High cellulose diet promotes intestinal motility through regulating intestinal immune homeostasis and serotonin biosynthesis

It is widely accepted dietary fiber intimately linked to inflammatory and nervous diseases, which often been described with altered gastrointestinal (GI) motility. However, how dose dietary fiber modulate inflammation and crosstalk influence GI function has not been explained in detail. We found fiber-free diet reduced intestinal motility, accompanied by upregulated proinflammatory immunocytes and inflammatory cytokines in colon of mice. We also discovered high-cellulose diet increased synthesis of serotonin and expression of neurotrophic factors, both of that have been reported involved in promoting intestinal motility. In addition, metabolomics analysis showed increased tryptophan metabolites in high-cellulose diet mice, which happened to be required for serotonin biosynthesis. Further analysis revealed high-cellulose diet changed the composition of gut microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes, consequently, concentration of short-chain fatty acids (SCFAs), especially acetate. Orally administration of acetate confirmed its modulating to serotonin synthesis, neurotrophic factors expression and immunocyte differentiation through regulating histone deacetylase (HDAC3) activity in colon. Together, our results demonstrated high-cellulose diet promote intestinal motility through regulating intestinal homeostasis and enteric nervous system by increasing acetate production and HDAC3 inhibition. Thus, rich cellulose diet or acetate supplement can be considered as dietary advice to improve clinically intestinal motility insufficiency.

Penambahan Asam Amino Triptofan Dalam Pakan Terhadap Tingkat Kanibalisme Dan Pertumbuhan Litopenaeus vannamei

Vannamei shrimp (Litopenaeus vannamei) is one of the leading fishery products of the fisheries sector. The problem that is often found in the failure of vannamei shrimp productions is the high level of mortality due to the nature of cannibalism during molting. One solution to minimize the cannibalism of vannamei shrimp is to provide tryptophan supplements in a feed. Tryptophan is a type of essential amino acid that serves as a precursor for serotonin biosynthesis. This study aims to determine the effect and optimal dose of tryptophan added to feed to reduce cannibalism and growth of vannamei shrimp. The test fish used in this study were vannamei shrimp with an average weight of 0,81 ± 0,26 g/individual. This study used an experimental method, a completely randomized design (CRD) consisting of 4 treatments and three replications. The test feed used in this study was artificial feed with a protein content of 38% plus tryptophan according to treatments A (0%/kg feed), B (0.75%/kg feed), C (1.5%/kg feed), and D (2.25%/kg feed). The results showed that the addition of Tryptophan in the feed had a noticeable effect (P<0,05) on cannibalism levels, survival, and molting rates but had no significant effect (P>0,05) on absolute weight growth, specific growth rates, efficiency ratios protein and efficiency feed utilization of vannamei shrimp. The best dose of tryptophan addition in feed to lower the rate of vannamei shrimp cannibalism in this study was 2,25%, capable of producing a cannibalism rate of 13,33%. Udang vaname (Litopenaeus vannamei) merupakan salah satu produk perikanan unggulan sektor perikanan. Permasalahan yang sering ditemukan dalam kegagalan produksi udang vaname adalah tingginya tingkat mortalitas karena adanya sifat kanibalisme pada saat terjadi molting. Solusi untuk meminimalisir kanibalisme udang vaname adalah dengan memberi suplemasi asam amino pada pakan, salah satunya adalah triptofan. Triptofan merupakan salah satu jenis asam amino esensial yang berfungsi sebagai prekursor untuk biosintesis serotonin. Penelitian ini bertujuan untuk mengkaji pengaruh dan dosis optimal triptofan yang ditambahkan ke dalam pakan untuk menurunkan tingkat kanibalisme dan pertumbuhan udang vaname. Ikan uji yang digunakan pada penelitian ini adalah udang vaname dengan bobot rata-rata 0,81±0,26 g/ekor. Penelitian ini menggunakan metode eksperimen, rancangan acak lengkap (RAL) yang terdiri atas 4 perlakuan dan 3 kali ulangan. Pakan uji yang digunakan dalam penelitian ini adalah pakan buatan dengan kandungan protein 38% ditambah triptofan sesuai perlakuan yaitu : A (0%/kg pakan), B (0,75%/kg pakan, C (1,5%/kg pakan), dan D (2,25%/kg pakan). Hasil penelitian menunjukkan bahwa penambahan triptofan dalam pakan berpengaruh nyata (P<0,05) terhadap tingkat kanibalisme, kelulushidupan dan tingkat molting, namun tidak berpengaruh nyata (P>0,05) terhadap pertumbuhan bobot mutlak, laju pertumbuhan spesifik, protein efisiensi rasio dan efisiensi pemanfaatan pakan. Dosis terbaik dari pemberian triptofan dalam pakan untuk menurunkan tingkat kanibalisme udang vaname dalam penelitian ini adalah 2,25%, mampu menghasilkan tingkat kanibalisme sebesar 13,33%.

Synthetic corticosteroids as tryptophan hydroxylase stabilizers

Background: Clinically, corticosteroids are used mainly for their immune-modulatory properties but are also known to influence mood. Despite evidence of a role in regulating tryptophan hydroxylases (TPHs), key enzymes in serotonin biosynthesis, a direct action of corticosteroids on these enzymes has not been systematically investigated. Methodology & Results: Corticosteroid effects on TPHs were tested using an in vitro assay. The compound with the strongest modulatory effect, beclomethasone dipropionate, activated TPH1 and TPH2 with low micromolar potency. Thermostability assays suggested a stabilizing mechanism, and computational docking indicated that Beclomethasone dipropionate interacts with the TPH active site. Conclusion: Beclomethasone dipropionate is a stabilizer of TPHs, acting as a pharmacological chaperone. Our findings may inspire further development of steroid scaffolds as putative antidepressant drugs.

Serotonin stimulates Echinococcus multilocularis larval development

Background Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development. Methods To study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments. Results We first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles. Conclusions Our results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.

The effects of 5-hydroxytryptophan on carrageenan-induced mouse paw oedemas

ABSTRACT Objective 5-Hydroxytryptophan is the precursor compound of serotonin biosynthesis. The oral absorption of 5-Hydroxytryptophan is close to 100% and, unlike serotonin, it crosses the blood-brain barrier freely. 5-Hydroxytryptophan has been used as a food supplement for many years to treat anxiety and depression. Recent studies have shown that 5-Hydroxytryptophan suppresses the pro-inflammatory mediators and is effective in some inflammatory diseases, such as arthritis and allergic asthma. However, the role of 5-Hydroxytryptophan supplements on acute peripheral inflammation has not been investigated yet. In this study, the in vivo anti-inflammatory activity of 5-Hydroxytryptophan was evaluated with a carrageenan-induced paw oedema test in mice. Methods For the investigation of the acute antiinflammatory activity, single oral doses of 5-Hydroxytryptophan (1.5, 5 and 20mg/kg) were given to mice 1.5 hours prior to the carrageenan test. For chronic activity, the same oral doses were administered daily for two weeks prior to the carrageenan test on the 14th day. To induce inflammation, 0.01mL of 2% carrageenan was injected into the paws of mice. Results Supplementation with 5-Hydroxytryptophan significantly reduced inflammation in a dose-independent manner which was irrespective of the duration of exposure (per cent inhibition in acute experiments was 35.4%, 20.9%, 24.0%, and per cent inhibition in chronic experiments was 29.5%, 35.3%, 40.8% for the doses of 1.5, 5, and 20mg/kg, respectively). Conclusion Our findings demonstrate for the first time that 5-HTP supplements have the potential of suppressing the measures of acute peripheral inflammation. It is suggested that, apart from several diseases where serotonin is believed to play an important role, including depression, patients with inflammatory conditions may also benefit from 5-HTP.

Antibiotic exposure postweaning disrupts the neurochemistry and function of enteric neurons mediating colonic motor activity

The period during and immediately after weaning is an important developmental window when marked shifts in gut microbiota can regulate the maturation of the enteric nervous system (ENS). Because microbiota-derived signals that modulate ENS development are poorly understood, we examined the physiological impact of the broad spectrum of antibiotic, vancomycin-administered postweaning on colonic motility, neurochemistry of enteric neurons, and neuronal excitability. The functional impact of vancomycin on enteric neurons was investigated by Ca2+ imaging in Wnt1-Cre;R26R-GCaMP3 reporter mice to characterize alterations in the submucosal and the myenteric plexus, which contains the neuronal circuitry controlling gut motility. 16S rDNA sequencing of fecal specimens after oral vancomycin demonstrated significant deviations in microbiota abundance, diversity, and community composition. Vancomycin significantly increased the relative family rank abundance of Akkermansiaceae, Lactobacillaceae, and Enterobacteriaceae at the expense of Lachnospiraceae and Bacteroidaceae. In sharp contrast to neonatal vancomycin exposure, microbiota compositional shifts in weaned animals were associated with slower colonic migrating motor complexes (CMMCs) without mucosal serotonin biosynthesis being altered. The slowing of CMMCs is linked to disruptions in the neurochemistry of the underlying enteric circuitry. This included significant reductions in cholinergic and calbindin+ myenteric neurons, neuronal nitric oxide synthase+ submucosal neurons, neurofilament M+ enteric neurons, and increased proportions of cholinergic submucosal neurons. The antibiotic treatment also increased transmission and responsiveness in myenteric and submucosal neurons that may enhance inhibitory motor pathways, leading to slower CMMCs. Differential vancomycin responses during neonatal and weaning periods in mice highlight the developmental-specific impact of antibiotics on colonic enteric circuitry and motility.