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Abstract Background Aronia melanocarpa is a berry rich in polyphenols known for health benefits. However, the bioavailability of polyphenols has been questioned, and the individual taste acceptance of the fruit with its specific flavor varies. We recently observed substantial differences in the tolerability of aronia juice among healthy females, with half of the individuals tolerating aronia juice without complaints. Given the importance of the gut microbiome in food digestion, we investigated in this secondary analysis of the randomized placebo-controlled parallel intervention study (ClinicalTrials.gov registration: NCT05432362) if aronia juice tolerability was associated with changes in intestinal microbiota and bacterial metabolites, seeking for potential mechanistic insights into the impact on aronia polyphenol tolerance and metabolic outcomes. Results Forty females were enrolled for this 6-week trial, receiving either 100 ml natural aronia juice (verum, V) twice daily or a polyphenol-free placebo (P) with a similar nutritional profile, followed by a 6-week washout. Within V, individuals were categorized into those who tolerated the juice well (Vt) or reported complaints (Vc). The gut microbiome diversity, as analyzed by 16S rRNA gene-based next-generation sequencing, remained unaltered in Vc but changed significantly in Vt. A MICOM-based flux balance analysis revealed pronounced differences in the 40 most predictive metabolites post-intervention. In Vc carbon-dioxide, ammonium and nine O-glycans were predicted due to a shift in microbial composition, while in Vt six bile acids were the most likely microbiota-derived metabolites. NMR metabolomics of plasma confirmed increased lipoprotein subclasses (LDL, VLDL) post-intervention, reverting after wash out. Stool samples maintained a stable metabolic profile. Conclusion In linking aronia polyphenol tolerance to gut microbiota-derived metabolites, our study explores adaptive processes affecting lipoprotein profiles during high polyphenol ingestion in Vt and examines effects on mucosal gut health in response to intolerance to high polyphenol intake in Vc. Our results underpin the importance of individualized hormetic dosing for beneficial polyphenol effects, demonstrate dynamic gut microbiome responses to aronia juice, and emphasize personalized responses in polyphenol interventions. Graphical Abstract Video Abstract

ABSTRACTThe partial or complete loss of the sense of smell, which affects about 20% of the population, impairs the quality of life in many ways. Dysosmia and anosmia are mainly caused by aging, trauma, infections, or even neurodegenerative disease. Recently, the olfactory area—a site containing the olfactory receptor cells responsible for odor perception—was shown to harbor a complex microbiome that reflects the state of olfactory function. This initially observed correlation between microbiome composition and olfactory performance needed to be confirmed using a larger study cohort and additional analyses. A total of 120 participants (middle-aged, no neurodegenerative disease) were enrolled in the study to further analyze the microbial role in human olfactory function. Olfactory performance was assessed using the Sniffin’ Stick battery, and participants were grouped accordingly (normosmia: n = 93, dysosmia: n = 27). The olfactory microbiome was analyzed by 16S rRNA gene amplicon sequencing and supplemented by metatranscriptomics in a subset (Nose 2.0). Propidium monoazide (PMA) treatment was performed to distinguish between intact and non-intact microbiome components. The gastrointestinal microbiome of these participants was also characterized by amplicon sequencing and metabolomics and then correlated with food intake. Our results confirm that normosmics and dysosmics indeed possess a distinguishable olfactory microbiome. Alpha diversity (i.e., richness) was significantly increased in dysosmics, reflected by an increase in the number of specific taxa (e.g., Rickettsia, Spiroplasma, and Brachybacterium). Lower olfactory performance was associated with microbial signatures from the oral cavity and periodontitis (Fusobacterium, Porphyromonas, and Selenomonas). However, PMA treatment revealed a higher accumulation of dead microbial material in dysosmic subjects. The gastrointestinal microbiome partially overlapped with the nasal microbiome but did not show substantial variation with respect to olfactory performance, although the diet of dysosmic individuals was shifted toward a higher meat intake. Dysosmia is associated with a higher burden of dead microbial material in the olfactory area, indicating an impaired clearance mechanism. As the microbial community of dysosmics (hyposmics and anosmics) appears to be influenced by the oral microbiome, further studies should investigate the microbial oral-nasal interplay in individuals with partial or complete olfactory loss.IMPORTANCEThe loss of the sense of smell is an incisive event that is becoming increasingly common in today’s world due to infections such as COVID-19. Although this loss usually recovers a few weeks after infection, in some cases, it becomes permanent—why is yet to be answered. Since this condition often represents a psychological burden in the long term, there is a need for therapeutic approaches. However, treatment options are limited or even not existing. Understanding the role of the microbiome in the impairment of olfaction may enable the prediction of olfactory disorders and/or could serve as a possible target for therapeutic interventions.

The analysis of fetal MRI data and follow-up language assessments reveal that temporal sulcus depth asymmetry is a potential biomarker for maturity and integrity of neural correlates of language.

Introduction: A functional reciprocity between the gut microbiome and vagal nerve activity has been suggested, however, human studies addressing this phenomenon are limited. Methods: 24- hour cardiac vagal activity (CVA) was assessed from 73 female participants (aged 24.5±4.3 years). Additionally, stool samples were subjected to 16SrRNA gene analysis (V1–V2). Quantitative Insights Into Microbial Ecology (QIIME) was used to analyze microbiome data. Additionally, inflammatory parameters (such as CRP and IL-6) were derived from serum samples. Results: Daytime CVA correlated significantly with gut microbiota diversity (r=0.254, p=0.030), CRP (r=-0.348, p= 0.003), and IL-6 (r=-0.320, p=0.006). When the group was divided at the median of 24 hour CVA (Mdn=1.322), the following features were more abundant in the high CVA group: Clostridia (Linear discriminant analysis effect size (LDA)= 4.195, p= 0.029), Clostridiales (LDA=4.195, p= 0.029), Lachnospira (LDA=3.489, p=0.004), Ruminococcaceae (LDA=4.073, p=0.010), Faecalibacterium (LDA=3.982, p= 0.042), Lactobacillales (LDA=3.317, p=0.029), Bacilli (LDA=3.294, p=0.0350), Streptococcaceae (LDA=3.353, p= 0.006), Streptococcus (LDA=3.332, p=0.011). Based on Dirichlet multinomial mixtures two enterotypes could be detected, which differed significantly in CVA, age, BMI, CRP, IL-6 and diversity. Conclusions: As an indicator of gut-brain communication, gut microbiome analysis could be extended by measurements of CVA to enhance our understanding of signalling via microbiota-gut-brain-axis and its alterations through psychobiotics.

Infection with Helicobacter pylori (H.pylori) may cause dyspepsia and/or unexplained functional nonspecific, gastrointestinal complaints of the irritable bowel syndrome (IBS) spectrum. Hitherto, in H. pylori infected patients with symptoms of the IBS spectrum the occurrence of additional food intolerance/malabsorption is not evaluated. We used a retrospective analysis of charts from 548 patients who presented with gastrointestinal complaints of the irritable bowel syndrome spectrum. An enzyme-linked IgA immunosorbent assay or histologic evaluation of gastric mucosa were used to detect H. pylori infection. A hydrogen breath (H2) test was performed to evaluate fructose malabsorption (FM) and lactose intolerance (LIT). Serum diamine oxidase value of

Abstract Background Methane is an end product of microbial fermentation in the human gastrointestinal tract. This gas is solely produced by an archaeal subpopulation of the human microbiome. Increased methane production has been associated with abdominal pain, bloating, constipation, IBD, CRC or other conditions. Twenty percent of the (healthy) Western populations innately exhale substantially higher amounts (>5 ppm) of this gas. The underlying principle for differential methane emission and its effect on human health is not sufficiently understood. Results We assessed the breath methane content, the gastrointestinal microbiome, its function and metabolome, and dietary intake of one-hundred healthy young adults (female: n = 52, male: n = 48; mean age =24.1). On the basis of the amount of methane emitted, participants were grouped into high methane emitters (CH4 breath content 5–75 ppm) and low emitters (CH4 < 5 ppm). The microbiomes of high methane emitters were characterized by a 1000-fold increase in Methanobrevibacter smithii. This archaeon co-occurred with a bacterial community specialized on dietary fibre degradation, which included members of Ruminococcaceae and Christensenellaceae. As confirmed by metagenomics and metabolomics, the biology of high methane producers was further characterized by increased formate and acetate levels in the gut. These metabolites were strongly correlated with dietary habits, such as vitamin, fat and fibre intake, and microbiome function, altogether driving archaeal methanogenesis. Conclusions This study enlightens the complex, multi-level interplay of host diet, genetics and microbiome composition/function leading to two fundamentally different gastrointestinal phenotypes and identifies novel points of therapeutic action in methane-associated disorders. Video Abstract

Introduction: Anorexia nervosa (AN) can co-occur with hypercarotenemia, a clinical condition characterized by elevated β-carotene in plasma and skin tissue. Carotenoids have known anti-obesogenic effects in adipocyte biology. Thus, carotenoids may potentially play a retarding role in weight gain during the recovery of AN patients. This study evaluated the plasma carotenoid profile and subcutaneous adipose tissue (SAT) in a cohort of AN patients and normal weight (NW) controls.Methods: Plasma concentrations of α-carotene, β-carotene, β-cryptoxanthin, and lycopene were determined by HPLC analysis. SAT thicknesses were measured by a highly accurate and reliable ultrasound technique. Information on dietary intakes were collected by repeated 24-h recalls.Results: Sixty-two females (AN: n = 18, NW: n = 44) were included. The concentrations of β-cryptoxanthin (p = 0.045) and lycopene (p = 0.004) were significantly lower in AN patients. β-carotene levels were higher in AN patients (n.s.) and α-carotene did not differ significantly. SAT thickness was significantly lower in AN patients compared to controls (p < 0.001). β-carotene was significantly negative (rs = −0.471) and lycopene significantly positive (rs = 0.366) correlated with SAT. The correlation of β-carotene and SAT was even higher in the AN group alone (rs = −0.742). Also, β- cryptoxanthin and the sum of provitamin A carotenoids were correlated to SAT (rs = −0.647 and rs = −0.746, respectively) in AN patients. Fruits and vegetable intake did not differ significantly between AN and NW but adjusted for SAT, AN patients consumed relatively higher amounts (p = 0.006).Conclusion: Higher plasma β-carotene concentrations were associated with reduced SAT levels, most probably due to a reduced ability of the remaining adipose tissue to store carotenoids. Thus, the antiobesity effects of carotenoids might impact the treatment success of undernutrition and AN. A systemic carotenoid overload may contribute to changes in adipogenesis and metabolic capacities for energy storage. Therefore, high plasma β-carotene may be a marker of delay in weight recovery in AN patients. Interventional studies should consider including carotenoid-status in AN treatment.

Background/Aims Food intolerance/malabsorption, particularly histamine intolerance (HIT), may cause nonspecific functional gastrointestinal and extraintestinal symptoms. We evaluated gastrointestinal and extraintestinal symptoms in patients with HIT. Methods In an analysis of outpatients’ charts we identified 133 patients, who presented with recurring nonspecific functional gastrointestinal, extraintestinal symptoms, and a diamine oxidase value

Dietary polyphenols, which are present in Aronia melanocarpa, have been associated with various beneficial effects on human health including antioxidant, antiviral, and anti-inflammatory activities. We aimed to investigate the immunomodulatory effects of aronia juice polyphenols in a randomized placebo-controlled human intervention study and cell culture experiments. A total of 40 females were asked to consume either 200 mL of aronia juice or a placebo drink for six weeks and were investigated again after a washout period of another six weeks. We observed that only half of the participants tolerated the aronia juice well (Vt) and the other half reported complaints (Vc). The placebo (P) was generally tolerated with one exception (p = 0.003). Plasma polyphenol levels increased significantly in Vt after the intervention (p = 0.024) but did neither in P nor in Vc. Regulatory T cell (Treg) frequencies remained constant in Vt and P during the intervention, whereas Tregs decreased in Vc (p = 0.018). In cell culture, inhibiting effects of ferulic acid (p = 0.0005) and catechin (p = 0.0393) on the differentiation of Tregs were observed as well as reduced activation of CD4-T cells in ferulic acid (p = 0.0072) and aronia juice (p = 0.0163) treated cells. Interestingly, a CD4+CD25−FoxP3+ cell population emerged in vitro in response to aronia juice, but not when testing individual polyphenols. In conclusion, our data strengthen possible individual hormetic effects, the importance of the food matrix for bioactivity, and the need for further investigations on possible impacts of specific physiological features such as the gut microbiota in the context of personalized nutrition.

Oxidative stress describes an imbalance of reactive oxygen species (ROS) and antioxidative defence systems. Recently, the consequences of oxidative stress have become a central field of research and have been linked to the genesis of multiple psychiatric diseases. Some oxidative stress parameters have not been investigated before in anorexia nervosa (AN) patients, including the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and polyphenols (PPm). In this cross-sectional pilot study, we evaluated these markers together with total peroxides (TOC), antioxidative capacity (TAC), endogenous peroxidase activity (EPA) and antibodies against oxidized LDL (oLAb) in serum samples of 20 patients with AN compared to 20 healthy controls. The antioxidative capacity was significantly decreased in AN patients, with a mean TAC of 1.57 mmol/L (SD: ±0.62); t (34) = −2.181, p = 0.036) compared to HC (mean = 1.91 mmol/L (SD: ±0.56), while the other investigated parameters were not significantly different between the two groups. In AN patients, TAC correlated with EPA (rsp = −0.630, p = 0.009). This study suggests that there is an antioxidative deficiency in AN patients. In this respect, there is a demand for interventional studies to determine whether antioxidants can be used as add-on therapy in the treatment of AN.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.

Background: Obesity increases the risk of coronary heart disease, partly due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol levels. Functional impairment of HDL may contribute to the increased cardiovascular mortality, but the effect of obesity on composition, structure, and function of HDL is not well understood. Design and Methods: We determined HDL composition, HDL subclass distribution, parameters of HDL function, and activities of most important enzymes involved in lipoprotein remodeling, including lecithin–cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) in relatively young normal weight (n = 26), overweight (n = 22), and obese (n = 20) women. Results: Obesity (body mass index (BMI) ≥ 30) was associated with noticeable changes in LCAT and CETP activities and altered HDL composition, such as decreased apolipoprotein A-I, cholesterol, and phospholipid content, while pro-inflammatory HDL serum amyloid a content was increased. We observed a marked shift towards smaller HDL subclasses in obesity linked to lower anti-oxidative capacity of serum. LCAT activity, HDL subclass distribution, and HDL-cholesterol were associated with soluble leptin receptor, adiponectin, and liver enzyme activities. Of note, most of these alterations were only seen in obese women but not in overweight women. Conclusions: Obesity markedly affects HDL metabolism, composition, and subclass distribution linked to changes in liver and adipose tissue. HDL dysfunction may contribute to increased cardiovascular risk in obesity.

Background: β-thalassemia minor is characterized by reduced β-haemoglobin chain synthesis and sometimes mild anaemia, although carriers of β-thalassemia minorare usually clinically asymptomatic.Nonspecific abdominal complaints may be caused by gastrointestinal carbohydrate malabsorption (lactose and fructose) and/or malabsorption of biogenic amines (histamine), or proteins (gluten). Objectives: We report on two patients with β-thalassemia minor suffering nonspecific abdominal symptoms due to a carbohydrate and histamine malabsorption. Design/methods: The diagnosis of β-thalassemia minorwas done with peripheral blood smear and cellulose acetate electrophoresis. Carbohydrate malabsorption was diagnosed with hydrogen breath tests and, histamine intolerance (HIT) with a serum diamine oxidase value

Primary Epiploic Appendagitis (PEA) is a rare cause of acute or subacute abdominal complaints and non-migratory pain. Usually the diagnosis of PEA is made when Computed Tomography (CT) reveals characteristic figures. Nonspecific abdominal complaints including diffuse abdominal pain may be caused by carbohydrate and/or protein malabsorption. We report a case of a patient with PEA who recovered without medication or surgical treatment within a few days. Eight months later, he was diagnosed with lactose- and histamine malabsorption and Helicobacter pylori infection. The malabsorption was treated successfully with an individually-tailored diet free of culprit triggers and the Helicobacter pylori infection was eradicated. A localized non-migratory abdominal pain caused by PEA needs to be differentiated from nonspecific abdominal complaints due to malabsorption and Helicobacter pylori infection.

Aspects of the female body may be attractive because they signal evolutionary fitness. Greater body fatness might reflect greater potential to survive famines, but individuals carrying larger fat stores may have poor health and lower fertility in non-famine conditions. A mathematical statistical model using epidemiological data linking fatness to fitness traits, predicted a peaked relationship between fatness and attractiveness (maximum at body mass index (BMI) = 22.8 to 24.8 depending on ethnicity and assumptions). Participants from three Caucasian populations (Austria, Lithuania and the UK), three Asian populations (China, Iran and Mauritius) and four African populations (Kenya, Morocco, Nigeria and Senegal) rated attractiveness of a series of female images varying in fatness (BMI) and waist to hip ratio (WHR). There was an inverse linear relationship between physical attractiveness and body fatness or BMI in all populations. Lower body fat was more attractive, down to at least BMI = 19. There was no peak in the relationship over the range we studied in any population. WHR was a significant independent but less important factor, which was more important (greater r2) in African populations. Predictions based on the fitness model were not supported. Raters appeared to use body fat percentage (BF%) and BMI as markers of age. The covariance of BF% and BMI with age indicates that the role of body fatness alone, as a marker of attractiveness, has been overestimated.