Exploring personalised care planning approaches for adults with long-term conditions to inform future musculoskeletal care planning: A mixed-methods systematic scoping review protocol.

INTRODUCTION: This systematic scoping review protocol outlines current research into care planning processes and highlights the need to synthesise the knowledge base available since the latest Cochrane review. Review results will underpin the formation of a future intervention designed to successfully optimise care planning consultations for musculoskeletal (MSK) physiotherapists, supporting shared decision-making processes and consequently influencing health care practices for the betterment of patient care. AIM: To systematically gather and synthesise the existing knowledge base surrounding personalised care planning approaches for long term conditions which may be informative for MSK care planning in the future. OBJECTIVES: 1. Following the Cochrane review in 2015, to synthesise new evidence available to inform personalised care planning interventions for patients with long-term conditions. 2. Of the identified studies providing strong evidence, to determine what high-quality training resources are available to support clinicians in delivering personalised care planning interventions. PIO FRAMEWORK: Population - Adults with long-term health conditions. Intervention - Personalised care planning. Outcome - Any subjective or objective heath improvement. DATABASES: 1. Cochrane Central Register of Controlled Trials (CENTRAL). 2. MEDLINE & MEDLINE In-process (Ovid). 3. EMBASE (Ovid). 4. PsycINFO (Ovid). 5. Trial registers (clinicaltrials.gov). 6. WHO International Clinical Trials Registry Platform. DISSEMINATION: Social media platforms including Twitter, Instagram, YouTube and Facebook will be used to maximise the viewership of the protocol. An abstract of the review will be submitted to present at relevant conferences. The review findings will also be presented to MSK stakeholders interested in MSK care planning approaches.

The gut microbiome influences the bioavailability of olanzapine in rats.

BACKGROUND: The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics. METHODS: In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. FINDINGS: The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone. INTERPRETATION: Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted. FUNDING: This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).

Gut microbiome-mediated modulation of hepatic cytochrome P450 and P-glycoprotein: impact of butyrate and fructo-oligosaccharide-inulin.

OBJECTIVES: Our objective was to demonstrate microbial regulation of hepatic genes implicated in drug metabolism and transport using germ-free (GF) mice and to explore the impact of a microbial metabolite, butyrate, and a prebiotic dietary intervention on hepatic gene expression in mice. METHODS: Using reverse-transcriptase PCR, we investigated cytochrome P450 (CYP) and multidrug-resistance protein 1 (MDR1) expression in conventional, GF and colonised GF mice. To investigate the effects of butyrate, sodium butyrate (3 g/l) was administered for 21 days to conventional or GF mice. In the prebiotic study, young adult and middle-aged mice received diet enriched with 10% fructo-oligosaccharide (FOS)-inulin for 14 weeks. KEY FINDINGS: Colonisation of GF animals normalised expression of Cyp3a11 and Mdr1b to conventional levels. Butyrate upregulated Cyp2b10 in conventional mice (P < 0.05) but overall did not induce widespread changes in hepatic genes. FOS-inulin increased Cyp3a13 expression and had the opposite effect on Mdr1a expression in young adult mice (P < 0.05). Age, on the other hand, influenced the prebiotic effect on Cyp2a4 expression (P < 0.01). CONCLUSION: The expression of hepatic genes implicated in drug metabolism and transport displays sensitivity to the microbiome, microbiome-derived metabolites and a microbial-targeted intervention. Our study may provide the impetus to explore microbiota-targeted interventions in normalising host metabolic activity and reducing inter-individual variability in drug pharmacokinetics.

Impact of host and environmental factors on ß-glucuronidase enzymatic activity: implications for gastrointestinal serotonin.

The gastrointestinal tract houses a reservoir of bacterial-derived enzymes that can directly catalyze the metabolism of drugs, dietary elements and endogenous molecules. Both host and environmental factors may influence this enzymatic activity, with the potential to dictate the availability of the biologically-active form of endogenous molecules in the gut and influence inter-individual variation in drug metabolism. We aimed to investigate the influence of the microbiota, and the modulation of its composition, on fecal enzymatic activity. Intrinsic factors related to the host, including age, sex and genetic background, were also explored. Fecalase, a cell-free extract of feces, was prepared and used in a colorimetric-based assay to quantify enzymatic activity. To demonstrate the functional effects of fecal enzymatic activity, we examined ß-glucuronidase-mediated cleavage of serotonin ß-d-glucuronide (5-HT-GLU) and the resultant production of free 5-HT by HPLC. As expected, ß-glucuronidase and ß-glucosidase activity were absent in germ-free mice. Enzymatic activity was significantly influenced by mouse strain and animal species. Sex and age significantly altered metabolic activity with implications for free 5-HT. ß-Glucuronidase and ß-glucosidase activity remained at reduced levels for nearly two weeks after cessation of antibiotic administration. This effect on fecalase corresponded to significantly lower 5-HT levels as compared with incubation with pre-antibiotic fecalase from the same mice. Dietary targeting of the microbiota using prebiotics did not alter ß-glucuronidase or ß-glucosidase activity. Our data demonstrate that multiple factors influence the activity of bacterial-derived enzymes which may have potential clinical implications for drug metabolism and the deconjugation of host-produced glucuronides in the gut.NEW & NOTEWORTHY This article explores a comprehensive range of host and environmental factors that introduce variability in the expression of bacterial-derived metabolic enzymes. Our results demonstrate that altered ß-glucuronidase activity has implications for the bioavailability of luminal serotonin. The experimental approach employed, fecalase, provides a mechanistic basis and translational platform to further delineate the functional outputs of altered metabolic activity, and the associated physiological effects of microbiota-targeted interventions on host response to drugs and host-produced glucuronides.

Drug-gut microbiota interactions: implications for neuropharmacology.

The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the effects that drugs can have on the function and composition of the gut microbiome. Both microbiota-mediated alterations in drug metabolism and drug-mediated alterations in the gut microbiome can have beneficial or detrimental effects on the host. Greater insights into the mechanisms driving these reciprocal drug-gut microbiota interactions are needed to guide the development of microbiome-targeted dietary or pharmacological interventions, which may have the potential to enhance drug efficacy or reduce drug side effects. In this review, we explore the relationship between drugs and the gut microbiome, with a specific focus on potential mechanisms underpinning the drug-mediated alterations on the gut microbiome and the potential implications for psychoactive drugs. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc.