Administration time effect of dietary proanthocyanidins on the metabolome of Fischer 344 rats is sex- and diet-dependent

Proanthocyanidins (PAs) are one of the most commonly ingested polyphenols in the human diet, with a wide range of beneficial health effects. Remarkably, PAs have been reported to influence core and peripheral clock genes expression, and their effects may change in a time-of-day dependent manner. Therefore, the aim of this study was to investigate whether the capacity of PAs to modulate the metabolome is conditioned by the time-of-day in which these compounds are consumed in a diet- and sexdependent manner. To do this, a grape seed proanthocyanidin extract (GSPE) was administered to female and male Fischer 344 rats at ZT0 (in the morning) and ZT12 (at night) and the GSPE administration time effect was evaluated on clock genes expression, melatonin hormone and serum metabolite levels in a healthy and obesogenic context. The results showed an administration time effect of GSPE on the metabolome in a sex and diet-dependent manner. Specifically, there was an effect on amino acid, lipid and cholate metabolite levels that correlated with the central clock genes expression. Therefore, this study shows a strong influence of sex and diet on the PAs effects on the metabolome, modulated in turn by the time-of-day

Impact of Seasonal rhythms on gut microbiota: influence on proanthocyanidins functionality in obesity

Els ritmes biològics són crucials per adaptar els processos fisiològics i metabòlics de l'organisme al moment del dia (ritmes circadians) o de l'any (ritmes estacionals). Aquesta sincronització és duta a terme per senyals externs (Zeitgeber), sent la llum més important. En aquest context, la microbiota intestinal, que exerceix un paper molt important en el manteniment de l'homeòstasi de l'organisme, es pot veure modulada pels canvis en la durada de llum del dia (fotoperíode). Aquest fet és de gran rellevància, ja que la microbiota intestinal està implicada en el metabolisme de compostos bioactius, com les proantocinidides (PAs), un dels polifenols més abundants de la dieta occidental, els quals han demostrat efectes beneficiosos en trastorns metabòlics com la obesitat. Per tant, la funcionalitat d'aquestes PAs podria variar segons el moment de l'any o fins i tot del dia en què són administrades. Per això, aquesta tesi té com a objectiu estudiar la relació entre els ritmes estacionals, els quals han estat menys estudiats que els circadians, i la microbiota intestinal, i el seu impacte a la funcionalitat de les PAs en un context d'obesitat. Per això, es va estudiar la influència dels ritmes estacionals a la composició microbiana intestinal i altres paràmetres fisiològics en rates Fischer 344 sanes i obeses (alimentades amb dieta de cafeteria), i es va avaluar l'efecte de l'administració de PAs en diferents condicions de disbiosi intestinal.Los ritmos biológicos son cruciales para adaptar los procesos fisiológicos y metabólicos del organismo al momento del día (ritmos circadianos) o del año (ritmos estacionales). Esta sincronización es llevada a cabo por señales externas (Zeitgeber), siendo la luz más importante. En este contexto, la microbiota intestinal, la cual desempeña un papel muy importante en el mantenimiento de la homeostasis del organismo, puede verse modulada por los cambios en la duración de luz del día (fotoperiodo). Este hecho es de gran relevancia, ya que la microbiota intestinal está implicada en el metabolismo de compuestos bioactivos, como las proantocinididas (PAs), uno de los polifenoles más abundantes de la dieta occidental, los cuales han demostrado efectos beneficiosos en trastornos metabólicos como la obesidad. Por tanto, la funcionalidad de estas PAs podría variar según el momento del año o incluso del día en el que son administradas. Por ello, esta tesis tiene como objetivo estudiar la relación entre los ritmos estacionales, los cuales han sido menos estudiados que los circadianos, y la microbiota intestinal, y su impacto en la funcionalidad de las PAs en un contexto de obesidad. Para ello, se estudió la influencia de los ritmos estacionales en la composición microbiana intestinal y otros parámetros fisiológicos en ratas Fischer 344 sanas y obesas (alimentadas con dieta de cafetería), y se evaluó el efecto de la administración de PAs en diferentes condiciones de disbiosis intestinal.Biological rhythms are crucial to adjust the physiological and metabolic processes of the organism to the time of day (circadian rhythms) or year (seasonal rhythms). This synchronization is orchestrated by external signals (Zeitgeber), being the light the most important one. In this context, the gut microbiota, which plays an important role to maintaining the homeostasis of the organism, can be modulated by changes in the light length of the day (photoperiod). This fact is of great relevance due to the gut microbiota is involved in the metabolism of bioactive compounds, such as proanthocyanidins (PAs), which are the most abundant polyphenols in western diet. In fact, these compounds have shown beneficial effects on metabolic disorders such as obesity. Therefore, the functionality of these PAs could be influenced by the time of the year or even the day in which they are administered. Hence, this thesis aims to study the relationship between seasonal rhythms, which have been less studied than circadian rhythms, gut microbiota, and their impact on the functionality of PAs in obesity. To do this, we studied the influence of seasonal rhythms on gut microbiota composition and other physiological parameters in healthy and cafeteria-induced obese Fischer 344 rats, and evaluated the effect of PAs administration in different conditions of gut microbiota dysbiosis. The results showed that seasonal rhythms alter the composition of the gut microbiota, which was associated with changes in weight, glucose tolerance, and levels of oxylipins (inflammatory mediators)

Gut Seasons: Photoperiod Effects on Fecal Microbiota in Healthy and Cafeteria-Induced Obese Fisher 344 Rats

Gut microbiota and biological rhythms are emerging as key factors in the modulation of several physiological and metabolic processes. However, little is known about their interaction and how this may affect host physiology and metabolism. Several studies have shown oscillations of gut microbiota that follows a circadian rhythmicity, but, in contrast, variations due to seasonal rhythms have not been sufficiently investigated yet. Thus, the goal of this study was to investigate the impact of different photoperiods, which mimic seasonal changes, on fecal microbiota composition and how this interaction affects diet-induced obesity development. To this aim, Fisher 344 male rats were housed under three photoperiods (L6, L12 and L18) and fed with standard chow diet or cafeteria diet (CAF) for 9 weeks. The 16S ribosomal sequencing of collected fecal samples was performed. The photoperiod exposure significantly altered the fecal microbiota composition under L18, especially in CAF-fed rats. Moreover, these alterations were associated with changes in body weight gain and different fat parameters. These findings suggest a clear impact of seasonal rhythms on gut microbiota, which ultimately translates into different susceptibilities to diet-induced obesity development. This is the first time to our knowledge that the photoperiod impact on gut microbiota composition has been described in an obesity context although further studies are needed in order to elucidate the mechanisms involved

Photoperiod Conditions Modulate Serum Oxylipins Levels in Healthy and Obese Rats: Impact of Proanthocyanidins and Gut Microbiota

Seasonal rhythms are emerging as a key factor influencing gut microbiota and bioactive compounds functionality as well as several physiological processes such as inflammation. In this regard, their impact on the modulation of oxylipins (OXLs), which are important lipid mediators of inflammatory processes, has not been investigated yet. Hence, we aimed to investigate the effects of photoperiods on OXLs metabolites in healthy and obesogenic conditions. Moreover, we evaluated if the impact of proanthocyanidins and gut microbiota on OXLs metabolism is influenced by photoperiod in obesity. To this purpose, Fischer 344 rats were housed under different photoperiod conditions (L6: 6 h light, L12: 12 h light or L18:18 h light) and fed either a standard chow diet (STD) or a cafeteria diet (CAF) for 9 weeks. During the last 4 weeks, obese rats were daily administered with an antibiotic cocktail (ABX), an oral dose of a grape seed proanthocyanidin extract (GSPE), or with their combination. CAF feeding and ABX treatment affected OXLs in a photoperiod dependent-manner. GSPE significantly altered prostaglandin E2 (PGE2) levels, only under L6 and mitigated ABX-mediated effects only under L18. In conclusion, photoperiods affect OXLs levels influenced by gut microbiota. This is the first time that the effects of photoperiod on OXLs metabolites have been demonstrated.Ministerio de Ciencia e Innovación AGL2016-77105-RDiputación de Tarragona 2021PGR-DIPTA-URV09Universitat Rovira i Virgili PMF-PIPF-35, EJ2018-002778-