Influence of aging, macronutrient composition and time-restricted feeding on the rat gut microbiome

Abstract Declining health and cognition are hallmarks of advanced age that reduce both the quality and length of the lifespan. While caloric restriction has been highlighted as a strategy for increasing healthspan, time-restricted feeding and changes in dietary macronutrient composition may be more feasible alternatives with similar health outcomes. Furthermore, age-related changes in gut microbiome composition may reciprocally interact with several physiological systems – providing a good target for future therapeutic interventions. To begin to investigate the potential utility of a ketogenic (high fat, low carbohydrate) diet and/or time-restricted feeding, fully mature young (5 mo) and older (22 mo) adult male Fischer Brown Norway Hybrid rats were placed on a time-restricted feeding regimen of a ketogenic or micronutrient and calorically matched control diet for 7 months. A third group of rats was permitted to eat standard chow ad libitum. Fecal samples collected at the conclusion of the study were submitted for 16S microbiome analysis, which revealed significant differences across age and diet groups, as well as across feeding paradigms. Beta diversity analysis demonstrated distinct microbiome composition across the three diet groups regardless of age. Furthermore, diet group significantly impacted abundance in expression of several microbiota at the phylum level, including Verrucomicrobia, Cyanobacteria, Actinobacteria and Patescibacteria, though age did not. Verrucomicrobia was significantly increased (p=0.02) and Actinobacteria and Patescibacteria (p<0.01) were significantly decreased in animals fed in a time-restricted fashion. These results indicate the value of both altered macronutrient composition and altered feeding methodology for therapeutic interventions targeting the gut microbiome.

Download Full-text

Time-restricted feeding from adulthood to old age improves biconditional associative learning in geriatric rats regardless of macronutrient composition

10.1101/2020.02.06.937532 ◽

2020 ◽

Author(s):

Abbi R. Hernandez ◽

Quinten P. Federico ◽

Sara N. Burke

Keyword(s):

Dietary Intervention ◽

Small Sample Size ◽

Control Diet ◽

Small Sample ◽

Restricted Feeding ◽

Macronutrient Composition ◽

Mature Adult ◽

Age Related ◽

Feeding Regimen ◽

Ad Libitum

AbstractDeclining health and cognition are hallmarks of advanced age that reduce both the quality and length of the lifespan. While caloric restriction has been highlighted as a dietary intervention capable of improving the healthspan by restoring metabolic function in late life, time-restricted feeding and changes in dietary macronutrient composition may be more feasible alternatives with similar health outcomes. To investigate the potential of these two interventions, a pilot cohort of fully mature adult rats were placed on a time-restricted feeding regimen of a ketogenic or micronutrient and calorically matched control diet from 8 to 21 months of age. A third group of rats was permitted to eat standard chow ad libitum. At 22 months, all rats were then placed on time-restricted feeding and tested on a biconditional association task. While the data presented here are preliminary (small sample size of 3-4/diet group), additional animals are currently undergoing the feeding regimen, and will be added into the behavioral studies at a later date. For the current data, regardless of dietary composition, time-restricted-fed rats performed significantly better than ad libitum-fed rats. This observation could not be accounted for by differences in motivation, procedural or sensorimotor impairments, indicating that mid-life dietary interventions capable of preventing metabolic impairments may also serve to prevent age-related cognitive decline.

Download Full-text

Polyphenol Supplementation Reverses Age-Related Changes in Microglial Signaling Cascades

International Journal of Molecular Sciences ◽

10.3390/ijms22126373 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6373

Author(s):

Ahmad Jalloh ◽

Antwoine Flowers ◽

Charles Hudson ◽

Dale Chaput ◽

Jennifer Guergues ◽

...

Keyword(s):

Protein Interactions ◽

Control Diet ◽

Bioinformatic Analysis ◽

Diet Group ◽

Differentially Expressed ◽

Signaling Cascades ◽

Complex Nature ◽

Differentially Expressed Proteins ◽

Ms Analysis ◽

Age Related

Microglial activity in the aging neuroimmune system is a central player in aging-related dysfunction. Aging alters microglial function via shifts in protein signaling cascades. These shifts can propagate neurodegenerative pathology. Therapeutics require a multifaceted approach to understand and address the stochastic nature of this process. Polyphenols offer one such means of rectifying age-related decline. Our group used mass spectrometry (MS) analysis to explicate the complex nature of these aging microglial pathways. In our first experiment, we compared primary microglia isolated from young and aged rats and identified 197 significantly differentially expressed proteins between these groups. Then, we performed bioinformatic analysis to explore differences in canonical signaling cascades related to microglial homeostasis and function with age. In a second experiment, we investigated changes to these pathways in aged animals after 30-day dietary supplementation with NT-020, which is a blend of polyphenols. We identified 144 differentially expressed proteins between the NT-020 group and the control diet group via MS analysis. Bioinformatic analysis predicted an NT-020 driven reversal in the upregulation of age-related canonical pathways that control inflammation, cellular metabolism, and proteostasis. Our results highlight salient aspects of microglial aging at the level of protein interactions and demonstrate a potential role of polyphenols as therapeutics for age-associated dysfunction.

Download Full-text

Long-Term Feeding of a High-Fat Diet Ameliorated Age-Related Phenotypes in SAMP8 Mice

Nutrients ◽

10.3390/nu12051416 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1416

Author(s):

Hideaki Oike ◽

Yukino Ogawa ◽

Kayo Azami

Keyword(s):

Control Diet ◽

Active Phase ◽

Restricted Feeding ◽

Long Term Effects ◽

High Fat ◽

Night Time ◽

Age Related ◽

Nutritional Studies ◽

Samp8 Mice

High-fat diets (HFD) have been thought to increase the risk of obesity and metabolic syndrome, as well as shorten lifespan. On the other hand, chrono-nutritional studies have shown that time-restricted feeding during active phase significantly suppresses the induction of HFD-induced obesity in mouse model. However, the long-term effects of time-restricted HFD feeding on aging are unknown. Therefore, in this study, we set up a total of four groups: mutual combination of ad libitum feeding or night-time-restricted feeding (NtRF) and an HFD or a control diet. We examined their long-term effects in a senescence-accelerated mouse strain, SAMP8, for over a year. Hearing ability, cognitive function, and other behavioral and physiological indexes were evaluated during the study. Unexpectedly, SAMP8 mice did not show early onset of death caused by the prolonged HFD intake, and both HFD and NtRF retarded age-related hearing loss (AHL). NtRF improved grip strength and cognitive memory scores, while HFD weakly suppressed age-related worsening of the appearance scores associated with the eyes. Notably, the HFD also retarded the progression of AHL in both DBA/2J and C57BL/6J mice. These results suggest that HFD prevents aging unless metabolic disorders occur and that HFD and NtRF are independently effective in retarding aging; thus, the combination of HFD and chrono-nutritional feeding may be an effective anti-aging strategy.

Download Full-text

Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

10.7287/peerj.preprints.1754v1 ◽

2016 ◽

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Introduction Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging”. While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of the study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model. Results We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age, and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 also stratify individuals by age. Discussion Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

Download Full-text

Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.658972 ◽

2021 ◽

Vol 15 ◽

Author(s):

Richard A. Altschuler ◽

Lisa Kabara ◽

Catherine Martin ◽

Ariane Kanicki ◽

Courtney E. Stewart ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Outer Hair Cell ◽

Control Diet ◽

Cell Loss ◽

Diet Group ◽

Age Related ◽

Significant Difference ◽

Basal Half ◽

And Control

Our previous study demonstrated rapamycin added to diet at 4 months of age had significantly less age-related outer hair cell loss in the basal half of the cochlea at 22 months of age compared to mice without rapamycin. The present study tested adding rapamycin to diet later in life, at 14 months of age, and added a longitudinal assessment of auditory brain stem response (ABR). The present study used UMHET4 mice, a 4 way cross in which all grandparental strains lack the Cdh23753A allele that predisposes to early onset, progressive hearing loss. UMHET4 mice typically have normal hearing until 16–17 months, then exhibit threshold shifts at low frequencies/apical cochlea and later in more basal high frequency regions. ABR thresholds at 4, 12, 24, and 48 kHz were assessed at 12, 18, and 24 months of age and compared to baseline ABR thresholds acquired at 5 months of age to determine threshold shifts (TS). There was no TS at 12 months of age at any frequency tested. At 18 months of age mice with rapamycin added to diet at 14 months had a significantly lower mean TS at 4 and 12 kHz compared to mice on control diet with no significant difference at 24 and 48 kHz. At 24 months of age, the mean 4 kHz TS in rapamycin diet group was no longer significantly lower than the control diet group, while the 12 kHz mean remained significantly lower. Mean TS at 24 and 48 kHz in the rapamycin diet group became significantly lower than in the control diet group at 24 months. Hair cell counts at 24 months showed large loss in the apical half of most rapamycin and control diet mice cochleae with no significant difference between groups. There was only mild outer hair cell loss in the basal half of rapamycin and control diet mice cochleae with no significant difference between groups. The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.

Download Full-text

Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

PeerJ ◽

10.7717/peerj.1854 ◽

2016 ◽

Vol 4 ◽

pp. e1854 ◽

Cited By ~ 47

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Introduction.Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging.” While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of our study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model.Results.We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 stratify individuals by age.Discussion.Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

Download Full-text

Consumption of a Western-Style Diet Modulates the Response of the Murine Gut Microbiome to Ciprofloxacin

mSystems ◽

10.1128/msystems.00317-20 ◽

2020 ◽

Vol 5 (4) ◽

Cited By ~ 1

Author(s):

Damien J. Cabral ◽

Jenna I. Wurster ◽

Benjamin J. Korry ◽

Swathi Penumutchu ◽

Peter Belenky

Keyword(s):

Gut Microbiome ◽

Transcriptional Activity ◽

Control Diet ◽

Structure And Function ◽

Western Diet ◽

Content Type ◽

Microbiome Composition ◽

Host Diet ◽

And Function ◽

The Impact

ABSTRACT Dietary composition and antibiotic use have major impacts on the structure and function of the gut microbiome, often resulting in dysbiosis. Despite this, little research has been done to explore the role of host diet as a determinant of antibiotic-induced microbiome disruption. Here, we utilize a multi-omic approach to characterize the impact of Western-style diet consumption on ciprofloxacin-induced changes to gut microbiome structure and transcriptional activity. We found that Western diet consumption dramatically increased Bacteroides abundances and shifted the community toward the metabolism of simple sugars and mucus glycoproteins. Mice consuming a Western-style diet experienced a greater expansion of Firmicutes following ciprofloxacin treatment than those eating a control diet. Transcriptionally, we found that ciprofloxacin reduced the abundance of tricarboxylic acid (TCA) cycle transcripts on both diets, suggesting that carbon metabolism plays a key role in the response of the gut microbiome to this antibiotic. Despite this, we observed extensive diet-dependent differences in the impact of ciprofloxacin on microbiota function. In particular, at the whole-community level we detected an increase in starch degradation, glycolysis, and pyruvate fermentation following antibiotic treatment in mice on the Western diet, which we did not observe in mice on the control diet. Similarly, we observed diet-specific changes in the transcriptional activity of two important commensal bacteria, Akkermansia muciniphila and Bacteroides thetaiotaomicron, involving diverse cellular processes such as nutrient acquisition, stress responses, and capsular polysaccharide (CPS) biosynthesis. These findings demonstrate that host diet plays a role in determining the impacts of ciprofloxacin on microbiome composition and microbiome function. IMPORTANCE Due to the growing incidence of disorders related to antibiotic-induced dysbiosis, it is essential to determine how our “Western”-style diet impacts the response of the microbiome to antibiotics. While diet and antibiotics have profound impacts on gut microbiome composition, little work has been done to examine their combined effects. Previous work has shown that nutrient availability, influenced by diet, plays an important role in determining the extent of antibiotic-induced disruption to the gut microbiome. Thus, we hypothesize that the Western diet will shift microbiota metabolism toward simple sugar and mucus degradation and away from polysaccharide utilization. Because of bacterial metabolism’s critical role in antibiotic susceptibility, this change in baseline metabolism will impact how the structure and function of the microbiome are impacted by ciprofloxacin exposure. Understanding how diet modulates antibiotic-induced microbiome disruption will allow for the development of dietary interventions that can alleviate many of the microbiome-dependent complications of antibiotic treatment.

Download Full-text

Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

10.7287/peerj.preprints.1754 ◽

2016 ◽

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Download Full-text

Long-Term Blackcurrant Supplementation Modified Gut Microbiome Profiles in Mice in an Age-Dependent Manner: An Exploratory Study

Nutrients ◽

10.3390/nu12020290 ◽

2020 ◽

Vol 12 (2) ◽

pp. 290 ◽

Cited By ~ 1

Author(s):

Lei Cao ◽

Sang Gil Lee ◽

Melissa M. Melough ◽

Junichi R. Sakaki ◽

Kendra R. Maas ◽

...

Keyword(s):

Gut Microbiome ◽

Beta Diversity ◽

Age Groups ◽

Dependent Manner ◽

16S Sequencing ◽

Microbiome Composition ◽

Age Related ◽

Regulatory Effects ◽

Old Mice ◽

Young Mice

Recent studies have suggested that blackcurrant (BC) anthocyanins have promising health benefits, possibly through regulating gut microbiome. Three- and eighteen-month old female mice were fed standard mouse diets for 4 months, each with or without BC (1% w/w) supplementation (n = 3 in each treatment group, 12 in total). We then assessed gut microbiome profiles using 16S sequencing of their feces. Old mice had a less diverse microbiome community compared to young mice and there was a remarkable age-related difference in microbiome composition in the beta diversity analysis. BC supplementation did not significantly affect alpha or beta diversity. The relative abundance of several phyla, including Firmicutes, Bacteroidetes, Proteobacteria and Tenericutes, was lower in old mice. BC downregulated Firmicutes abundance in young mice and upregulated Bacteroidetes in both age groups, leading to a decreased Firmicutes/Bacteroidetes ratio. There were age-specific differences in the effect of BC supplementation on the microbiome. Twenty-four operational taxonomic units showed a significant interaction between age and BC supplementation (p < 0.01), which suggests that the ecosystem and the host health status affect the functions and efficiency of BC intake. These results indicate that BC supplementation favorably modulates gut microbiome, but there are distinct age-specific differences. Studies with human hosts are needed to better understand BC’s regulatory effects on the gut microbiome.

Download Full-text

Consumption of a Western-style diet modulates the response of the murine gut microbiome to ciprofloxacin

10.1101/780049 ◽

2019 ◽

Author(s):

Damien J. Cabral ◽

Jenna I. Wurster ◽

Benjamin J. Korry ◽

Swathi Penumutchu ◽

Peter Belenky

Keyword(s):

Antibiotic Treatment ◽

Stress Responses ◽

Gut Microbiome ◽

Transcriptional Activity ◽

Control Diet ◽

Transcriptional Level ◽

Microbiome Composition ◽

Host Diet ◽

And Function ◽

The Impact

AbstractDietary composition and antibiotic use are known to have major impacts on the structure and function of the gut microbiome, often resulting in dysbiosis. Despite this, little research has been done to explore the role of host diet as a determinant of antibiotic-induced microbiome disruption.Here, we utilize a multi-omic approach to characterize the impact of Western-style diet consumption on ciprofloxacin-induced changes to gut microbiome community structure and transcriptional activity. We found that mice consuming a Western-style diet experienced a greater expansion of Firmicutes following ciprofloxacin treatment than those eating a control diet. At the transcriptional level, we found that ciprofloxacin induced a reduction in the abundance of TCA cycle transcripts on both diets, suggesting that carbon metabolism plays a key role in the response of the gut microbiome to this antibiotic. Despite this shared response, we observed extensive differences in the response of the microbiota to ciprofloxacin on each diet. In particular, at the whole-community level we detected an increase in starch degradation, glycolysis, and pyruvate fermentation following antibiotic treatment in mice on the Western diet, which we did not observe in mice on the control diet. Similarly, we observed diet-specific changes in the transcriptional activity of two important commensal bacteria, Akkermansia muciniphila and Bacteroides thetaiotaomicron, involving diverse cellular processes such as nutrient acquisition, stress responses, and capsular polysaccharide (CPS) biosynthesis. These findings demonstrate that host diet plays a key role in determining the extent of disruption of microbiome composition and function induced by antibiotic treatment.ImportanceWhile both diet and antibiotics are individually known to have profound impacts on gut microbiome composition, little work has been done to examine the effect of these two factors combined. A number of negative health outcomes, including diabetes and obesity, are associated with diets high in simple sugars in fats but low in host-indigestible fiber, and some of these outcomes may be mediated by the gut microbiome. Likewise, treatment with broad-spectrum antibiotics and the resulting dysbiosis is associated with many of the same detrimental side effects. Previous work has shown that nutrient availability, as influenced by host diet, plays an important role in determining the extent of antibiotic-induced disruption to the gut microbiome. Due to the growing incidence of disorders related to antibiotic-induced dysbiosis, it is essential to determine how the prevalence of high fat and sugar “Western”-style diets impacts the response of the microbiome to antibiotics.

Download Full-text