived 5-HT on the microbiota and the susceptibility to colitis. Methods Gut microbiota of Tph1-/- and Tph1+/- mice were investigated by deep sequencing. Direct influence of 5-HT on bacteria was assessed by using in vitro system of isolated commensals. The indirect influence of 5-HT on microbiota was assessed by measuring antimicrobial peptides, specifically β-defensins, in the colon of mice and HT-29 colonic epithelial cells. The impact of gut microbiota on the development of dextran sulfate sodium–induced colitis was assessed by transferring gut microbiota from Tph1-/- mice to Tph1+/- littermates and vice versa, as well as in germ-free mice. Results A significant difference in microbial composition between Tph1-/- and Tph1+/- littermates was observed. 5-HT directly stimulated and inhibited the growth of commensal bacteria in vitro, exhibiting a concentration-dependent and species-specific effect. 5-HT also inhibited β-defensin production by HT-29 cells. Microbial transfer from Tph1-/- to Tph1+/- littermates and vice versa altered colitis severity, with microbiota from Tph1-/- mice mediating the protective effects. Furthermore, germ-free mice colonized with microbiota from Tph1-/- mice exhibited less severe dextran sulfate sodium–induced colitis. Conclusions These findings demonstrate a novel role of gut-derived 5-HT in shaping gut microbiota composition in relation to susceptibility to colitis, identifying 5-HT–microbiota axis as a potential new therapeutic target in intestinal inflammatory disorders., Graphical abstract

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that mediates various physiological processes in the gut. Enterochromaffin (EC) cells in the mucosal layer of the gut are the main source of 5-HT in the body and are situated in close proximity to the gut microbiota. In this study, we identify a pivotal role of TLR2 in 5-HT production in the gut. Antibiotic treatment reduces EC cell numbers and 5-HT levels in naive C57BL/6 mice, which is associated with downregulation of TLR2 expression but not TLR1 or TLR4. TLR2-deficient (Tlr2−/−) and Myd88−/− mice express lower EC cell numbers and 5-HT levels, whereas treatment with TLR2/1 agonist upregulates 5-HT production in irradiated C57BL/6 mice, which are reconstituted with Tlr2−/− bone marrow cells, and in germ-free mice. Human EC cell line (BON-1 cells) release higher 5-HT upon TLR2/1 agonist via NF-κB pathway. Tlr2−/− mice and anti-TLR2 Ab–treated mice infected with enteric parasite, Trichuris muris, exhibited attenuated 5-HT production, compared with infected wild-type mice. Moreover, excretory-secretory products from T. muris induce higher 5-HT production in BON-1 cells via TLR2 in a dose-dependent manner, whereby the effect of excretory-secretory products is abrogated by TLR2 antagonist. These findings not only suggest an important role of TLR2 in mucosal 5-HT production in the gut by resident microbiota as well as by a nematode parasite but also provide, to our knowledge, novel information on the potential benefits of targeting TLR2 in various gut disorders that exhibit aberrant 5-HT signaling.

It is well known that the weight of the structural system for a high-rise building to resist lateral loads increases in nonlinear fashion with increase in building height and slenderness ratio. For a given building height or slenderness ratio, the weight of the structural system for a high-rise building subjected to lateral loads depends on the degree of stiffness of the building structure. Therefore, at the final stage of the structural design process, it has been a challenge to structural engineers to improve the efficiency of a structural system by either minimizing the weight of a structure for a given limit on lateral displacement or maximizing the degree of stiffness for a given weight of a structure. In this paper, a resizing design method that can minimize the magnitudes of lateral displacement and inter-story drift of a high-rise building with respect to structural weights is presented. Based on the proposed design method, the relation between the structural weight and the magnitude of lateral displacement is investigated using two examples, including a 60-story high-rise building. Copyright © 2007 John Wiley & Sons, Ltd.

Recent developments of resizing algorithms based on displacement participation factor have had a significant impact on drift design of high-rise buildings. However, most drift design methods based on resizing algorithms have considered only lateral load and overlooked the effect of the vertical load in the calculation of member displacement participation factors. Therefore, in this paper, the practical drift design method of high-rise buildings is presented in the form of a resizing algorithm by developing product integral modules required for the calculation of displacement participation factors with the consideration of both lateral and vertical loads. The effect of vertical load on the drift design model based on member displacement participation factors is investigated in detail using the verifying example of a 20-story building structure. The drift design method in combination with the strength design module is then applied to the drift design of a 60-story high-rise building structure. Copyright © 2007 John Wiley & Sons, Ltd.

To make use of a new technology in the field of structural health monitoring, various displacement measuring techniques such as a global positioning system (GPS) and vision-based techniques have been studied and proposed. It was previously introduced a new displacement measuring technique using terrestrial laser scanning (TLS) that remotely samples the surface of an object using laser pulses and generates the three-dimensional (3D) coordinates of numerous points on the surface. In this paper, for an assessment of the capabilities of the measuring technique about existing structures, the field tests for vertical displacement measurement of an existing long span steel box-girder are experimentally carried out. The performance of the technique is evaluated by comparing the displacements obtained from TLS system and displacements directly measured from linear variable displacement transducer (LVDT).

In structural health monitoring, the safety of a multi-span steel beam is assessed by a comparison between the maximum stress measured during monitoring and the allowable stress of the beam calculated by a design code. The locations and magnitudes of the maximum stress to be monitored keep changing since multi-span beams in buildings and infrastructures are actually subjected to physical loads that have variable positions as well as variable magnitudes. However, most fiber optic sensors measuring the strain only at a local or specified point of a beam cannot consider the variations in the positions of applied loads. Long gage fiber optic sensors that measure average or integrated strain over a relatively long length can consider the variations in magnitudes and positions. On the other hand, the maximum strain in a beam cannot be measured with long gage optic sensors. Therefore, in this paper, analytical models are presented for estimation of the maximum values of strains or stresses in multi-span beams based on the average strains measured by long gage optic sensors. The model was tested in an experiment by comparing the maximum strains directly obtained from electrical gages and the estimated maximum strains from long gage optic sensors.

Even though several genetic algorithm (GA)-based optimization algorithms have been successfully applied to complex optimization problems in various engineering fields, such methods are computationally too expensive for practical use in the field of structural optimization, particularly for large-scale problems. Furthermore, the successful implementation of GA-based optimization algorithm requires a cumbersome routine through trial-and-error for tuning the GA parameters that are different depending on each problem. Therefore, to overcome these difficulties, a high-performance GA is developed in the form of a distributed hybrid genetic algorithm for structural optimization, implemented on a cluster of personal computers. The distributed hybrid genetic algorithm proposed in this paper consists of a μ-GA running on a master computer and multiple simple GAs running on slave computers. The algorithm is implemented on a PC cluster and applied to the minimum weight design of steel structures. The results show that the computation time required for GA-based optimization can be drastically reduced and the problem-dependent parameter tuning process can be avoided.

Structural monitoring is concerned with the safety and serviceability of the users of structures, especially for the case of building structures and infrastructures. When considering the safety of a structure, the maximum stress in a member due to live load, earthquake, wind, or other unexpected loadings must be checked not to exceed the stress specified in a code. Although the steel will not fail at yield, excessively large deflections will deteriorate the serviceability of a structure. Therefore, to guarantee the safety and serviceability of steel beams, the maximum stress and deflection in a steel beam must be monitored. However, no practical method has been reported to monitor both the maximum stress and deflection. In this paper, assessment model for both safety and serviceability of a steel beam is proposed. The model was tested in an experiment by comparing stress level estimated by LiDAR system and stress level directly measured from electrical or fiber optic sensors. The maximum deflection measured from LiDAR system is also compared with the maximum deflection directly measured from LVDTs. In addition to displacement measurement, the proposed system can provide information on deformed shapes of steel beams.

Most fiber optic sensors are point sensors that can measure the strain only at a local point of a beam, although strain distribution is non-uniform along the length of a beam. Long gage fiber optic sensors that measure integrated strain over a relatively long length can consider strain variation. This type of sensor was found to be efficient and useful for monitoring large-scale structures. On the other hand, the maximum strain in a beam cannot be measured with long gage optic sensors; the safety of a steel beam is analyzed by a comparison between the maximum stress measured during monitoring and the allowable stress of the beam calculated by a design code. Therefore, in this paper, simple mathematical models are presented for the determination of the maximum values of strains or stresses in a beam based on the average strains measured by long gage optic sensors. The model was tested in an experiment by comparing the maximum strain directly obtained from electrical gages and the calculated maximum strain from long gage optic sensors.