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Type 2 diabetes (T2D) is a growing health problem worldwide, but the currently available strategies for therapy and prevention are insufficient. Recent observations indicate that bile acid homeostasis is altered in T2D. Bile acids are metabolic regulators that act as signaling molecules through receptor-dependent and -independent pathways. The most prominent signaling molecules mediating bile acid signaling are the nuclear receptor farnesoid X receptor (FXR) and the membrane receptor TGR5. Both are implicated in the regulation of lipid, glucose, and energy metabolism. Dysregulation of these pathways might contribute to the development of T2D and associated complications. Interestingly, data from studies with bile acids or bile acid sequestrants indicate that the manipulation of bile acid homeostasis might be an attractive approach for T2D therapy. In this review, we summarize the mechanisms of bile acid–mediated metabolic control that might be relevant in the pathogenesis of T2D.

This study examined whether consuming collagen peptides (CP) before and after strenuous exercise alters markers of muscle damage, inflammation and bone turnover. Using a double-blind, independent group’s design, 24 recreationally active males consumed either 20 g day−1 of CP or a placebo control (CON) for 7 days before and 2 days after performing 150 drop jumps. Maximal isometric voluntary contractions, countermovement jumps (CMJ), muscle soreness (200 mm visual analogue scale), pressure pain threshold, Brief Assessment of Mood Adapted (BAM +) and a range of blood markers associated with muscle damage, inflammation and bone turnover C-terminal telopeptide of type 1 collagen (β-CTX) and N-terminal propeptides of type 1 pro-collagen (P1NP) were measured before supplementation (baseline; BL), pre, post, 1.5, 24 and 48 h post-exercise. Muscle soreness was not significantly different in CP and CON (P = 0.071) but a large effect size was evident at 48 h post-exercise, indicative of lower soreness in the CP group (90.42 ± 45.33 mm vs. CON 125.67 ± 36.50 mm; ES = 2.64). CMJ height recovered quicker with CP than CON at 48 h (P = 0.050; CP 89.96 ± 12.85 vs. CON 78.67 ± 14.41% of baseline values; ES = 0.55). There were no statistically significant effects for the other dependent variables (P > 0.05). β-CTX and P1NP were unaffected by CP supplementation (P > 0.05). In conclusion, CP had moderate benefits for the recovery of CMJ and muscle soreness but had no influence on inflammation and bone collagen synthesis.

Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.

Protein hydrolysates are an important part of the human diet. Often, they are prepared from milk, soy, or collagen. In the present study, four different collagen hydrolysates were tested, varying in the average molecular weight and the animal source. Three types of samples, the dissolved start products, in vitro generated dialysates (containing the digested components that are potentially available for small intestinal absorption), and human serum collected after product ingestion, were analyzed using LC-MS to compare the state of the hydrolysates before and after absorption, i.e., uptake into the blood. It was found that the composition of the collagen hydrolysates prior to and after ingestion was highly complex and dynamic, which made it challenging to predefine a strategy for a targeted analysis. Therefore, we implemented a new analytical approach to first map hydrolysate data sets by performing non-targeted LC-MS analysis followed by non-targeted and targeted data analysis. It was shown that the insight gained by following such a top down (data) analytical workflow could be crucial for defining a suitable targeted setup and considering data trends beyond the defined targets. After having defined and performed a limited targeted analysis, it was found that, in our experimental setup, Hyp-Gly and especially Pro-Hyp contributed significantly as carrier to the total Hyp increase in blood after ingestion of collagen hydrolysate.

Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.

The effect of dietary collagen on managing digestive symptoms is currently lacking in the literature. To gain a better understanding of this issue, we conducted a 2-phase mixed methods study. Phase 1 was a mixed methods design to explore current attitude and practice among consumers and health care practitioners. The findings were used to design an 8-week phase 2 digital study called Gutme! conducted in the United States in healthy female volunteers (BMI>25 kg/m ). Our aim was, first, to determine the feasibility of conducting a fully digital mixed methods study; second, the study explored the effect of an 8-week daily supplementation of 20 g dietary collagen peptide (Peptan) on digestive symptoms. Phase 2 was a prospective, open-label, longitudinal, single-arm study. Participation involved 2 weeks of baseline tracking (digestive symptoms, mood, stool, and lifestyle) using an app, followed by 8 weeks of tracking and taking 20 g collagen peptide supplement split into 2 dosages per day. Participants were required to complete a web-based symptom questionnaire at baseline, week 2, and week 8, as well as participate in 2 scheduled video interviews. Phase 1 revealed that consumer awareness of collagen for digestive health is low (64/204, 31.4%). Among the dietitians prescribing collagen for their patients, the most common dosage was 20 g a day with notable effects after 6 weeks of intake. Within the phase 2 study, of the 40 recruited participants, 14 (35%) completed the full course of supplementation. The findings indicate that 93% (13/14) of those who completed the study experienced a reduction in digestive symptoms, which included bloating. A mixed methods digital study design is feasible and acceptable for collecting relevant data in a real-life setting. The use of a 20 g daily collagen peptide supplement may reduce bloating and improve mild digestive symptoms in otherwise healthy female adults in the absence of any other dietary or lifestyle interventions. ClinicalTrials.gov NCT04245254; https://clinicaltrials.gov/ct2/show/NCT04245254.

Joint discomfort is a widespread and growing problem in active adults. The rising interest in preventative nutrition has increased the demand for supplements reducing joint discomfort. Protocols assessing the effect of a nutritional intervention on health commonly involve a series of face-to-face meetings between participants and study staff that can weigh on resources, participant availabilities, and even increase dropout rates. Digital tools are increasingly added to protocols to facilitate study conduct, but fully digitally run studies are still scarce. With the increasing interest in real-world studies, the development of health apps for mobile devices to monitor study outcomes is of great importance. The purpose of this real-world study was to develop a specific mobile app, Ingredients for Life, to conduct a 100% digital study testing the effectiveness of a hydrolyzed cartilage matrix (HCM) supplement on joint discomfort in a heterogeneous group of healthy, active consumers. The Ingredients for Life mobile app using a visual analog scale was specifically developed to monitor the variation in joint pain after exercise by the study participants. A total of 201 healthy and physically active women and men (18-72 years old) with joint pain completed the study over a period of 16 weeks. Participants were randomly allocated to the study groups and did not receive any dietary or lifestyle advice. Each participant indicated one area of joint pain and logged the type and duration of their weekly activities. They received blinded study supplements and took a daily regimen of 1 g of HCM (HCM group) or 1 g of maltodextrin (placebo group) for 12 weeks while weekly logging joint pain scores in the app. This was followed by a 4-week washout period during which participants continued reporting their joint pain scores (until the end of week 16). Joint pain was reduced within 3 weeks of taking a low dosage of HCM (1 g/day), regardless of gender, age group, and activity intensity when compared with the placebo group. After stopping supplementation, joint pain scores gradually increased but still remained significantly lower than those of the placebo group after 4 weeks of washout. The low dropout rate (<6% of participants, mainly in the placebo group) demonstrates that the digital study was well received by the study population. The digital tool allowed us to measure a heterogeneous group of active adults in a real-world setting (without any lifestyle intervention), thus promoting inclusivity and diversity. With low dropout rates, it demonstrates that mobile apps can generate qualitative, quantifiable, real-world data showcasing supplement effectiveness. The study confirmed that the oral intake of a low dose (1 g/day) of HCM led to a significant reduction of joint pain from 3 weeks after starting supplementation.

Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS–BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo , FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes. Bile acids exert metabolic effects by modulating FXR receptor activity. Here, Trabelsi et al. show that FXR negatively regulates production of the incretin GLP-1 in enteroendocrine L-cells by reducing glycolysis and that inhibition of FXR improves glucose metabolism by increasing GLP-1 in obese mice.

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis.

Purpose The primary aim of this study was to examine whether a glycine-rich collagen peptides (CP) supplement could enhance sleep quality in physically active men with self-reported sleep complaints. Methods In a randomized, crossover design, 13 athletic males (age: 24 ± 4 years; training volume; 7 ± 3 h·wk 1 ) with sleep complaints (Athens Insomnia Scale, 9 ± 2) consumed CP (15 g·day 1 ) or a placebo control (CON) 1 h before bedtime for 7 nights. Sleep quality was measured with subjective sleep diaries and actigraphy for 7 nights; polysomnographic sleep and core temperature were recorded on night 7. Cognition, inflammation, and endocrine function were measured on night 7 and the following morning. Subjective sleepiness and fatigue were measured on all 7 nights. The intervention trials were separated by ≥ 7 days and preceded by a 7-night familiarisation trial. Results Polysomnography showed less awakenings with CP than CON (21.3 ± 9.7 vs. 29.3 ± 13.8 counts, respectively; P = 0.028). The 7-day average for subjective awakenings were less with CP vs. CON (1.3 ± 1.5 vs. 1.9 ± 0.6 counts, respectively; P = 0.023). The proportion of correct responses on the baseline Stroop cognitive test were higher with CP than CON (1.00 ± 0.00 vs. 0.97 ± 0.05 AU, respectively; P = 0.009) the morning after night 7. There were no trial differences in core temperature, endocrine function, inflammation, subjective sleepiness, fatigue and sleep quality, or other measures of cognitive function or sleep (P > 0.05). Conclusion CP supplementation did not influence sleep quantity, latency, or efficiency, but reduced awakenings and improved cognitive function in physically active males with sleep complaints.