Differences in bacterial taxa between treatment-naive patients with major depressive disorder and non-affected controls may be related to a proinflammatory profile.

BACKGROUND: Major depressive disorder (MDD) is characterized by sadness and anhedonia, but also physical symptoms such as changes in appetite and weight. Gut microbiota has been hypothesized to be involved in MDD through gut-brain axis signaling. Moreover, antidepressants display antibacterial properties in the gastrointestinal tract. The aim of this study was to compare the gut microbiota and systemic inflammatory profile of young patients with MDD before and after initiation of antidepressant treatment and/or psychotherapy in comparison with a non-depressed control group (nonMDD). METHODS: Fecal and blood samples were collected at baseline and at follow-up after four and twelve weeks, respectively. Patients started treatment immediately after collection of the baseline samples. The gut microbiota was characterized by 16 S rRNA gene sequencing targeting the hypervariable V4 region. Plasma levels of 49 unique immune markers were assessed using Mesoscale. RESULTS: In total, 27 MDD patients and 32 nonMDD controls were included in the study. The gut microbiota in the baseline samples of MDD versus nonMDD participants did not differ regarding α- or ß-diversity. However, there was a higher relative abundance of the genera Ruminococcus gnavus group, and a lower relative abundance of the genera Desulfovibrio, Tyzzerella, Megamonas, Olsenella, Gordonibacter, Allisonella and Rothia in the MDD group compared to the nonMDD group. In the MDD group, there was an increase in the genera Rothia, Desulfovibrio, Gordinobacteer and Lactobacillus, while genera belonging to the Firmicutes phylum were found depleted at twelve weeks follow-up compared to baseline. In the MDD group, IL-7, IL-8 and IL-17b levels were elevated compared to the nonMDD group at baseline. Furthermore, MDI score in the MDD group was found to correlate with Bray-Curtis dissimilarity at baseline, and several inflammatory markers at both baseline and after initiation of antidepressant treatment. CONCLUSION: Several bacterial taxa differed between the MDD group and the nonMDD group at baseline and changed in relative abundance during antidepressant treatment and/or psychotherapy. The MDD group was furthermore found to have a pro-inflammatory profile compared to the nonMDD group at baseline. Further studies are required to investigate the gut microbiota and pro-inflammatory profile of patients with MDD.

Children and adolescents with attention deficit hyperactivity disorder and autism spectrum disorder share distinct microbiota compositions.

An association has been suggested between altered gut microbiota, and attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), respectively. Thus, we analyzed the gut microbiota composition in children and adolescents with or without these disorders and evaluated the systemic effects of these bacteria. We recruited study participants diagnosed with ADHD, ASD, and comorbid ADHD/ASD, while the control groups consisted both of siblings and non-related children. The gut microbiota was analyzed by 16S rRNA gene sequencing of the V4 region, while the concentration of lipopolysaccharide-binding protein (LBP), cytokines, and other signaling molecules were measured in plasma. Importantly the gut microbiota compositions of cases with ADHD and ASD were highly similar for both alpha- and beta-diversity while differing from that of non-related controls. Furthermore, a subset of ADHD and ASD cases had an increased LBP concentration compared to non-affected children, which was positively correlated with interleukin (IL)-8, 12, and 13. These observations indicate disruption of the intestinal barrier and immune dysregulation among the subset of children with ADHD or ASD.

Elevated Antibody Titers to Epstein-Barr Virus and Cytomegalovirus in Patients with Drug-Induced Lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which has been associated with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) infection. Drug-induced lupus (DIL) is a lupus-like disease caused by the intake of therapeutic drugs, which has been estimated to cause approximately 10-15% of lupus-like cases. Although SLE and DIL share common clinical symptoms, there are some fundamental differences between DIL and SLE onset. Moreover, it remains to be examined whether environmental factors, such as EBV and CMV infections, may contribute to the development of DIL. This study focused on examining the possible association between DIL and EBV and CMV infections, by examining IgG titers to EBV and CMV antigens in serum samples by enzyme-linked immunosorbent assays. Antibody titers to EBV early antigen-diffuse and CMV pp52 were found to be significantly elevated in both SLE and DIL patients compared to healthy controls, although no correlation was found for antibodies to the two virus antigens in the respective disease groups. Moreover, total IgG titers were reduced in SLE and DIL serum samples, which may reflect a general lymphocytopenia, which commonly is associated with SLE. The current findings support that EBV and CMV infections may contribute to the development of DIL and that onset of both diseases are related.

The Neonicotinoid Imidacloprid Impairs Learning, Locomotor Activity Levels, and Sucrose Solution Consumption in Bumblebees (Bombus terrestris).

Bumblebees carry out the complex task of foraging to provide for their colonies. They also conduct pollination, an ecosystem service of high importance to both wild plants and entomophilous crops. Insecticides can alter different aspects of bumblebee foraging behavior, including the motivation to leave the hive, finding the right flowers, handling flowers, and the ability to return to the colony. In the present study, we assessed how the neonicotinoid imidacloprid affects bumblebees' foraging behavior after exposure to four different treatment levels, including field-realistic concentrations (0 [control], 1, 10, and 100 µg/L), through sucrose solution over 9 days. We observed the behavior of several free-flying bumblebees simultaneously foraging on artificial flowers in a flight arena to register the bees' complex behavior postexposure. To conduct a detailed assessment of how insecticides affect bumblebee locomotor behavior, we used video cameras and analyzed the recordings using computer vision. We found that imidacloprid impaired learning and locomotor activity level when the bumblebees foraged on artificial flowers. We also found that imidacloprid exposure reduced sucrose solution intake and storage. By using automated analyses of video recordings of bumblebee behavior, we identified sublethal effects of imidacloprid exposure at field-realistic doses. Specifically, we observed negative impacts on consumption of sucrose solution as well as on learning and locomotor activity level. Our results highlight the need for more multimodal approaches when assessing the sublethal effects of insecticides and plant protection products in general. Environ Toxicol Chem 2023;42:1337-1345. © 2023 SETAC.

Efficacy of FODMAP Elimination and Subsequent Blinded Placebo-Controlled Provocations in a Randomised Controlled Study in Patients with Ulcerative Colitis in Remission and Symptoms of Irritable Bowel Syndrome: A Feasibility Study.

Background: Patients with inflammatory bowel disease (IBD) and symptoms of irritable bowel syndrome (IBS) may be intolerant to fermentable carbohydrates (FODMAPs). The aim of this study was to test the feasibility of eliminating and subsequently reintroducing FODMAPs in patients with IBS symptoms as part of the IBD manifestation and to compare the severity of IBS symptoms and pain, bloating and quality of life (QoL). Methods: An eight-week randomised open-label FODMAP elimination with double-blinded, crossover provocations of FODMAP and placebo. Diet patients were on a low-FODMAP diet for eight weeks with blinded two-week provocations after two and six weeks. Questionnaires, blood and stool samples were collected. Results: Patient enrolment was challenging. Nineteen participants were included in the study. Eliminating low FODMAP for two weeks resulted in significant decreases in pain and bloating scores (p < 0.003), whereas there were no statistical differences in pain scores between diet patients and controls. Pain and bloating scores increased, returning to baseline levels after two weeks of double-blinded provocations with placebo, (p > 0.05). Conclusions: The results document the possibility of performing a randomised controlled study following the gold standard for testing food intolerance with blinding of the Low FODMAP diet. Recruitment of participants was challenging.

Faecal microbiota transplantation from patients with depression or healthy individuals into rats modulates mood-related behaviour.

Differences in gut microbiota composition have been observed in patients with major depressive disorder (MDD) compared to healthy individuals. Here, we investigated if faecal microbiota transplantation (FMT) from patients with MDD into rats could induce a depressive-like phenotype. We performed FMT from patients with MDD (FMT-MDD) and healthy individuals (FMT-Healthy) into male Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats and assessed depressive-like behaviour. No behavioural differences were observed in the FSL rats. In FRL rats, the FMT-Healthy group displayed significantly less depressive-like behaviour than the FMT-MDD group. However, there was no difference in behaviour between FMT-MDD FRL rats and negative controls, indicating that FMT-Healthy FRL rats received beneficial bacteria. We additionally found different taxa between the FMT-MDD and the FMT-Healthy FRL rats, which could be traced to the donors. Four taxa, three belonging to the family Ruminococcaceae and the genus Lachnospira, were significantly elevated in relative abundance in FMT-MDD rats, while the genus Coprococcus was depleted. In this study, the FMT-MDD group was different from the FMT-Healthy group based on behaviour and intestinal taxa.

Within-Body Distributions and Feeding Effects of the Neonicotinoid Insecticide Clothianidin in Bumblebees (Bombus terrestris).

Bumblebees can be exposed to neonicotinoid pesticides through nectar and pollen collected from treated crops, which can cause lethal and sublethal effects in these nontarget pollinators. However, the body distribution of the compound after exposure to neonicotinoids in bumblebees is not well studied. Bumblebee colonies (Bombus terrestris, n = 20) were exposed to field-realistic concentrations of clothianidin through artificial nectar (3.6-13 µg/L) for 9 d. Comparison of the nominal with the measured exposure in nectar indicated good compliance, confirming the applicability of the method. When quantified, clothianidin showed a concentration-dependent occurrence in the head and body of workers (head: <0.2-2.17 µg/kg; body: <0.2-3.17 µg/kg), and in the body of queens (<0.2-2.49 µg/kg), although concentrations were below those measured in the nectar (bioaccumulation factor = 0.2). Exposure to clothianidin did not affect mortality nor brood production, nor did it have a statistically significant effect on nectar consumption and size of food storage. However, visual inspection suggests higher nectar consumption of nectar with low clothianidin content compared with nectar with no or high clothianidin content. Our results show that dietary clothianidin is taken up in bumblebees, but does not bioaccumulate to elevated levels compared with exposure. Still, clothianidin may elicit responses that affect feeding behavior of the pollinator B. terrestris, although our endpoints were not significantly affected. Environ Toxicol Chem 2021;40:2781-2790. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Gut microbiota variations in patients diagnosed with major depressive disorder-A systematic review.

OBJECTIVE: The etiology of major depressive disorder (MDD) is multi-factorial and has been associated with a perturbed gut microbiota. Thus, it is therefore of great importance to determine any variations in gut microbiota in patients with MDD. METHODS: A systematic literature search was conducted including original research articles based on gut microbiota studies performed in patients with MDD. Demographic and clinical characteristics, applied methodology and observed gut microbiota composition were compared between included studies. RESULTS: Seventeen studies were included with a total of 738 patients with MDD and 782 healthy controls using different DNA purification methods, sequencing platforms and data analysis models. Four studies found a reduced α-diversity in patients with MDD, while gut microbiota compositions clustered separately according to ß-diversity between patients and controls in twelve studies. Additionally, there was an increase in relative abundance of Eggerthella, Atopobium, and Bifidobacterium and a decreased relative abundance of Faecalibacterium in patients with MDD compared with healthy controls. CONCLUSION: Gut microbiota differs significantly when comparing patients with MDD and healthy controls, though inconsistently across studies. The heterogeneity in gut microbiota compositions between the studies may be explained by variations in study design.

Gut Microbiota in Bone Health and Diabetes.

PURPOSE OF REVIEW: Patients with diabetes mellitus (DM) are at increased risk of developing osteopathogenesis and skeletal fragility. The role of the gut microbiota in both DM and osteopathy is not fully explored and may be involved in the pathology of both diseases. RECENT FINDINGS: Gut microbiota alterations have been observed in DM and osteopathogenic disorders as compared with healthy controls, such as significantly lower abundance of Prevotella and higher abundance of Lactobacillus, with a diminished bacterial diversity. Other overlapping gastro-intestinal features include the loss of intestinal barrier function with translocation of bacterial metabolites to the blood stream, induction of immunological deficits and changes in hormonal and endocrinal signalling, which may lead to the development of diabetic osteopathy. Signalling pathways involved in both DM and osteopathy are affected by gut bacteria and their metabolites. Future studies should focus on gut microbiota involvement in both diseases.

Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic literature review.

Accumulating evidence has implicated an involvement of the gut-brain axis in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), however with highly diverse results. This systematic review aims to describe and evaluate studies investigating the gut microbiota composition in individuals with ASD or ADHD and to evaluate if variations in gut microbiota are associated with these disorders. Twenty-four articles were identified in a systematic literature search of PubMed and Embase up to July 22, 2019. They consisted of 20 studies investigating ASD and four studies investigating ADHD. For ASD, several studies agreed on an overall difference in ß-diversity, although no consistent bacterial variation between all studies was reported. For ADHD, the results were more diverse, with no clear differences observed. Several common characteristics in gut microbiota function were identified for ASD compared to controls. In contrast, highly heterogeneous results were reported for ADHD, and thus the association between gut microbiota composition and ADHD remains unclear. For both disorders, methodological differences hampered the comparison of studies.

The effect of remote ischaemic preconditioning on myocardial injury in emergency hip fracture surgery (PIXIE trial): phase II randomised clinical trial.

OBJECTIVE: To investigate whether remote ischaemic preconditioning (RIPC) prevents myocardial injury in patients undergoing hip fracture surgery. DESIGN: Phase II, multicentre, randomised, observer blinded, clinical trial. SETTING: Three Danish university hospitals, 2015-17. PARTICIPANTS: 648 patients with cardiovascular risk factors undergoing hip fracture surgery. 286 patients were assigned to RIPC and 287 were assigned to standard practice (control group). INTERVENTION: The RIPC procedure was initiated before surgery with a tourniquet applied to the upper arm and consisted of four cycles of forearm ischaemia for five minutes followed by reperfusion for five minutes. MAIN OUTCOME MEASURES: The original primary outcome was myocardial injury within four days of surgery, defined as a peak plasma cardiac troponin I concentration of 45 ng/L or more caused by ischaemia. The revised primary outcome was myocardial injury within four days of surgery, defined as a peak plasma cardiac troponin I concentration of 45 ng/L or more or high sensitive troponin I greater than 24 ng/L (the primary outcome was changed owing to availability of testing). Secondary outcomes were peak plasma troponin I and total troponin I release during the first four days after surgery (cardiac and high sensitive troponin I), perioperative myocardial infarction, major adverse cardiovascular events, and all cause mortality within 30 days of surgery, length of postoperative stay, and length of stay in the intensive care unit. Several planned secondary outcomes will be reported elsewhere. RESULTS: 573 of the 648 randomised patients were included in the intention-to-treat analysis (mean age 79 (SD 10) years; 399 (70%) women). The primary outcome occurred in 25 of 168 (15%) patients in the RIPC group and 45 of 158 (28%) in the control group (odds ratio 0.44, 95% confidence interval 0.25 to 0.76; P=0.003). The revised primary outcome occurred in 57 of 286 patients (20%) in the RIPC group and 90 of 287 (31%) in the control group (0.55, 0.37 to 0.80; P=0.002). Myocardial infarction occurred in 10 patients (3%) in the RIPC group and 21 patients (7%) in the control group (0.46, 0.21 to 0.99; P=0.04). Statistical power was insufficient to draw firm conclusions on differences between groups for the other clinical secondary outcomes (major adverse cardiovascular events, 30 day all cause mortality, length of postoperative stay, and length of stay in the intensive care unit). CONCLUSIONS: RIPC reduced the risk of myocardial injury and infarction after emergency hip fracture surgery. It cannot be concluded that RIPC overall prevents major adverse cardiovascular events after surgery. The findings support larger scale clinical trials to assess longer term clinical outcomes and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344797.

[The human gut microbiota].

Characterization of the human gut microbiota has caused a paradigm shift in modern biomedical research. Maintenance of gut microbiota depends on mutual microbe-host interactions, which when disturbed can lead to dysbiosis. Dysbiosis has been associated with a variety of autoimmune and metabolic diseases. Studies attempt to define bacterial compositional changes, immunity responses or molecular patterns associated with specific diseases. The immense research in the human microbiota may lead to novel therapeutic strategies by development of commensal microbe products in management of diseases.

[Gut microbiota and depressive symptoms].

The gut microbiota is believed to affect a wide variety of mental disorders, including depression. The hypothesis involves bacterial signalling to the host through metabolic, endocrinal, immunologic and neuronal pathways. Few studies of patients with depression have shown altered microbiota profiles and increased levels of systemic endotoxin, which can be detected by leucocytes and result in expression of cytokines. Studies performed so far have lacked statistical power and provide no causal explanation for the gut-brain hypothesis. Further research into the matter is certainly warranted.

Low Constitutive Cell Surface Expression of HLA-B Is Caused by a Posttranslational Mechanism Involving Glu180 and Arg239.

HLA class I cell surface expression is crucial for normal immune responses, and variability in HLA expression may influence the course of infections. We have previously shown that classical HLA class I expression on many human cell types is biased with greatly reduced expression of HLA-B compared with HLA-A in the absence of inflammatory signals. In the search for the mechanisms responsible for this discrepancy, we have recently reported that the regulation is mainly posttranslational and that the C-terminal part of the α2 domain and the α3 domain contain the molecular determinants that explain most of the variability of expression between common HLA-A and -B allomorphs. In this study, we present a fine mapping of the structural determinants that allow such variability by exchanging key amino acids located within the C-terminal part of the α2 domain and the α3 domain of HLA-A2 and -B8, including Glu/Asp at position 177, Gln/Glu at position 180, Gly/Arg at position 239, and Pro/Ser at position 280. We found that the HLA-A2 and -B8 expression profiles could be interconverted to a large extent by mutual exchange of Gln/Glu at position 180 or by Gly/Arg at position 239. The presence of Gln180 and Gly239, as in HLA-A2, led to higher cell surface expression levels when compared with the presence of Glu180 and Arg239, as in HLA-B8. This indicates that the amino acids at positions 180 and 239 determine the level of cell surface expression of common HLA-A and -B allomorphs, probably by affecting HLA processing in the Ag presentation pathway.