Butyrate acts as a positive allosteric modulator of the 5-HT transporter to decrease availability of 5-HT in the ileum.

BACKGROUND AND PURPOSE: Radiation therapy-induced gastrointestinal distress is partly associated with the elimination of gut microbiota. The effectiveness of 5-HT receptor antagonists to treat radiation therapy-induced emesis implies a pathophysiological role of 5-HT. Peripheral 5-HT is derived from intestinal epithelium. We have investigated the role of gut microbiota in regulating intestinal 5-HT availability. EXPERIMENTAL APPROACH: A radiation therapy murine model accompanied by faecal microbiota transplantation from donors fed different diets was investigated, and mouse ileal organoids were used for mechanistic studies. The clinical relevance was validated by a small-scale human study. KEY RESULTS: Short-term high-fat diet (HFD) induced gut bacteria to produce butyrate. Irradiated mice receiving HFD-induced microbiome had the lowest ileal levels of 5-HT, compared with other recipients. Treatment with butyrate increased 5-HT uptake in mouse ileal organoids, assayed by the real-time tracking of a fluorescent substrate for monoamine transporters. Silencing the 5-HT transporter (SERT) in the organoids abolished butyrate-stimulated 5-HT uptake. The competitive tests using different types of selective 5-HT reuptake inhibitors suggested that butyrate acted as a positive allosteric modulator of SERT. In human gut microbiota, butyrate production was associated with the interconversion between acetate and butyrate. Faecal contents of both acetate and butyrate were negatively associated with serum 5-HT, but only butyrate was positively correlated with body mass index in humans. CONCLUSION AND IMPLICATIONS: Short-term HFD may be beneficial for alleviating gastrointestinal reactions by increasing butyrate to suppress local 5-HT levels and providing energy to cancer patients given radiation therapy.

Development of a patient and clinician co-led education program to promote living well with an implantable cardioverter defibrillator: Insights from a pilot project.

Objective: To evaluate a pilot education program designed to improve patients' experience of living well with an implantable cardioverter-defibrillator (ICD). Methods: Patient Partners with previously implanted ICD and clinicians collaboratively performed monthly education sessions for potential and recent ICD recipients. Curriculum development was informed by current evidence of ICD patients' unique educational needs; delivery format transitioned to a virtual platform following the onset of COVID-19. Participants' experience was evaluated using a tailored questionnaire to explore preliminary insights. Results: 126 participants (median age: 62 years; women: 30%) attended 24 sessions. In-person participants (n = 62, 49.2%) reported sessions as helpful (n = 56, 94%) with regards to format and Patient Partner interactions. Virtual participants 64 (50.8%) completed an electronic survey (n = 27, 45%); reporting sufficient information for most topics with the exception of potential psychological effects of ICD implantation. Patient Partners as collaborative session leaders was perceived to be very helpful (n = 22, 82%) or somewhat helpful (n = 5, 18%). Conclusion: This novel educational partnership met the learning needs of patients at the vulnerable time of new cardiac device implantation of both in-person and virtual formats. Innovation: The inclusion of Patient Partners in co-led cardiac education informs novel approach to care that may improve patients' experiences of living well with complex technology.

Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver.

RATIONALE: Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development. OBJECTIVE: We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level. METHODS AND RESULTS: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on Apoa1 promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient (Apoe-/-) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin. CONCLUSIONS: Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.

Anger response styles in Chinese and Dutch children: a socio-cultural perspective on anger regulation.

In this study, we evaluated hypotheses about cultural convergence and divergence in the nature and correlates of anger expressions. With a sample of 141 11-year-olds from the Netherlands and Hong Kong, we first examined a broad range of strategies for responding to a provocateur, finding that both Chinese and Dutch children were more likely to use intrapersonal strategies (for coping internally with the angry feelings) than interpersonal responses (to communicate anger to the provocateur). No cultural divergence was shown in the overall extent to which anger would be verbally expressed, but differences became apparent when we asked children precisely what they would say to an aggressor in a hypothetical anger-eliciting situation. As predicted, Chinese children were more likely to react tolerantly to the aggressor than their Dutch peers, whereas Dutch children indicated that they would verbally confront the aggressor more often, trying to reinstate their personal goals. In comparison with Dutch children, the Chinese sample viewed their chosen strategies as more likely to elicit positive reactions from the aggressor and to reduce anger. Directions for further research on the personal and socio-cultural functionality of anger response styles are discussed.

Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity.

While statins, hydroxymethylglutaryl-coenzyme A reductase (HMGCR) inhibitors, are clinically proven to reduce plasma cholesterol levels, a wide variation in inter-individual response to statin therapy has been observed. Pharmacogenetic studies have identified multiple loci that potentially contribute towards the statin response, including the HMGCR gene. To examine, if a statin-resistant, catalytically-active isoform of the human HMGCR could be generated, we have rationally altered the protein to include additional residues in the flap domain, which has a role in statin binding. Comparative enzyme assays with purified wild-type and mutant isoforms reveal the alteration imposes a slight (38%) decrease in the K(app)(M) for the substrate, a near 2-fold increase in turnover number, and a 480% increase in the Ki for lovastatin. Thus, alterations in HMGCR could contribute towards the synergistic effects of multiple loci in the statin response.