Lower plasma concentrations of short-chain fatty acids (SCFAs) in patients with ADHD

Short-chain fatty acids (SCFAs), produced during bacterial fermentation, have been shown to be mediators in the microbiota-gut-brain axis. This axis has been proposed to influence psychiatric symptoms seen in attention deficit hyperactivity disorder (ADHD). However, there is no report of plasma SCFA concentrations in ADHD. The aim of this study was to explore the plasma concentrations of SCFAs in children and adults with ADHD and the possible factors that could influence those levels. We collected data on age group, sex, serum vitamin D levels, delivery mode, body mass index, diet, medication and blood samples from 233 ADHD patients and 36 family-related healthy controls. The concentrations of SCFAs and the intermediary metabolite succinic acid, were measured using liquid chromatography-mass spectrometry. Adults with ADHD had lower plasma concentrations of formic, acetic, propionic and succinic acid than their healthy family members. When adjusting for SCFA-influential factors among those with ADHD, children had lower concentrations of formic, propionic and isovaleric acid than adults, and those who had more antibiotic medications during the last 2 years had lower concentrations of formic, propionic and succinic acid. When adjusting for antibiotic medication, we found that among children, those currently on stimulant medication had lower acetic and propionic acid levels, and adults with ADHD had lower formic and propionic acid concentrations than adult healthy family members. In all, our findings show lower-than-normal plasma concentrations of SCFAs in ADHD explained in-part by antibiotic medication, age and stimulant medication. Whether or not this is of clinical significance is yet to be explored

Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial

Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels

Exploring the gut microbiome in ADHD and schizophrenia spectrum disorder

Emerging research indicates a complex relationship between the gut bacterial microbiome and psychiatric disorders, though findings are not always consistent. The gut-brain axis, involving gut microbiota, plays a crucial role in the connection between the gut and the brain. Research, mainly in animal models, has begun to unravel how this communication influences behavior, with limited but growing evidence in humans. However, many of the studies in humans have been performed in small cohorts with little information about confounding variables, such as diet, antibiotic drug medication and stool consistency, and lack of proper use of statistical methods suited for this type of data. As for now, replicating findings and determining causation is challenging, highlighting the need for more research in well-characterized large cohorts. This thesis aims to investigate the gut microbiome and related biological markers in patients with Attention Deficit Hyperactivity Disorder (ADHD) and in young patients with Schizophrenia Spectrum Disorder (SSD). Through five studies, we analyzed: 1. Plasma levels of vascular inflammatory markers, n= 154, (study I) and the bacterial metabolites, short-chain fatty acids (SCFAs), n= 233, (study II) in children and adults with ADHD. 2. The fecal bacterial microbiome, n=147, (study III), and the impact of a placebocontrolled synbiotic intervention in children and adults with ADHD, ncompleters=101, (study IV). 3. The fecal microbiome of young SSD patients, n=52, (study V). The results indicated higher vascular inflammation and lower SCFAs plasma levels associated with ADHD diagnosis in adults and medication use in children with ADHD. A difference in microbiome diversity was found across ADHD diagnosis in adults and medication use in children with ADHD. Specifically, adult ADHD patients had different enzyme and strain β- diversity, along with differently abundant bacterial species and genes. Furthermore, we found the genus Prevotella to be more abundant, and bacterial genes encoding vitamin B12 synthesis to be less abundant in children on psychostimulant medication (vs not). Daily intake of an antiinflammatory multispecies probiotic and associated dietary fibers (Synbiotic 2000), previously reported to improve psychiatric symptoms, resulted in changes to the fecal microbiome, also impacting bacterial species beyond those included in the Synbiotic 2000. Results suggest that the synbiotic-bacteria stayed in the large intestine for at least 2 weeks. In SSD patients, differences in bacterial microbiome diversity and bacterial enzyme function were observed, with oral-origin species and amino-acid synthesis pathways being more abundant, while butyrate synthesis and acetate degradation pathways were less abundant in SSD. Our findings continue to support the presence of gut microbiome changes in these disorders, while also revealing associations between psychostimulant medication usage and biological markers, as well as with the microbiome. Further research that elucidates the causality between the microbiome and pathophysiology of these disorders is warranted

Snabba mikrofluidiska test möjliggör specialanpassad sjukvård : Utveckling av två designförslag med fokus på material, struktur och pump

Två designförslag har utvecklats för ett snabbtest av antibiotikakänslighet baserat på ettmikrofluidiskt system av Gradientech AB. Antibiotikaresistens är ett stort och växande problem ivärlden. För att förbättra diagnostiken av bakteriella blodinfektioner krävs snabbarediagnostiska tester vilket möjliggör specialanpassad behandling. Linjära gradienter av antibiotikai det mikrofluidiska systemet möjliggör snabbare detektion av antibiotikakänslighet jämfört meddiagnostiska test som används idag. Projektet har syftat till att anpassa testet utvecklat avGradientech AB för en klinisk marknad. Fokus har varit på material, pumpsystem och strukturför snabbtestet. De två designförslagen baseras på krav på ett pålitligt och billigt test som äranvändarvänligt och som minimerar smittorisker. Det ena designförslaget använder sig av enchipbaserad peristaltisk pump och det andra förslaget är ett trelagersystem med endiafragmapump. De två förslagen består av både hårdplast och ett elastiskt material. När dettatest kommer ut på den kliniska marknaden så kommer det förbättra vården av patienter medbakteriella blodinfektioner och minska sjukvårdskostnader. Testet kommer även minskabehovet av behandling med bredspektrumantibiotika och därmed hjälpa till att stoppa spridningav antibiotikaresistens.Two designs were developed for a fast antibiotic susceptibility test (AST) based on a microfluidicsystem by Gradientech AB. Antibiotic resistance is a big and growing global problem. Fasterdiagnostic tests are needed to improve the diagnostics of bacterial infections and enablespecialized antibiotic therapy. Linear gradients of antibiotics in the microfluidic system in thisproject enables faster detection of antibiotic susceptibility compared to ASTs used today inhealth care. The aim of this project has been to adapt the test developed by Gradientech AB fora clinical market. The main focus has been on materials, pumping systems and structure of theAST. The two designs are based on requirements of a reliable and cheap test that is easy to useand minimizes the biohazard. The first design uses a chip-based peristaltic pump and the otherdesign is a three-layer structure with a diaphragm pump. The two designs consists of both arigid plastic material and an elastic material. When this test becomes available to the clinicalmarket it will improve the care of patients with bacterial blood infections and reduce healthcarecosts. It will also reduce the use of broad-spectrum treatment of antibiotics and help counteractincreased global antibiotic resistance

Snabba mikrofluidiska test möjliggör specialanpassad sjukvård : Utveckling av två designförslag med fokus på material, struktur och pump

Två designförslag har utvecklats för ett snabbtest av antibiotikakänslighet baserat på ettmikrofluidiskt system av Gradientech AB. Antibiotikaresistens är ett stort och växande problem ivärlden. För att förbättra diagnostiken av bakteriella blodinfektioner krävs snabbarediagnostiska tester vilket möjliggör specialanpassad behandling. Linjära gradienter av antibiotikai det mikrofluidiska systemet möjliggör snabbare detektion av antibiotikakänslighet jämfört meddiagnostiska test som används idag. Projektet har syftat till att anpassa testet utvecklat avGradientech AB för en klinisk marknad. Fokus har varit på material, pumpsystem och strukturför snabbtestet. De två designförslagen baseras på krav på ett pålitligt och billigt test som äranvändarvänligt och som minimerar smittorisker. Det ena designförslaget använder sig av enchipbaserad peristaltisk pump och det andra förslaget är ett trelagersystem med endiafragmapump. De två förslagen består av både hårdplast och ett elastiskt material. När dettatest kommer ut på den kliniska marknaden så kommer det förbättra vården av patienter medbakteriella blodinfektioner och minska sjukvårdskostnader. Testet kommer även minskabehovet av behandling med bredspektrumantibiotika och därmed hjälpa till att stoppa spridningav antibiotikaresistens.Two designs were developed for a fast antibiotic susceptibility test (AST) based on a microfluidicsystem by Gradientech AB. Antibiotic resistance is a big and growing global problem. Fasterdiagnostic tests are needed to improve the diagnostics of bacterial infections and enablespecialized antibiotic therapy. Linear gradients of antibiotics in the microfluidic system in thisproject enables faster detection of antibiotic susceptibility compared to ASTs used today inhealth care. The aim of this project has been to adapt the test developed by Gradientech AB fora clinical market. The main focus has been on materials, pumping systems and structure of theAST. The two designs are based on requirements of a reliable and cheap test that is easy to useand minimizes the biohazard. The first design uses a chip-based peristaltic pump and the otherdesign is a three-layer structure with a diaphragm pump. The two designs consists of both arigid plastic material and an elastic material. When this test becomes available to the clinicalmarket it will improve the care of patients with bacterial blood infections and reduce healthcarecosts. It will also reduce the use of broad-spectrum treatment of antibiotics and help counteractincreased global antibiotic resistance

Effects of a synbiotic on symptoms, and daily functioning in attention deficit hyperactivity disorder - A double-blind randomized controlled

Some prebiotics and probiotics have been proposed to improve psychiatric symptoms in children with autism. However, few studies were placebo-controlled, and there is no study on persons with an attention deficit hyperactivity disorder (ADHD) diagnosis. Our aim was to study effects of Synbiotic 2000 on psychiatric symptoms and functioning in children and adults with ADHD without an autism diagnosis. Children and adults (n = 182) with an ADHD diagnosis completed the nine weeks randomized double-blind parallel placebo-controlled trial examining effects of Synbiotic 2000 on the primary endpoints ADHD symptoms, autism symptoms and daily functioning, and the secondary endpoint emotion regulation, measured using the questionnaires SNAP-IV, ASRS, WFIRS, SCQ, AQ and DERS-16. Levels at baseline of plasma C-reactive protein and soluble vascular cell adhesion molecule-1 (sVCAM-1), central to leukocyte-endothelial cell adhesion facilitating inflammatory responses in tissues, were measured using Meso Scale Discovery. Synbiotic 2000 and placebo improved ADHD symptoms equally well, and neither active treatment nor placebo had any statistically significant effect on functioning or sub-diagnostic autism symptoms. However, Synbiotic 2000, specifically, reduced sub-diagnostic autism symptoms in the domain restricted, repetitive and stereotyped behaviors in children, and improved emotion regulation in the domain of goal-directed behavior in adults. In children with elevated sVCAM-1 levels at baseline as well as in children without ADHD medication, Synbiotic 2000 reduced both the total score of autism symptoms, and the restricted, repetitive and stereotyped behaviors. In adults with elevated sVCAM-1 at baseline, Synbiotic 2000 significantly improved emotion regulation, both the total score and four of the five subdomains. To conclude, while no definite Synbiotic 2000-specific effect was detected, the analysis of those with elevated plasma sVCAM-1 levels proposed a reduction of autism symptoms in children and an improvement of emotion regulation in adults with ADHD. Trial registration number: ISRCTN57795429

Physical exercise is associated with a reduction in plasma levels of fractalkine, TGF-beta 1, eotaxin-1 and IL-6 in younger adults with mobility disability

Mobility disability (MD) refers to substantial limitations in life activities that arise because of movement impairments. Although MD is most prevalent in older individuals, it can also affect younger adults. Increasing evidence suggests that inflammation can drive the development of MD and may need to be targeted for MD prevention. Physical exercise has anti-inflammatory properties and has been associated with MD prevention. However, no studies to date have examined whether exercise interventions affect the peripheral inflammatory status in younger adults with MD. To this end, we used blood samples from young and middle-aged adults with MD (N = 38; median age = 34 years) who participated in a 12-week intervention that included aerobic and resistance exercise training. A pre-post assessment of inflammatory biomarkers was conducted in plasma from two timepoints, i.e., before the exercise trial and at follow-up (3-7 days after the last exercise session). We successfully measured 15 inflammatory biomarkers and found that exercise was associated with a significant reduction in levels of soluble fractalkine, transforming growth factor beta 1 (TGF-beta 1), eotaxin-1 and interleukin (IL) 6 (corrected alpha = 0.004). We also found significant male-specific effects of exercise on (i) increasing IL-16 and (ii) decreasing vascular endothelial growth factor-A (VEGF-A). In line with our results, previous studies have also found that exercise can reduce levels of TGF-beta 1, eotaxin-1 and IL-6. However, our finding that exercise reduces plasma levels of fractalkine in younger adults with MD, as well as the sex-dependent findings, have not been previously reported and warrant replication in larger cohorts. Given the suggested role of inflammation in promoting MD development, our study provides additional support for the use of physical exercise as a treatment modality for MD