The association of socio-economic and psychological factors with limitations in day-to-day activity over 7 years in newly diagnosed osteoarthritis patients

Previous research has established links between chronic pain and impaired cognitive ability, as well as between chronic pain and anxiety, in osteoarthritis. Furthermore, there is evidence linking risk of osteoarthritis to lower educational attainment. However, the inter-play of these factors with key social factors (e.g., social deprivation) at the early stages of osteoarthritis are not understood. Here, we used data from waves 4, 5, 6 and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 971) and selected a subsample of respondents who initially did not report a diagnosis of osteoarthritis until wave 6. We used path models to test how social deprivation, education and anxiety, before diagnosis (waves 4 and 5), affect the relationship between cognitive ability, pain and limitations in activities of daily living following diagnosis (waves 6 and 7). We show that high social deprivation before diagnosis predicts greater limitations in activities of daily living after diagnosis, with this effect partly mediated by impaired cognitive ability. We also find that higher educational attainment before diagnosis may protect against limitations in activities of daily living after diagnosis via better cognitive ability and lower anxiety. Therefore, improving cognitive ability and managing anxiety may mitigate the associations of social deprivation and low educational attainment with limitations in activities of daily living

Different genes may be involved in distal and local sensitization: A genome‐wide gene‐based association study and meta‐analysis

Background: Neuropathic pain symptoms and signs of increased pain sensitization in osteoarthritis (OA) patients may explain persistent pain after total joint replacement (TJR). Therefore, identifying genetic markers associated with pain sensitization and neuropathic-like pain phenotypes could be clinically important in identifying targets for early intervention. Methods: We performed a genome-wide gene-based association study (GWGAS) using pressure pain detection thresholds (PPTs) from distal pain-free sites (anterior tibia), a measure of distal sensitization, and from proximal pain-affected sites (lateral joint line), a measure of local sensitization, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene-based fixed-effects meta-analysis of PPTs and a neuropathic-like pain phenotype using genome-wide association study (GWAS) data from KPIC and from an independent cohort of 613 post-TJR participants, respectively. Results: The most significant genes associated with distal and local sensitization were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain-associated genes—KCNA1, MTOR, ADORA1 and SCN3B—associated with PPT at the anterior tibia and an inflammatory pain gene—PTAFR—associated with PPT at the lateral joint line. Meta-analysis results of anterior tibia and neuropathic-like pain phenotypes revealed genes associated with bone morphogenesis, neuro-inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function. Conclusions: Overall, our results suggest that different biological processes might be involved in distal and local sensitization, and common genetic mechanisms might be implicated in distal sensitization and neuropathic-like pain. Future studies are needed to replicate these findings. Significance: To the best of our knowledge, this is the first GWAS for pain sensitization and the first gene-based meta-analysis of pain sensitization and neuropathic-like pain. Higher pain sensitization and neuropathic pain symptoms are associated with persistent pain after surgery hence, identifying genetic biomarkers and molecular pathways associated with these traits is clinically relevant

The anti-inflammatory effect of bacterial short chain fatty acids is partially mediated by endocannabinoids

The endocannabinoid (EC) system has pleiotropic functions in the body. It plays a key role in energy homeostasis and the development of metabolic disorders being a mediator in the relationship between the gut microbiota and host metabolism. In the current study we explore the functional interactions between the endocannabinoid system and the gut microbiome in modulating inflammatory markers. Using data from a 6week exercise intervention (treatment n =38 control n =40) and a cross sectional validation cohort (n=35), we measured the associations of 2-arachidonoylglycerol (2-AG), anandamide (AEA), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) with gut microbiome composition, gut derived metabolites (SCFAs) and inflammatory markers both cross-sectionally and longitudinally. At baseline AEA and OEA were positively associated with alpha diversity (β(SE)=.32 (.06), P =.002;.44 (.04), P <.001) and with SCFA producing bacteria such as Bifidobacterium (2-AG β(SE)=.21 (.10), P <.01; PEA β(SE)=.23 (.08), P <.01), Coprococcus 3 and Faecalibacterium (PEA β(SE)=.29 (.11), P =.01;.25 (.09), P <.01) and negatively associated with Collinsella (AEA β(SE)=−.31 (.12), P =.004). Additionally, we found AEA to be positively associated with SCFA Butyrate (β(SE)=.34 (.15), P =.01). AEA, OEA and PEA all increased significantly with the exercise intervention but remained constant in the control group. Changes in AEA correlated with SCFA butyrate and increases in AEA and PEA correlated with decreases in TNF-ɑ and IL-6 statistically mediating one third of the effect of SCFAs on these cytokines. Our data show that the anti-inflammatory effects of SCFAs are partly mediated by the EC system suggesting that there may be other pathways involved in the modulation of the immune system via the gut microbiome

Chronic social stress induces peripheral and central immune activation, blunted mesolimbic dopamine function, and reduced reward-directed behaviour in mice

Psychosocial stress is a major risk factor for depression, stress leads to peripheral and central immune activation, immune activation is associated with blunted dopamine (DA) neural function, DA function underlies reward interest, and reduced reward interest is a core symptom of depression. These states might be inter-independent in a complex causal pathway. Whilst animal-model evidence exists for some specific steps in the pathway, there is currently no animal model in which it has been demonstrated that social stress leads to each of these immune, neural and behavioural states. Such a model would provide important existential evidence for the complex pathway and would enable the study of causality and mediating mechanisms at specific steps in the pathway. Therefore, in the present mouse study we investigated for effects of 15-day resident-intruder chronic social stress (CSS) on each of these states. Relative to controls, CSS mice exhibited higher spleen levels of granulocytes, inflammatory monocytes and T helper 17 cells; plasma levels of inducible nitric oxide synthase; and liver expression of genes encoding kynurenine pathway enzymes. CSS led in the ventral tegmental area to higher levels of kynurenine and the microglia markers Iba1 and Cd11b and higher binding activity of DA D1 receptor; and in the nucleus accumbens (NAcc) to higher kynurenine, lower DA turnover and lower c-fos expression. Pharmacological challenge with DA reuptake inhibitor identified attenuation of DA stimulatory effects on locomotor activity and NAcc c-fos expression in CSS mice. In behavioural tests of operant responding for sucrose reward validated as sensitive assays for NAcc DA function, CSS mice exhibited less reward-directed behaviour. Therefore, this mouse study demonstrates that a chronic social stressor leads to changes in each of the immune, neural and behavioural states proposed to mediate between stress and disruption of DA-dependent reward processing. The model can now be applied to investigate causality and, if demonstrated, underlying mechanisms in specific steps of this immune-neural-behavioural pathway, and thereby to identify potential therapeutic targets

Preoperative inflammatory biomarkers reveal renal involvement in postsurgical mortality in hip fracture patients: an exploratory study

BackgroundHip fractures in frail patients result in excess mortality not accounted for by age or comorbidities. The mechanisms behind the high risk of mortality remain undetermined but are hypothesized to be related to the inflammatory status of frail patients.MethodsIn a prospective observational exploratory cohort study of hospitalized frail hip fracture patients, 92 inflammatory markers were tested in pre-operative serum samples and markers were tested against 6-month survival post-hip fracture surgery and incidence of acute kidney injury (AKI). After correcting for multiple testing, adjustments for comorbidities and demographics were performed on the statistically significant markers.ResultsOf the 92 markers tested, circulating levels of fibroblast growth factor 23 (FGF-23) and interleukin-15 receptor alpha (IL15RA), both involved in renal disease, were significantly correlated with 6-month mortality (27.5% overall) after correcting for multiple testing. The incidence of postoperative AKI (25.4%) was strongly associated with 6-month mortality, odds ratio = 10.57; 95% CI [2.76–40.51], and with both markers plus estimated glomerular filtration rate (eGFR)– cystatin C (CYSC) but not eGFR-CRE. The effect of these markers on mortality was significantly mediated by their effect on postoperative AKI.ConclusionHigh postoperative mortality in frail hip fracture patients is highly correlated with preoperative biomarkers of renal function in this pilot study. The effect of preoperative circulating levels of FGF-23, IL15RA, and eGFR-CYSC on 6-month mortality is in part mediated by their effect on postoperative AKI. Creatinine-derived preoperative renal function measures were very poorly correlated with postoperative outcomes in this group

Metagenomic changes in response to antibiotic treatment in severe orthopedic trauma patients

We investigated changes in microbiome composition and abundance of antimicrobial resistance (AMR) genes post-antibiotic treatment in severe trauma patients. Shotgun sequencing revealed beta diversity (Bray-Curtis) differences between 16 hospitalized multiple rib fractures patients and 10 age- and sex-matched controls (p = 0.043), and between antibiotic-treated and untreated patients (p = 0.015). Antibiotic-treated patients had lower alpha diversity (Shannon) at discharge (p = 0.003) and 12-week post-discharge (p = 0.007). At 12 weeks, they also exhibited a 5.50-fold (95% confidence interval [CI]: 2.86–8.15) increase in Escherichia coli (p = 0.0004) compared to controls. Differential analysis identified nine AMRs that increased in antibiotic-treated compared to untreated patients between hospital discharge and 6 and 12 weeks follow-up (false discovery rate [FDR] < 0.20). Two aminoglycoside genes and a beta-lactamase gene were directly related to antibiotics administered, while five were unrelated. In trauma patients, lower alpha diversity, higher abundance of pathobionts, and increases in AMRs persisted for 12 weeks post-discharge, suggesting prolonged microbiome disruption. Probiotic or symbiotic therapies may offer future treatment avenues

A biopsychosocial approach to understanding the contributors to chronic pain

Background: The biopsychosocial model suggests that chronic pain is the result of a dynamic interplay between biological, psychological, and social factors. Psychological variables, such as anxiety, are recognised as key contributors to chronic pain. However, their role, and particularly that of cognitive ability, in chronic pain from osteoarthritis (OA) ¬- the main cause of chronic pain worldwide - is less well understood. Social stressors, such as social deprivation may further explain the pain experience and may predict increased functional disability (limitations in activities of daily living), but their interaction with psychological factors has not been studied much, especially in the early stages of OA. Meanwhile, anxiety and social isolation extending over many months during the coronavirus pandemic may exacerbate pain in chronic pain patients, but this has not been investigated over time. Chronic pain in OA is underpinned by neuropathic and pain sensitization mechanisms that may predict resistance to therapy. Considering biological factors, such as host genetics, may enhance our understanding of these key mechanisms in OA. Lastly, little is known about the gut microbiome’s role in chronic pain. Identifying the gut microbiome’s link with anxiety may give us some understanding of how it might be linked to pain. Therefore, the aim of the current thesis was to explore how psychosocial factors (cognitive ability, anxiety and social deprivation/isolation), host genetics and the gut microbiome, interact in their contribution to chronic pain. Objectives: [1] to design a study aimed at investigating the specific neuro-cognitive domains that are impaired in OA pain, [2] to explore the dynamic interplay between key socioeconomic (i.e. social deprivation, education) and psychological factors (i.e. cognitive function, anxiety) and limitations in activities of daily living in OA pain; [3] to explore the potential impact of the first coronavirus lockdown on social isolation, anxiety, pain and overall quality of life in chronic pain patients; [4] to identify genetic markers associated with pain sensitisation and neuropathic-like pain in OA; and [5] to identify bacterial taxa reproducibly associated with anxiety and the role of serum levels of microbial metabolites and neuromodulators. Methods: [1] We recruited eight participants from the Nottinghamshire area to conduct a feasibility study. Distinct cognitive functions were measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Pain measures included Quantitative Sensory Testing and pain questionnaires, such as painDETECT. Confounders were measured, including depression/anxiety, sleep quality, quality of life and physical function. Additional cognitive measures were taken, along with the National Adult Reading Test that served as a proxy of general premorbid IQ. Data on prosociality were also collected. For identifying molecular biomarkers, gut microbiome measures and genetic markers, blood, urine and faecal samples were collected. We assessed the feasibility of the study based on the experiences of the patients. Descriptive statistics were reported and correlational analysis was used to investigate the relationship between cognitive function, anxiety and pain. [2] We used data from waves 4, 5, 6 and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 971) and selected a subsample of respondents who initially did not report a diagnosis of OA until wave 6. We used path models to test how social deprivation, education and anxiety, before diagnosis (waves 4 and 5), affect the relationship between cognitive ability, pain and limitations in activities of daily living following diagnosis (waves 6 and 7). [3] We analysed data from a sample of chronic pain patients (N = 305 of which 28.9% reported having OA) from Investigating Musculoskeletal Health and Wellbeing cohort thrice during the pandemic (May 2020, July 2020, September 2020). We employed repeated measures ANOVAs (and Kruskal–Wallis where appropriate) to compare measures of affect, social isolation, exercise changes due to COVID-19, quality of life and pain at the various time points. [4] We performed a genome-wide gene-based association study using pressure pain detection thresholds (PPTs) from distal pain-free site (anterior tibia), a measure of distal sensitisation, and from proximal pain-affected site (lateral joint line), a measure of local sensitisation, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene-based fixed-effects meta-analysis of PPTs and a neuropathic-like pain phenotype (painDETECT) using genome-wide association study data from KPIC and from an independent cohort of 613 OA participants, respectively. [5] We meta-analysed data from two cohorts (WebEx: n = 37 and Omega 3/Fibre: n = 58) and published literature (n = 60) in order to identify bacterial taxa reproducibly associated with anxiety. We further investigated the role of serum levels of SCFAs and indoles on anxiety and the links between anxiety-associated operational taxonomic units (OTUs) and neuromodulators involved in anxiety. Gut microbiota was characterized using 16S rRNA sequencing in stool samples. OTU data were transformed and normalized. Serum metabolites were measured using tandem mass spectrometry. Results: [1] The study was feasible and all practical aspects were executed as planned, and the study was well received by the patients. Our preliminary findings suggested that anxiety, pain and cognitive ability are correlated and that global cognitive impairment and impairments in certain aspects of cognitive ability might be associated with poor physical function, increased neuropathic-like pain and increased central pain processing. [2] We showed that high social deprivation before diagnosis predicted greater limitations in activities of daily living after diagnosis, with this effect partly mediated by impaired cognitive ability. We also found that higher educational attainment before diagnosis may protect against limitations in activities of daily living after diagnosis via better cognitive ability and lower anxiety. [3] Covid-19 lockdown increased anxiety in May and September, whereas pain levels were unaffected. The highest levels of social isolation and depression occurred in the early stages of lockdown but declined thereafter. The at least a bit anxious group had heightened pain in May and September compared to the not at all anxious group. Doing at least an hour of exercise per day (on a typical day) was a protective factor against increased anxiety during lockdown, and quality of life improved by September when lockdown rules were eased. [4] The most significant genes associated with distal and local sensitisation were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain-associated genes – KCNA1, MTOR, ADORA1, and SCN3B – associated with PPT at the anterior tibia and an inflammatory pain gene – PTAFR – associated with PPT at the lateral joint line. Meta-analysis results of anterior tibia and neuropathic-like pain phenotypes revealed genes associated with bone morphogenesis, neuro-inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function. [5] We identified reproducible microbiome associations of anxiety with Escherichia-Shigella (fixed-effect beta (95% CI) = 0.28 (0.11, 0.45), False Detection Rate (FDR)-adj. p = 3 x 10−3), Christensenellaceae R-7 group (fixed-effect beta (95% CI) = -0.32 (-0.48, -0.15), FDR-adj. p = 1 x 10−3) and Ruminococcaceae UCG-010 (fixed-effect beta (95% CI) = -0.24 (-0.40, -0.08), FDR- adj. p = 6 x 10−3). We found no significant associations between anxiety and gut-derived metabolites nor between anxiety-associated bacteria and anxiety-related markers after meta-analysis and correcting for multiple testing. Conclusion: This thesis showed that improving cognitive ability and reducing anxiety early in the disease course might protect against the negative impact of socioeconomic factors on subsequent functional disability in painful OA. Furthermore, regular exercise during lockdown and a balanced gut microbiome may contribute to reduced anxiety levels in chronic pain. Therefore, interventions like cognitive behavioural therapy, exercise, and probiotic supplementation might alleviate the influence of pain and anxiety on poor health outcomes in older adults with OA. Future research will investigate the role of inflammation, and the gut microbiome in the link between pain sensitisation and psychosocial factors, such as cognitive ability

A biopsychosocial approach to understanding the contributors to chronic pain

Background: The biopsychosocial model suggests that chronic pain is the result of a dynamic interplay between biological, psychological, and social factors. Psychological variables, such as anxiety, are recognised as key contributors to chronic pain. However, their role, and particularly that of cognitive ability, in chronic pain from osteoarthritis (OA) ¬- the main cause of chronic pain worldwide - is less well understood. Social stressors, such as social deprivation may further explain the pain experience and may predict increased functional disability (limitations in activities of daily living), but their interaction with psychological factors has not been studied much, especially in the early stages of OA. Meanwhile, anxiety and social isolation extending over many months during the coronavirus pandemic may exacerbate pain in chronic pain patients, but this has not been investigated over time. Chronic pain in OA is underpinned by neuropathic and pain sensitization mechanisms that may predict resistance to therapy. Considering biological factors, such as host genetics, may enhance our understanding of these key mechanisms in OA. Lastly, little is known about the gut microbiome’s role in chronic pain. Identifying the gut microbiome’s link with anxiety may give us some understanding of how it might be linked to pain. Therefore, the aim of the current thesis was to explore how psychosocial factors (cognitive ability, anxiety and social deprivation/isolation), host genetics and the gut microbiome, interact in their contribution to chronic pain. Objectives: [1] to design a study aimed at investigating the specific neuro-cognitive domains that are impaired in OA pain, [2] to explore the dynamic interplay between key socioeconomic (i.e. social deprivation, education) and psychological factors (i.e. cognitive function, anxiety) and limitations in activities of daily living in OA pain; [3] to explore the potential impact of the first coronavirus lockdown on social isolation, anxiety, pain and overall quality of life in chronic pain patients; [4] to identify genetic markers associated with pain sensitisation and neuropathic-like pain in OA; and [5] to identify bacterial taxa reproducibly associated with anxiety and the role of serum levels of microbial metabolites and neuromodulators. Methods: [1] We recruited eight participants from the Nottinghamshire area to conduct a feasibility study. Distinct cognitive functions were measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Pain measures included Quantitative Sensory Testing and pain questionnaires, such as painDETECT. Confounders were measured, including depression/anxiety, sleep quality, quality of life and physical function. Additional cognitive measures were taken, along with the National Adult Reading Test that served as a proxy of general premorbid IQ. Data on prosociality were also collected. For identifying molecular biomarkers, gut microbiome measures and genetic markers, blood, urine and faecal samples were collected. We assessed the feasibility of the study based on the experiences of the patients. Descriptive statistics were reported and correlational analysis was used to investigate the relationship between cognitive function, anxiety and pain. [2] We used data from waves 4, 5, 6 and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 971) and selected a subsample of respondents who initially did not report a diagnosis of OA until wave 6. We used path models to test how social deprivation, education and anxiety, before diagnosis (waves 4 and 5), affect the relationship between cognitive ability, pain and limitations in activities of daily living following diagnosis (waves 6 and 7). [3] We analysed data from a sample of chronic pain patients (N = 305 of which 28.9% reported having OA) from Investigating Musculoskeletal Health and Wellbeing cohort thrice during the pandemic (May 2020, July 2020, September 2020). We employed repeated measures ANOVAs (and Kruskal–Wallis where appropriate) to compare measures of affect, social isolation, exercise changes due to COVID-19, quality of life and pain at the various time points. [4] We performed a genome-wide gene-based association study using pressure pain detection thresholds (PPTs) from distal pain-free site (anterior tibia), a measure of distal sensitisation, and from proximal pain-affected site (lateral joint line), a measure of local sensitisation, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene-based fixed-effects meta-analysis of PPTs and a neuropathic-like pain phenotype (painDETECT) using genome-wide association study data from KPIC and from an independent cohort of 613 OA participants, respectively. [5] We meta-analysed data from two cohorts (WebEx: n = 37 and Omega 3/Fibre: n = 58) and published literature (n = 60) in order to identify bacterial taxa reproducibly associated with anxiety. We further investigated the role of serum levels of SCFAs and indoles on anxiety and the links between anxiety-associated operational taxonomic units (OTUs) and neuromodulators involved in anxiety. Gut microbiota was characterized using 16S rRNA sequencing in stool samples. OTU data were transformed and normalized. Serum metabolites were measured using tandem mass spectrometry. Results: [1] The study was feasible and all practical aspects were executed as planned, and the study was well received by the patients. Our preliminary findings suggested that anxiety, pain and cognitive ability are correlated and that global cognitive impairment and impairments in certain aspects of cognitive ability might be associated with poor physical function, increased neuropathic-like pain and increased central pain processing. [2] We showed that high social deprivation before diagnosis predicted greater limitations in activities of daily living after diagnosis, with this effect partly mediated by impaired cognitive ability. We also found that higher educational attainment before diagnosis may protect against limitations in activities of daily living after diagnosis via better cognitive ability and lower anxiety. [3] Covid-19 lockdown increased anxiety in May and September, whereas pain levels were unaffected. The highest levels of social isolation and depression occurred in the early stages of lockdown but declined thereafter. The at least a bit anxious group had heightened pain in May and September compared to the not at all anxious group. Doing at least an hour of exercise per day (on a typical day) was a protective factor against increased anxiety during lockdown, and quality of life improved by September when lockdown rules were eased. [4] The most significant genes associated with distal and local sensitisation were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain-associated genes – KCNA1, MTOR, ADORA1, and SCN3B – associated with PPT at the anterior tibia and an inflammatory pain gene – PTAFR – associated with PPT at the lateral joint line. Meta-analysis results of anterior tibia and neuropathic-like pain phenotypes revealed genes associated with bone morphogenesis, neuro-inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function. [5] We identified reproducible microbiome associations of anxiety with Escherichia-Shigella (fixed-effect beta (95% CI) = 0.28 (0.11, 0.45), False Detection Rate (FDR)-adj. p = 3 x 10−3), Christensenellaceae R-7 group (fixed-effect beta (95% CI) = -0.32 (-0.48, -0.15), FDR-adj. p = 1 x 10−3) and Ruminococcaceae UCG-010 (fixed-effect beta (95% CI) = -0.24 (-0.40, -0.08), FDR- adj. p = 6 x 10−3). We found no significant associations between anxiety and gut-derived metabolites nor between anxiety-associated bacteria and anxiety-related markers after meta-analysis and correcting for multiple testing. Conclusion: This thesis showed that improving cognitive ability and reducing anxiety early in the disease course might protect against the negative impact of socioeconomic factors on subsequent functional disability in painful OA. Furthermore, regular exercise during lockdown and a balanced gut microbiome may contribute to reduced anxiety levels in chronic pain. Therefore, interventions like cognitive behavioural therapy, exercise, and probiotic supplementation might alleviate the influence of pain and anxiety on poor health outcomes in older adults with OA. Future research will investigate the role of inflammation, and the gut microbiome in the link between pain sensitisation and psychosocial factors, such as cognitive ability

Machine Learning Metabolomics Profiling of Dietary Interventions from a Six-Week Randomised Trial

Metabolomics can uncover physiological responses to prebiotic fibre and omega-3 fatty acid supplements with known health benefits and identify response-specific metabolites. We profiled 534 stool and 799 serum metabolites in 64 healthy adults following a 6-week randomised trial comparing daily omega-3 versus inulin supplementation. Elastic net regressions were used to separately identify the serum and stool metabolites whose change in concentration discriminated between the two types of supplementations. Random forest was used to explore the gut microbiome’s contribution to the levels of the identified metabolites from matching stool samples. Changes in serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate and indoleproprionate levels accurately discriminated between fibre and omega-3 (area under the curve (AUC) = 0.87 [95% confidence interval (CI): 0.63–0.99]), while stool eicosapentaenoate indicated omega-3 supplementation (AUC = 0.86 [95% CI: 0.64–0.98]). Univariate analysis also showed significant increases in indoleproprionate with fibre, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, and eicosapentaenoate with omega-3. Out of these, only the change in indoleproprionate was partly explained by changes in the gut microbiome composition (AUC = 0.61 [95% CI: 0.58–0.64] and Rho = 0.21 [95% CI: 0.08–0.34]) and positively correlated with the increase in the abundance of the genus Coprococcus (p = 0.005). Changes in three metabolites discriminated between fibre and omega-3 supplementation. The increase in indoleproprionate with fibre was partly explained by shifts in the gut microbiome, particularly Coprococcus, previously linked to better health