Background: Obesity among older adults has increased tremendously. Obesity accelerates ageing and predisposes to age‐related conditions and diseases, such as loss of endurance capacity, insulin resistance and features of the metabolic syndrome. Namely, ectopic lipids play a key role in the development of nonalcoholic fatty liver disease (NAFLD) and myosteatosis, two severe burdens of ageing and metabolic diseases. Adiponectin (ApN) is a hormone, mainly secreted by adipocytes, which exerts insulin‐sensitizing and fat‐burning properties in several tissues including the liver and the muscle. Its overexpression also increases lifespan in mice. In this study, we investigated whether an ApN receptor agonist, AdipoRon (AR), could slow muscle dysfunction, myosteatosis and degenerative muscle markers in middle‐aged obese mice. The effects on myosteatosis were compared with those on NAFLD.Methods: Three groups of mice were studied up to 62 weeks of age: One group received normal diet (ND), another, high‐fat diet (HFD); and the last, HFD combined with AR given orally for almost 1 year. An additional group of young mice under an ND was used. Treadmill tests and micro‐computed tomography (CT) were carried out in vivo. Histological, biochemical and molecular analyses were performed on tissues ex vivo. Bodipy staining was used to assess intramyocellular lipid (IMCL) and lipid droplet morphology.Results: AR did not markedly alter diet‐induced obesity. Yet, this treatment rescued exercise endurance in obese mice (up to 2.4‐fold, P < 0.05), an event that preceded the improvement of insulin sensitivity. Dorsal muscles and liver densities, measured by CT, were reduced in obese mice (−42% and −109%, respectively, P < 0.0001), suggesting fatty infiltration. This reduction tended to be attenuated by AR. Accordingly, AR significantly mitigated steatosis and cellular ballooning at liver histology, thereby decreasing the NALFD activity score (−30%, P < 0.05). AR also strikingly reversed IMCL accumulation either due to ageing in oxidative fibres (types 1/2a, soleus) or to HFD in glycolytic ones (types 2x/2b, extensor digitorum longus) (−50% to −85%, P < 0.05 or less). Size of subsarcolemmal lipid droplets, known to be associated with adverse metabolic outcomes, was reduced as well. Alleviation of myosteatosis resulted from improved mitochondrial function and lipid oxidation. Meanwhile, AR halved aged‐related accumulation of dysfunctional proteins identified as tubular aggregates and cylindrical spirals by electron microscopy (P < 0.05).Conclusions: Long‐term AdipoRon treatment promotes ‘healthy ageing’ in obese middle‐aged mice by enhancing endurance and protecting skeletal muscle and liver against the adverse metabolic and degenerative effects of ageing and caloric excess.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. Molecules developed to activate the bile acid-receptor TGR5 regulate pathways involved in MALFD pathogenesis, but the therapeutic value of TGR5 activation on the active form of MAFLD, non-alcoholic steatohepatitis (NASH), still needs to be evaluated. As TGR5 agonism is low in MAFLD, we used strategies to promote the production of endogenous TGR5 ligands or administered pharmacological TGR5 agonists, INT-777 and RO5527239, to study the effect of TGR5 activation on liver and metabolic diseases in high-fat diet-fed foz/foz mice. Although described in the literature, treatment with fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5 ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status. INT-777 and RO5527239 directly activated TGR5. INT-777 only increased the TGR5 activation capacity of the portal blood; RO5527239 also amplified the TGR5 activation capacity of systemic blood. Both molecules improved glucose tolerance. In spite of the TGR5 activation capacity, INT-777, but not RO5527239, reduced liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on glucose tolerance and MAFLD.

Bile acids exert diverse actions on host metabolism and immunity through bile acid-activated receptors, including Takeda G protein-coupled receptor 5 (TGR5). We have recently evidenced an alteration in bile acids in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. This current study aims to further explore the links emerging between bile acids and cancer cachexia. First, we showed that bile flow is reduced in cachectic mice. Next, comparing mice inoculated with cachexia-inducing and with non-cachexia-inducing C26 colon carcinoma cells, we demonstrated that alterations in the bile acid pathways and profile are directly associated with cachexia. Finally, we performed an interventional study using ursodeoxycholic acid (UDCA), a compound commonly used in hepatobiliary disorders, to induce bile acid secretion and decrease inflammation. We found that UDCA does not improve hepatic inflammation and worsens muscle atrophy in cachectic mice. This exacerbation of the cachectic phenotype upon UDCA was accompanied by a decreased TGR5 activity, suggesting that TGR5 agonists, known to reduce inflammation in several pathological conditions, could potentially counteract cachectic features. This work brings to light major evidence sustaining the emerging links between bile acids and cancer cachexia and reinforces the interest in studying bile acid-activated receptors in this context.

An imbalance between primary and secondary bile acids contributes to the development of metabolic dysfunction-associated steatohepatitis (MASH). The precise mechanisms underlying changes in the bile acid pool in MASH remain to be identified. As gut bacteria convert primary bile acids to secondary bile acids, we investigated the contribution of the gut microbiota and its metabolizing activities to bile acid alterations in MASH. To disentangle the influence of MASH from environmental and dietary factors, high-fat diet fed foz/foz mice were compared with their high-fat diet fed wildtype littermates. We developed functional assays (stable isotope labeling and in vitro experiments) to extend the analyses beyond a mere study of gut microbiota composition (16S rRNA gene sequencing). Key findings were confirmed in C57BL/6J mice were fed a Western and high-fructose diet, as an independent mouse model of MASH. Although mice with MASH exhibited lower levels of secondary 7α-dehydroxylated bile acids (3.5-fold lower, p = 0.0008), the gut microbial composition was similar in mice with and without MASH. Similar gut microbial bile salt hydrolase and 7α-dehydroxylating activities could not explain the low levels of secondary 7α-dehydroxylated bile acids. Furthermore, the 7α-dehydroxylating activity was unaffected by Clostridium scindens administration in mice with a non-standardized gut microbiota. By exploring alternative mechanisms, we identified an increased bile acid 7α-rehydroxylation mediated by liver CYP2A12 and CYP2A22 enzymes (4.0-fold higher, p <0.0001), that reduces secondary 7α-dehydroxylated bile acid levels in MASH. This study reveals a gut microbiota-independent mechanism that alters the level of secondary bile acids and contributes to the development of MASH in mice. Although changes in bile acid levels are implicated in the development of metabolic dysfunction-associated steatohepatitis (MASH), the precise mechanisms underpinning these alterations remain elusive. In this study, we investigated the mechanisms responsible for the changes in bile acid levels in mouse models of MASH. Our results support that neither the composition nor the metabolic activity of the gut microbiota can account for the alterations in the bile acid pool. Instead, we identified hepatic 7α-rehydroxylation of secondary bile acids as a gut microbiota-independent factor contributing to the reduced levels of secondary bile acids in mice with MASH. Further investigation is warranted to understand bile acid metabolism and its physiological implications in clinical MASH. Nonetheless, our findings hold promise for exploring novel therapeutic interventions for MASH.

Over the past 20 years, basic research has robustly demonstrated the regulatory role of bile acids in physiological processes, primarily by the discovery and the study of their specific receptors and the understanding of the pathways they modulate. The dysregulation of the bile acid pool and the perturbation of bile acid signaling have been implicated in the pathophysiology of various clinical conditions, including cardiometabolic, cholestatic and inflammatory diseases. Consequently, bile acids have emerged as promising therapeutic targets, with compounds to modulate bile acid metabolism and signaling being actively investigated in pre-clinical and clinical settings. Despite these advancements, much remains to be understood before bile acid metabolism and bile acid-regulated pathways can be effectively manipulated for health protection. As a step forward in this direction, Clinical Science has curated a themed collection on the new discoveries in bile acids, gut microbiota and host interactions in health and diseases. This collection emphasizes mechanistic research papers, connecting basic science to disease mechanisms, aiming to enhance the understanding of the role of bile acids in physiological and pathophysiological conditions.

Bile acids are signaling mediators, enabling intricate communication between tissues and the gut microbiota, and are involved in the pathophysiology of several immune and metabolic disorders. In this commentary, we discuss the importance of the gut microbiota in the Cyp2c70 knock-out mice, which are considered as a promising ‘humanized’ experimental resource for studying bile acids and their role in pathological conditions. We also discuss how Cyp2c70-deficient mice contribute to enhancing the translatability of preclinical studies in murine models to humans.