Effect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial.

Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (ß = 0.579; 95% CI -1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (ß = -0.482; 95% CI,-0.813, -0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292.

A Fecal Metabolite Signature of Impaired Fasting Glucose: Results From Two Independent Population-Based Cohorts.

Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicotinate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02-5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16-1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97-8], P = 0.0002). Although these are host-produced metabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset. ARTICLE HIGHLIGHTS: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We investigated whether there is a fecal metabolite signature of impaired fasting glucose (IFG) and the possible underlying mechanisms of action. We identified a fecal metabolite signature of IFG associated with prevalent IFG in two independent cohorts and incident type 2 diabetes in a subanalysis. Although the signature consists of metabolites of nonmicrobial origin, it is strongly correlated with gut microbiome composition. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes by affecting intestinal absorption or excretion of host compounds and xenobiotics.

Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation.

Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK, n = 2507; ZOE PREDICT-1, n = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average h2: serum = 14%(SD = 14%); stool = 12%(SD = 6%)). Furthermore, we find that gut microbiome can accurately predict their fecal levels (AUC>0.71) while presenting weaker associations with serum. Finally, we report different correlation patterns with inflammatory markers depending on the type of inflammatory response (chronic or acute trauma). Our results illustrate the breadth of the physiological relevance of SCFAs on human inflammatory and metabolic responses highlighting the need for a deeper understanding of this important class of molecules.

The secondary bile acid isoursodeoxycholate correlates with post-prandial lipemia, inflammation, and appetite and changes post-bariatric surgery.

Primary and secondary bile acids (BAs) influence metabolism and inflammation, and the gut microbiome modulates levels of BAs. We systematically explore the host genetic, gut microbial, and habitual dietary contribution to a panel of 19 serum and 15 stool BAs in two population-based cohorts (TwinsUK, n = 2,382; ZOE PREDICT-1, n = 327) and assess changes post-bariatric surgery and after nutritional interventions. We report that BAs have a moderately heritable genetic component, and the gut microbiome accurately predicts their levels in serum and stool. The secondary BA isoursodeoxycholate (isoUDCA) can be explained mostly by gut microbes (area under the receiver operating characteristic curve [AUC] = ∼80%) and associates with post-prandial lipemia and inflammation (GlycA). Furthermore, circulating isoUDCA decreases significantly 1 year after bariatric surgery (ß = -0.72, p = 1 × 10-5) and in response to fiber supplementation (ß = -0.37, p < 0.03) but not omega-3 supplementation. In healthy individuals, isoUDCA fasting levels correlate with pre-meal appetite (p < 1 × 10-4). Our findings indicate an important role for isoUDCA in lipid metabolism, appetite, and, potentially, cardiometabolic risk.

The PROMOTe study: targeting the gut microbiome with prebiotics to overcome age-related anabolic resistance: protocol for a double-blinded, randomised, placebo-controlled trial.

BACKGROUND: Loss of skeletal muscle mass and strength occurs with increasing age and is associated with loss of function, disability, and the development of sarcopenia and frailty. Dietary protein is essential for skeletal muscle function, but older adults do not anabolise muscle in response to protein supplementation as well as younger people, so called 'anabolic resistance'. The aetiology and molecular mechanisms for this are not understood, however the gut microbiome is known to play a key role in several of the proposed mechanisms. Thus, we hypothesise that the gut microbiome may mediate anabolic resistance and therefore represent an exciting new target for ameliorating muscle loss in older adults. This study aims to test whether modulation of the gut microbiome using a prebiotic, in addition to protein supplementation, can improve muscle strength (as measured by chair-rise time) versus protein supplementation alone. METHODS: The study is a randomised, double-blinded, placebo-controlled trial, with two parallel arms; one will receive prebiotic and protein supplementation, and the other will receive placebo (maltodextrin) and protein supplementation. Participants will be randomised as twin pairs, with one twin from each pair in each arm. Participants will be asked to take supplementation once daily for 12 weeks in addition to resistance exercises. Every participant will receive a postal box, containing their supplements, and the necessary equipment to return faecal, urine, saliva and capillary blood samples, via post. A virtual visit will be performed using online platform at the beginning and end of the study, with measures taken over video. Questionnaires, food diary and cognitive testing will be sent out via email at the beginning and end of the study. DISCUSSION: This study aims to provide evidence for the role of the gut microbiome in anabolic resistance to dietary protein. If those who take the prebiotic and protein supplementation have a greater improvement in muscle strength compared with those who take protein supplementation alone, this would suggest that strategies to modify the gut microbiome may reduce anabolic resistance, and therefore potentially mitigate sarcopenia and frailty in older adults. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04309292 . Registered on the 2nd May 2020.

An association between chronic widespread pain and the gut microbiome.

OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP. METHODS: CWP was assessed using a standardized screening questionnaire in female volunteers from the TwinsUK cohort including 113 CWP cases and 1623 controls. The stool microbiome was characterized using 16S rRNA amplicon sequencing and amplicon sequence variants, and associations with CWP examined using linear mixed-effects models adjusting for BMI, age, diet, family relatedness and technical factors. RESULTS: Alpha diversity was significantly lower in CWP cases than controls (Mann-Whitney test, P-values 2.3e-04 and 1.2e-02, for Shannon and Simpson indices respectively). The species Coprococcus comes was significantly depleted in CWP cases (Padj = 3.04e-03). A genome-wide association study (GWAS) performed for C. comes in TwinsUK followed by meta-analysis with three Dutch cohorts (total n = 3521) resulted in nine suggestive regions, with the most convincing on chromosome 4 near the TRAM1L1 gene (rs76957229, P = 7.4e-8). A Mendelian randomization study based on the results of the GWAS did not support a causal role for C. comes on the development of CWP. CONCLUSIONS: We have demonstrated reduced diversity in the microbiome in CWP, indicating an involvement of the gut microbiota in CWP; prospectively the microbiome may offer therapeutic opportunities for this condition.