Citrus flavanones, with hesperidin and naringin as the most abundant representatives, have various beneficial effects, including anti-oxidative and anti-inflammatory activities. Evidence also indicates that they may impact the intestinal microbiome and are metabolized by the microbiota as well, thereby affecting their bioavailability. In this review, we provide an overview on the current evidence on the intestinal fate of hesperidin and naringin, their interaction with the gut microbiota, and their effects on intestinal barrier function and intestinal inflammation. These topics will be discussed as they may contribute to gastrointestinal health in various diseases. Evidence shows that hesperidin and naringin are metabolized by intestinal bacteria, mainly in the (proximal) colon, resulting in the formation of their aglycones hesperetin and naringenin and various smaller phenolics. Studies have also shown that citrus flavanones and their metabolites are able to influence the microbiota composition and activity and exert beneficial effects on intestinal barrier function and gastrointestinal inflammation. Although the exact underlying mechanisms of action are not completely clear and more research in human subjects is needed, evidence so far suggests that citrus flavanones as well as their metabolites have the potential to contribute to improved gastrointestinal function and health.

Ageing is associated with an increased risk of frailty, intestinal microbiota perturbations, immunosenescence and oxidative stress. Prebiotics such as galacto-oligosaccharides (GOS) may ameliorate these ageing-related alterations. We aimed to compare the faecal microbiota composition, metabolite production, immune and oxidative stress markers in prefrail elderly and younger adults, and investigate the effects of GOS supplementation in both groups. In a randomised controlled cross-over study, 20 prefrail elderly and 24 healthy adults received 21.6 g/day Biotis™ GOS (containing 15.0 g/day GOS) or placebo. Faecal 16S rRNA gene-based microbiota and short-chain fatty acids were analysed at 0, 1 and 4 weeks of intervention.Volatile organic compounds were analysed in breath, and stimulated cytokine production, CRP, malondialdehyde, trolox equivalent antioxidant capacity (TEAC) and uric acid (UA) in blood at 0 and 4 weeks. Principle coordinate analysis showed differences in microbial composition between elderly and adults (P≤0.05), with elderly having lower bifidobacteria (P≤0.033) at baseline. In both groups, GOS affected microbiota composition (P≤0.05), accompanied by increases in bifidobacteria (P<0.001) and decreased microbial diversity (P≤0.023). Faecal and breath metabolites, immune and oxidative stress markers neither differed between groups (P ≥ 0.125) nor were affected by GOS (P ≥ 0.236). TEAC values corrected for UA were higher in elderly versus adults (P<0.001), but not different between interventions (P ≥ 0.455). Elderly showed lower faecal bifidobacterial (relative) abundance than adults, which increased after GOS intake in both groups. Faecal and breath metabolites, parameters of immune function and oxidative stress were not different at baseline, and not impacted by GOS supplementation. CLINICALTRIALS. NCT03077529.

Cognitive decline is associated with lifestyle-related factors such as overweight, blood pressure, and dietary composition. Studies have reported beneficial effects of dietary anthocyanins on cognition in older adults and children. However, the effect of anthocyanin-rich Aronia melanocarpa extract (AME) on cognition is unknown. Therefore, this study aimed to determine the effect of long-term supplementation with AME on cognitive performance, mood, and vascular function in healthy, middle-aged, overweight adults. In a randomized double-blind placebo-controlled parallel study, 101 participants either consumed 90 mg AME, 150 mg AME, or placebo for 24 weeks. The grooved pegboard test, number cross-out test, and Stroop test were performed as measures for psychomotor speed, attention, and cognitive flexibility. Mood was evaluated with a visual analogue scale, serum brain-derived neurotrophic factor (BDNF) was determined, and vascular function was assessed by carotid ultrasounds and blood pressure measurements. AME improved psychomotor speed compared to placebo (90 mg AME: change = −3.37; p = 0.009). Furthermore, 150 mg AME decreased brachial diastolic blood pressure compared to 90 mg AME (change = 2.44; p = 0.011), but not compared to placebo. Attention, cognitive flexibility, BDNF, and other vascular parameters were not affected. In conclusion, AME supplementation showed an indication of beneficial effects on cognitive performance and blood pressure in individuals at risk of cognitive decline.

Purpose: Overweight and obesity are associated with many health problems, including cardiovascular disease (CVD). Evidence from previous studies has shown that extracts from olive leaves rich in olive phenolics are able to positively affect CVD risk factors, such as high blood pressure and dyslipidemia. The aim of this study was to investigate the effect of 8-week olive leaf extract (OLE) administration on blood lipid profiles in overweight/obese subjects with mildly elevated cholesterol levels. Methods: In this randomized, double-blind, placebo-controlled study, 77 healthy adult overweight/obese subjects (aged 56 ± 10 years and BMI 29.0 ± 2.7 kg/m²) with total cholesterol levels of 5.0–8.0 mmol/L (5.9 ± 0.7 mmol/L) were randomly assigned to receive 500 mg of OLE (n = 39) or placebo (n = 38) for 8 weeks. In total, 74 subjects completed the entire study protocol. At baseline, after 4 weeks, and after 8 weeks of supplementation, blood lipid profiles, oxidized low-density lipoprotein (oxLDL), blood pressure, glucose, and insulin levels were assessed. In addition, liver function parameters were measured at baseline and after 8 weeks. Results: OLE supplementation did not significantly affect blood lipid levels after 4 weeks or after 8 weeks compared to placebo (all p > 0.05). For oxLDL, blood pressure, glucose, and insulin levels and liver function parameters, also no statistically significant differences were found between the two intervention groups (all p > 0.05). Conclusions: Blood lipid profiles were not significantly affected by 8 weeks OLE supplementation in overweight/obese subjects with mildly elevated cholesterol levels. Trial registered: The trial has been registered at ClinicalTrials.gov (NCT02990637).

Nutritional supplementation is commonly used by athletes to improve their exercise performance. Previous studies demonstrated that citrus flavonoid extract (CFE) supplementation may be an effective strategy to improve exercise performance in male athletes. Yet, no conclusive research has been performed to investigate the effect of chronic CFE supplementation on high-intensity exercise performance under anaerobic conditions. Therefore, the aim of the study was to assess whether CFE supplementation in daily dosages of 400 and 500 mg for a period of 4 and 8 weeks improves anaerobic exercise capacity. A randomized, double-blind, placebo controlled, parallel clinical study was conducted in 92 moderately trained healthy men and women. Subjects were randomized to receive 400 mg of CFE (n = 30), 500 mg of CFE (n = 31) or placebo (n = 31) daily, for 8 consecutive weeks. The Wingate anaerobic test was used to assess anaerobic exercise capacity and power output at baseline, after 4 weeks and after 8 weeks. After 4 weeks supplementation, average power output significantly increased in the 400 mg group (Estimated difference [ED] = 38.2 W [18.0, 58.3]; p < 0.001; effect size [ES] = 0.27) and in the 500 mg group (ED = 21.2 W [0.91, 41.4]; p = 0.041; ES = 0.15) compared to placebo. The 5 s peak power output was also increased in the 400 mg group (ED = 53.6 [9.96, 97.2]; p = 0.017; ES = 0.25) after 4 weeks compared to placebo. After 8 weeks of supplementation, average power output was significantly improved in the group receiving 400 mg of CFE (ED = 31.6 [8.33, 54.8]; p = 0.008; ES = 0.22) compared to placebo. These results demonstrate that CFE supplementation improved anaerobic capacity and peak power during high intensity exercise in moderately trained individuals. Further research is needed to identify the underlying mechanisms that are affected by CFE supplementation. ClinicalTrials.gov ( NCT03044444 ). Registered 7 February 2017

Hesperidin and naringin are citrus flavonoids with known anti-oxidative and anti-inflammatory properties. Evidence from previous studies indicates that both these compounds and the metabolites that are formed during intestinal metabolism are able to exert beneficial effects on intestinal barrier function and inflammation. However, so far, studies investigating the relative contributions of the various compounds are lacking. Therefore, we assessed the effect of citrus flavonoids and their intestinal metabolites on immune-mediated barrier disruption in an in vitro co-culture model. Caco-2 cell monolayers were placed in co-culture with phorbol 12-myristate 13-acetate-stimulated THP-1-Blue™ NF-κB cells for 30 h. At baseline, the citrus flavonoids and their metabolites were added to the apical compartment (50 or 100 µM per compound). After 24 h, THP-1 cells were incubated with lipopolysaccharide (LPS) in the basolateral compartment for 6 h. Incubation with citrus flavonoids and their metabolites did not induce changes in transepithelial electrical resistance, fluorescein isothiocyanate–dextran 4 kDa permeation or gene expression of barrier-related genes for any of the compounds tested. After LPS stimulation, NF-κB activity was significantly inhibited by all compounds (100 µM) except for one metabolite (all P ≤ 0·03). LPS-induced production of the cytokines IL-8, TNF-α and IL-6 was inhibited by most compounds (all P < 0·05). However, levels of IL-1β were increased, which may contribute to the lack of an improved barrier effect. Overall, these results suggest that citrus flavonoids may decrease intestinal inflammation via reduction of NF-κB activity and that the parent compounds and their metabolites formed during intestinal metabolism are able to exert comparable effects.