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Gut microbiota: Changes throughout the lifespan from infancy to elderly

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Abstract

Our understanding of the composition and function of the human gut microbiota has improved dramatically in recent years. In this review, major milestones along this path will be reviewed. The methodological developments that underpinned this acceleration of scientific progress are discussed. We review the infant microbiota with special reference to colonization, succession and stabilization events. The healthy adult microbiota is then described, including reference to selected conditions that perturb the microbiota such as antibiotic treatment, bowel dysfunction and obesity. We put special emphasis on the special issues that characterize elderly subjects, including the challenges provided by “inflamm-aging”, with reference to how the microbiota might interact with these processes. Lastly, the elderly intestinal metagenomics project ELDERMET is described, which aims to establish the composition and function of the gut microbiota in several hundred Irish subjects.

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... From lifespan experiments in animals [109,110] to the analysis of the microbiome over the human lifespan (for an overview, see [111,112]) and of centenarians [113,114], a plethora of evidence shows that the microbiome is not only associated with diseases, e.g., gastrointestinal diseases such as IBS (for an overview, see [115]) and IBD (for an overview, see [116]), diabetes, metabolic liver disease [117], and allergies (for an overview, see [118]), but also aging (for an overview, see [119]) and inflammaging (for an overview, see [8]). ...
... When evaluating the microbiome, two factors are commonly considered that have a substantial impact on health and disease: stability and diversity, with a more stable and diverse microbiome generally being associated with better health (for an overview, see [120]). Starting with birth [121], the individual microbiome is subject to change throughout life [111,122]. The greatest alterations occur during our infancy when the personal microbiome is in its developing stage. ...
... This stage is followed by the adult microbiome, which has the highest stability. With further aging, the microbiome becomes again less stable (Figure 3) [123] (and for an overview, see [111,124,125]). . Stability of microbiota composition over the lifetime. ...
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The intestinal barrier, composed of the luminal microbiota, the mucus layer, and the physical barrier consisting of epithelial cells and immune cells, the latter residing underneath and within the epithelial cells, plays a special role in health and disease. While there is growing knowledge on the changes to the different layers associated with disease development, the barrier function also plays an important role during aging. Besides changes in the composition and function of cellular junctions, the entire gastrointestinal physiology contributes to essential age-related changes. This is also reflected by substantial differences in the microbial composition throughout the life span. Even though it remains difficult to define physiological age-related changes and to distinguish them from early signs of pathologies, studies in centenarians provide insights into the intestinal barrier features associated with longevity. The knowledge reviewed in this narrative review article might contribute to the definition of strategies to prevent the development of diseases in the elderly. Thus, targeted interventions to improve overall barrier function will be important disease prevention strategies for healthy aging in the future.
... Microbiome alteration occurs throughout human life and plays an important role in health and wellbeing 27 . Microbiome changes with age, antibiotics use and the prevalence of diseases. ...
... However, the mechanism regarding age-associated DC tolerance is not clear.The studies are required to find out the reasons behind this phenomenon. Contradictory observations have been reported on the differences in the microbiome between young and old subjects, especially the presence of Bifidobacterium, Ruminococcus, and Bacteroides 27 . ...
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Aging is an inevitable natural process that impacts every individual, and understanding its effect on the gut microbiome and dendritic cell (DC) functionality in elderly subjects is crucial. DCs are vital antigen-presenting cells (APCs) that orchestrate the immune response, maintaining immune tolerance to self-antigens and bridging innate and adaptive immunity. With aging, there is a shift toward nonspecific innate immunity, resulting in a decline in adaptive immune responses. This alteration raises significant concerns about managing the health of an elderly population. However, the precise impact of aging and microbiome changes on DC function and their implications in lung-associated diseases remain relatively understudied. To illuminate this subject, we will discuss recent advancements in understanding the connections between aging, gut dysbiosis, DCs, and lung diseases. Emphasizing the key concepts linking age-related gut microbiome changes and DC functions, we will focus on their relevance to overall health and immune response in elderly individuals. This article aims to improve our understanding of the intricate relationship between aging, gut microbiome, and DCs, potentially benefiting the management of age-associated diseases and promoting healthy aging.
... Our sequencing results of the gut microbiome indicated dysbiosis in HDGECs at both baseline and follow-up, demonstrating consistency of group gut microbiome differences between HDGECs and HCs. Stability of the gut microbiome has been supported in previous research, where across the lifespan, gut microbiome composition develops in childhood, becoming stable and resilient in early adulthood [48]. Most adults develop a 'core' set of microbiota, and disruption to the constitution of this 'core' micro-biota in adulthood is thought to occur in the context of underlying disease processes or medical interventions (e.g., chemotherapy), which disrupts the richness, evenness, and composition of the microbiome [48]. ...
... Stability of the gut microbiome has been supported in previous research, where across the lifespan, gut microbiome composition develops in childhood, becoming stable and resilient in early adulthood [48]. Most adults develop a 'core' set of microbiota, and disruption to the constitution of this 'core' micro-biota in adulthood is thought to occur in the context of underlying disease processes or medical interventions (e.g., chemotherapy), which disrupts the richness, evenness, and composition of the microbiome [48]. Longitudinal characterization of the gut microbiome in HD is needed to establish signature HD gut microbiome differences. ...
Article
Background: Gastrointestinal symptoms are clinical features of Huntington's disease (HD), which adversely affect people's quality of life. We recently reported the first evidence of gut dysbiosis in HD gene expansion carriers (HDGECs). Here, we report on a randomized controlled clinical trial of a 6-week probiotic intervention in HDGECs. Objective: The primary objective was to determine whether probiotics improved gut microbiome composition in terms of richness, evenness, structure, and diversity of functional pathways and enzymes. Exploratory objectives were to determine whether probiotic supplementation improved cognition, mood, and gastrointestinal symptoms. Methods: Forty-one HDGECs, including 19 early manifest and 22 premanifest HDGECs were compared with 36 matched-healthy controls (HCs). Participants were randomly assigned probiotics or placebo and provided fecal samples at baseline and 6-week follow-up, which were sequenced using 16S-V3-V4 rRNA to characterize the gut microbiome. Participants completed a battery of cognitive tests and self-report questionnaires measuring mood and gastrointestinal symptoms. Results: HDGECs had altered gut microbiome diversity when compared to HCs, indicating gut dysbiosis. Probiotic intervention did not ameliorate gut dysbiosis or have any effect on cognition, mood, or gastrointestinal symptoms. Gut microbiome differences between HDGECs and HCs were unchanged across time points, suggesting consistency of gut microbiome differences within groups. Conclusion: Despite the lack of probiotic effects in this trial, the potential utility of the gut as a therapeutic target in HD should continue to be explored given the clinical symptomology, gut dysbiosis, and positive results from probiotics and other gut interventions in similar neurodegenerative diseases.
... This, in turn, triggers a systemic inflammatory response that weakens the blood-brain barrier (BBB) and promotes inflammation in the central nervous system (CNS) [37]. Chronic inflammation in the CNS causes prolonged activation of glial cells, which generate cytokines and neurotoxins, leading to neural degeneration [38]. The microbiota can regulate these processes [39]. ...
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Introduction: The gut microbiota plays an important role in regulating the function of the gut-brain axis. Incorrect dietary habits promote the development of metabolic syndrome, which negatively affects the biodiversity of the microbiome. The aim of the study was to determine the influence of the gut microbiota on the function of the gut-brain axis and the development of mental and neurodegenerative diseases. Material and methods: A review of available literature was performed by searching the official databases PubMed and Google Scholar using the following keywords: metabolic syndrome, gut microbiome, metabolic microbiome, mental illness, neurodegenerative diseases with reference to original papers, meta-analyses and reviews in Polish, Ukrainian and English published in scientific journals and articles. Results: Studies evaluating the role of gut microbiota in the pathogenesis of psychiatric and neurodegenerative diseases show promising results, suggesting that gut microbiota influences brain function by modulating the gut-brain axis, the immune system, and neurotransmitter production. Despite the growing evidence implicating microbiota in the development of diseases such as depression, schizophrenia, Alzheimer's disease, and Parkinson's disease, study results often remain inconsistent, which may be due to methodological differences, heterogeneity of study populations, and sample size limitations. Conclusions: Further research on the influence of gut microbiota on the development of psychiatric and neurodegenerative diseases may contribute to a better understanding of the pathophysiology of these disorders and the discovery of new strategies for their treatment and prevention. Further research in this direction is needed to better understand the influence of gut microbiota on psychiatric and neurodegenerative disorders. Keywords: metabolic syndrome, mental illness, neurodegenerative diseases, gut microbiome, metabolic microbiome Abbreviations: International Diabetes Federation (IDF), short-chain fatty acids (SCFA), peptide YY (PYY), glucagon-like peptide-1 agonist (GLP-1), adenosine triphosphate (ATP), blood-brain barrier (BBB), central nervous system (CNS), Alzheimer's disease (AD), pathogen-associated molecular patterns (PAMPs), Toll-like receptors (TLRs), autism spectrum disorder (ASD), social anxiety disorder (SAD), bipolar disorder (BD), Young's Mania Rating Scale (YMRS), World Health Organization (WHO), Parkinson’s disease (PD), attention deficit hyperactivity disorder (ADHD)
... NGPs have the potential to be tailored to individual needs, based on the composition of the microbiome and the specific disease being treated. 8 They can also be designed to survive GIT's harsh conditions and have greater stability and viability. Eventually, advances in high-throughput sequencing and bioinformatics such as metagenomic sequencing to identify potential NGPs, 9 functional annotation studies for metabolic pathway analysis, 10 Genome-Wide Association Studies (GWAS) for host-microbe interaction, 11 and transcriptome analysis 12 enabled the identification of new microbial strains with potential health benefits that can serve as candidates for NGPs. ...
Article
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The burgeoning field of microbiome research has profoundly reshaped our comprehension of human health, particularly highlighting the potential of probiotics and fecal microbiota transplantation (FMT) as therapeutic interventions. While the benefits of traditional probiotics are well-recognized, the efficacy and mechanisms remain ambiguous, and FMT’s long-term effects are still being investigated. Recent advancements in high-throughput sequencing have identified gut microbes with significant health benefits, paving the way for next-generation probiotics (NGPs). These NGPs, engineered through synthetic biology and bioinformatics, are designed to address specific disease states with enhanced stability and viability. This review synthesizes current research on NGP stability, challenges in delivery, and their applications in preventing and treating chronic diseases such as diabetes, obesity, and cardiovascular diseases. We explore the physiological characteristics, safety profiles, and mechanisms of action of various NGP strains while also addressing the challenges and opportunities presented by their integration into clinical practice. The potential of NGPs to revolutionize microbiome-based therapies and improve clinical outcomes is immense, underscoring the need for further research to optimize their efficacy and ensure their safety.
... Aging is believed to be a complex, multi-factorial phenomenon with progressive decline in several physiological functions including in the gastrointestinal and immune system 11,12 . Not surprisingly, many studies have therefore identified correlations between gut microbiome composition and age 13,14 . For example, in recent work, Zhang et al. 15 have shown that there are distinct age and gender-associated trajectories in the gut microbiome that are consistent across populations. ...
Article
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While rapid demographic changes in Asia are driving the incidence of chronic aging-related diseases, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun-metagenomic sequencing for high-resolution taxonomic and functional characterization of their gut microbiomes (n = 234). Joint species-level analysis with other Asian cohorts identified distinct age-associated shifts characterized by reduction in microbial richness, and specific Alistipes and Bacteroides species enrichment (e.g., Alistipes shahii and Bacteroides xylanisolvens). Functional analysis confirmed these changes correspond to metabolic potential expansion in aging towards alternate pathways synthesizing and utilizing amino-acid precursors, vis-à-vis dominant microbial guilds producing butyrate in gut from pyruvate (e.g., Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species (e.g., Parabacteroides goldsteinii) and pathobionts (e.g., Klebsiella pneumoniae), highlighting the microbiome’s role as biomarkers and potential targets for promoting healthy aging.
... The human GI tract is home to a huge and complex microbial ecosystem made up of trillions of microorganisms, including bacteria, fungi, parasites, and viruses [44] . This community, known as the gut microbiota, plays an imperative role in human health and disease. ...
Article
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The global prevalence of obesity currently exceeds 1 billion people and is accompanied by an increase in the aging population. Obesity and aging share many hallmarks and are leading risk factors for cardiometabolic disease and premature death. Current anti-obesity and pro-longevity pharmacotherapies are limited by side effects, warranting the development of novel therapies. The gut microbiota plays a major role in human health and disease, with a dysbiotic composition evident in obese and aged individuals. The bidirectional communication system between the gut and the central nervous system, known as the gut-brain axis, may link obesity to unhealthy aging. Modulating the gut with microbiome-targeted therapies, such as biotics, is a novel strategy to treat and/or manage obesity and promote longevity. Biotics represent material derived from living or once-living organisms, many of which have therapeutic effects. Pre-, pro-, syn- and post-biotics may beneficially modulate gut microbial composition and function to improve obesity and the aging process. However, the investigation of biotics as next-generation therapeutics has only just begun. Further research is needed to identify therapeutic biotics and understand their mechanisms of action. Investigating the function of the gut-brain axis in obesity and aging may lead to novel therapeutic strategies for obese, aged and comorbid (e.g., sarcopenic obese) patient populations. This review discusses the interrelationship between obesity and aging, with a particular emphasis on the gut microbiome, and presents biotics as novel therapeutic agents for obesity, aging and related disease states.
... Probiotics are crucial for maintaining the balance and stability of the intestinal flora and have the capacity to alleviate a variety of diseases (Sanders et al. 2013). Nevertheless, unbalanced diets and excessive use of antibiotics can significantly diminish the diversity of the intestinal flora, evidenced by a decrease in the number of Lactobacillus and Bifidobacterium and an increase in Enterobacteriaceae and some Aspergillus spp (O'Toole and Claesson 2010). Modifying the human gut microbiota has emerged as an increasingly important objective in the field of nutrition. ...
Article
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Lactic acid bacteria (LAB) are the main probiotics currently available in the markets and are essential for maintaining gut health. To guarantee probiotic function, it is imperative to boost the culture yield of probiotic organisms, ensure the sufficient viable cells in commercial products, or develop effective prebiotics. Recent studies have shown that protein hydrolysates and their derived peptides promote the proliferation of probiotic in vitro and the abundance of gut flora. This article comprehensively reviews different sources of protein hydrolysates and their derived peptides as growth-promoting factors for probiotics including Lactobacillus, Bifidobacterium, and Saccharomyces. We also provide a preliminary analysis of the characteristics of LAB proteolytic systems focusing on the correlation between their elements and growth-promoting activities. The structure-activity relationship and underlying mechanisms of growth-promoting peptides and their research perspectives are thoroughly discussed. Overall, this review provides valuable insights into growth-promoting protein hydrolysates and their derived peptides for proliferating probiotics in vivo or in vitro, which may inspire researchers to explore new options for industrial probiotics proliferation, dairy products fermentation, and novel prebiotics development in the future.
... ; https://doi.org/10.1101/2024.07.01.601610 doi: bioRxiv preprint sexual development is the primary factor driving maturation of the gut microbiome during puberty [61] is incomplete. It also contradicts previous hypotheses that age-related gut microbiome maturation is complete before puberty [62,63]. Our data showed that age, independent of sex or HPG axis activation exerts a considerable effect on broad changes in the gut microbiota composition and putative functions. ...
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The gut microbiome plays a key role in human health and gut dysbiosis is linked to many sex-specific diseases including autoimmune, metabolic, and neurological disorders. Activation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty leads to sexual maturation and development of sex differences through the action of gonadal sex steroids. While the gut microbiome also undergoes sex differentiation, the mechanisms involved remain poorly understood. Using a genetic hypogonadal (hpg) mouse model, we sampled the fecal microbiome of male and female wild-type and hpg mutant mice before and after puberty to determine how microbial taxonomy and function are influenced by age, sex, and the HPG axis. We showed that HPG axis activation during puberty is required for sexual maturation of the gut microbiota composition, community structure, and metabolic functions. We also demonstrated that some sex differences in taxonomic composition and amine metabolism developed independently of the HPG axis, indicating that sex chromosomes are sufficient for certain sex differences in the gut microbiome. In addition, we showed that age, independent of HPG axis activation, led to some aspects of pubertal maturation of the gut microbiota community composition and putative functions. These results have implications for microbiome-based treatments, indicating that sex, hormonal status, and age should be considered when designing microbiome-based therapeutics.
... This pattern of bacterial acquisition is influenced by perinatal factors, including mode of delivery, method of feeding and volume and type of antibiotic usage [20]. The infant gut microbiota is characterised by instability with rapid turnover of organisms within the gut, often with low diversity [21]. It can take up to two years for the gut microbiome to become stable and achieve adult patterns of gut microbial colonisation. ...
Article
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Chronic lung disease (CLD) of prematurity, a common cause of morbidity and mortality in preterm-born infants, has a multifactorial aetiology. This review summarizes the current evidence for the effect of the gut and airway microbiota on the development of CLD, highlighting the differences in the early colonisation patterns in preterm-born infants compared to term-born infants. Stool samples from preterm-born infants who develop CLD have less diversity than those who do not develop CLD. Pulmonary inflammation, which is a hallmark in the development of CLD, may potentially be influenced by gut bacteria. The respiratory microbiota is less abundant than the stool microbiota in preterm-born infants. There is a lack of clear evidence for the role of the respiratory microbiota in the development of CLD, with results from individual studies not replicated. A common finding is the presence of a single predominant bacterial genus in the lungs of preterm-born infants who develop CLD. Probiotic preparations have been proposed as a potential therapeutic strategy to modify the gut or lung microbiota with the aim of reducing rates of CLD but additional robust evidence is required before this treatment is introduced into routine clinical practice.
... Numerous studies have now implicated the gut microbiota in the aetiology of neurological and neuropsychiatric diseases [1] including Alzheimer's [2], Parkinson's [3] and depression [4]. The gut microbiota composition changes throughout the lifespan [5], depending on environmental or lifestyle factors, notably diet and exercise [6][7][8]. ...
Article
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Lifestyle factors, especially exercise, impact the manifestation and progression of psychiatric and neurodegenerative disorders such as depression and Alzheimer’s disease, mediated by changes in hippocampal neuroplasticity. The beneficial effects of exercise may be due to its promotion of adult hippocampal neurogenesis (AHN). Gut microbiota has also been showed to be altered in a variety of brain disorders, and disturbances of the microbiota have resulted in alterations in brain and behaviour. However, whether exercise can counteract the negative effects of altered gut microbiota on brain function remains under explored. To this end, chronic disruption of the gut microbiota was achieved using an antibiotic cocktail in rats that were sedentary or allowed voluntary access to running wheels. Sedentary rats with disrupted microbiota displayed impaired performance in hippocampal neurogenesis-dependent tasks: the modified spontaneous location recognition task and the novelty suppressed feeding test. Performance in the elevated plus maze was also impaired due to antibiotics treatment. These behaviours, and an antibiotics-induced reduction in AHN were attenuated by voluntary exercise. The effects were independent of changes in the hippocampal metabolome but were paralleled by caecal metabolomic changes. Taken together these data highlight the importance of the gut microbiota in AHN-dependent behaviours and demonstrate the power of lifestyle factors such as voluntary exercise to attenuate these changes.
... The gut microbiota is essential for development and adult homeostasis, and alterations have been associated with inflammatory and metabolic problems in adults, including inflammatory bowel disease and obesity [20,[33][34][35]. While the gut microbiota remains stable and individual-specific in healthy adults, there is a significant fluctuation in older individuals compared to younger people [36,37]. ...
Article
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The increased prevalence of obesity with several other metabolic disorders, including diabetes and non-alcoholic fatty liver disease, has reached global pandemic proportions. Lifestyle changes may result in a persistent positive energy balance, hastening the onset of these age-related disorders and consequently leading to a diminished lifespan. Although suggestions have been raised on the possible link between obesity and the gut microbiota, progress has been hampered due to the extensive diversity and complexities of the gut microbiota. Being recognized as a potential biomarker owing to its pivotal role in metabolic activities, the dysregulation of the gut microbiota can give rise to a persistent low-grade inflammatory state associated with chronic diseases during aging. This chronic inflammatory state, also known as inflammaging, induced by the chronic activation of the innate immune system via the macrophage, is controlled by the gut microbiota, which links nutrition, metabolism, and the innate immune response. Here, we present the functional roles of prebiotics, probiotics, synbiotics, and postbiotics as bioactive compounds by underscoring their putative contributions to (1) the reduction in gut hyperpermeability due to lipopolysaccharide (LPS) inactivation, (2) increased intestinal barrier function as a consequence of the upregulation of tight junction proteins, and (3) inhibition of proinflammatory pathways, overall leading to the alleviation of chronic inflammation in the management of obesity.
... Furthermore, disruptions in the microbiome-gut-brain axis could lead to the development of central nervous system pathologies [18][19][20][21] and behavioral disorders [12,22]. Notably, intestinal flora richness and diversity correlate with the extent of human social interactions, with reduced interactions causing decreased microbial diversity [23]. Moreover, targeting the microbiota during aging may be an effective strategy to prevent cognitive and social alterations. ...
Article
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Aging is characterized by a decline in social behavior and cognitive functions leading to a decrease in life quality. In a previous study, we show that a fish hydrolysate supplementation prevents age-related decline in spatial short-term memory and long-term memory and anxiety-like behavior and improves the stress response in aged mice. The aim of this study was to determine the effects of a fish hydrolysate enriched with EPA/DHA or not on the cognitive ability and social interaction during aging and the biological mechanisms involved. We showed for the first time that a fish hydrolysate enriched with EPA/DHA or not improved memory performance and preference for social novelty that were diminished by aging. These changes were associated with the modulation of the gut microbiota, normalization of corticosterone, and modulation of the expression of genes involved in the mitochondrial respiratory chain, circadian clock, neuroprotection, and antioxidant activity. Thus, these changes may contribute to the observed improvements in social behavior and memory and reinforced the innovative character of fish hydrolysate in the prevention of age-related impairments.
... GI microbiota affect human health, either directly by generating biological substances such as essential amino acids, vitamins and lipids, or indirectly by mediating metabolism, intestinal epithelium barrier function, and immune responses [74]. Gut microbial diversity varies among individuals due to genetic and lifestyle factors [74], and typically declines with age [75,76]. Improve-ments to detrimental lifestyle factors such as poor diet, suboptimal sleep, circadian rhythm disturbance, chronic noise, and sedentary behavior have been shown to improve and protect against agerelated decline in gut microbial diversity [77]. ...
Article
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Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer’s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-β and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia.
... These changes can have important implications for overall health and the risk of developing diseases such as cancer [13]. Furthermore, significant advances have been made in comprehending the complexities of the human gut ecosystem as a result of recent developments in lifestyle independent approaches for microbiota assessment [14][15][16]. ...
Article
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Recent scientific research has indicated that the gut microbiota constitutes a nuanced, diverse ecosystem of microorganisms that have gained significant attention due to its crucial involvement in shaping human health and diseases. In particular, the gut microbiota plays a pivotal role in cancer prevention, and disturbances in its composition and function, known as dysbiosis, that have been linked to an increased risk of developing various malignancies. The gut microbiota exerts a myriad of effects on the production of anti-cancer compounds, the host's immune system and inflammation, underscoring its crucial involvement in cancer. Additionally, recent studies have shown that the gut microbiota has a role in the development of cancer, influencing cancer risk, co-infections, disease progression, and treatment response. The observation of reduced efficacy of immunotherapy in patients receiving antibiotic treatment indicates a substantial influence of the microbiota in mediating the toxicity and response of cancer therapy, notably immunotherapy, and its immune-related side effects. A growing body of research has focused on cancer treatments that target the microbiome, including probiotics, dietary modifications, and faecal microbiota transplantation (FMT). The forthcoming era of personalised cancer therapies is anticipated to prioritise tumor evolution, molecular and phenotypic heterogeneity, and immunological profiling, with gut microbiota assuming a pivotal position in this domain. This review aims to offer clinicians a comprehensive perspective on the microbiota-cancer axis, including its influence on cancer prevention and therapy and highlights the importance of integrating microbiome science into the design and implementation of cancer therapies.
... However, since CVA shows a circadian rhythm, 24-h measurements could provide more precise insights into microbiota-brain communication (Valladares et al. 2008). Moreover, HRV and microbiota patterns seem to be age-dependent and change throughout the lifespan (Umetani et al. 1998;Lehofer et al. 1999;O'Toole and Claesson 2010). Additionally, both, gut microbiota and vagal nerve function seem to be closely interconnected with inflammation (Pavlov and Tracey 2012;Soares-Miranda et al. 2012;Al Bander et al. 2020). ...
... The human gut microbiome comprises 10 trillion diverse symbionts (50 bacterial phyla and about 100-1000 bacterial species) [1], which maintain a close symbiotic relationship with the human body [2]. The gut microbiota remains relatively stable during adulthood, but its compositions are constantly changed during infancy and old age [3]. The alterations of gut microbiota with age are characterized by progressive decreases of overall diversity, core microbiota, and other health-associated bacteria, ultimately leading to gut microbiota dysbiosis [4][5][6][7][8]. ...
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Several experimental studies have suggested that individual essential metal(loid)s (EMs) could regulate the gut microbiota. However, human studies assessing the associations between EMs and gut microbiota are limited. This study aimed to examine the associations of individual and multiple EMs with the compositions of the gut microbiota in older adults. A total of 270 Chinese community-dwelling people over 60 years old were included in this study. Urinary concentrations of selected EMs, including vanadium (V), cobalt (Co), selenium (Se), strontium (Sr), magnesium (Mg), calcium (Ca), and molybdenum (Mo), were examined by inductively coupled plasma mass spectrometry. The gut microbiome was assessed using the 16S rRNA gene sequencing analysis. The zero-inflated probabilistic principal components analysis PCA (ZIPPCA) model was performed to denoise substantial noise in microbiome data. Linear regression and the Bayesian Kernel Machine Regression (BKMR) models were utilized to determine the associations between urine EMs and gut microbiota. No significant association between urine EMs and gut microbiota was found in the total sample, whereas some significant associations were found in subgroup analyses: Co was negatively associated with the microbial Shannon (β = −0.072, p < 0.05) and the inverse-Simpson (β = −0.045, p < 0.05) indices among urban older adults; Ca (R2 = 0.035) and Sr (R2 = 0.023) exhibited significant associations with the altercations of beta diversity in females, while V (R2 = 0.095) showed a significant association with altercations of beta diversity in those who often drank. Furthermore, the associations between partial EMs and specific bacterial taxa were also found: the negative and linear associations of Mo with Tenericutes, Sr with Bacteroidales, and Ca with Enterobacteriaceae and Lachnospiraceae, and a positive and linear association of Sr with Bifidobacteriales were found. Our findings suggested that EMs may play an important role in maintaining the steady status of gut microbiota. Prospective studies are needed to replicate these findings.
... In general, advancing age leads to a decrease in physical fitness and an increased susceptibility to infections due to irreversible changes in the immune system leading to chronic low-grade inflammation or 'inflammaging'. This frailty can lead to dysbiosis in the gut microbiota, which can cause pathogen overgrowth and disease onset, and is associated with a decrease in alpha diversity [135][136][137]. Several studies suggest that the human gut's microbial composition changes continuously with increasing age of the host [136,138]. ...
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The role of the gut microbiota in human health and disease has garnered heightened attention over the past decade. A thorough understanding of microbial variation over the life course and possible ways to influence and optimize the microbial pattern is essential to capitalize on the microbiota’s potential to influence human health. Here, we review our current understanding of the concept of plasticity of the human gut microbiota throughout the life course. Characterization of the plasticity of the microbiota has emerged through recent research and suggests that the plasticity in the microbiota signature is largest at birth when the microbial colonization of the gut is initiated and mode of birth imprints its mark, then decreases postnatally continuously and becomes less malleable and largely stabilized with advancing age. This continuing loss of plasticity has important implication for the impact of the exposome on the microbiota and health throughout the life course and the identification of susceptible ‘windows of opportunity’ and methods for interventions.
... It may interact directly with intestinal epithelial barrier cells [61]. Rifaximin and amoxicillin can act on the class of gram-positive and gram-negative bacteria producing peptides [62][63][64]. In the bacteriophage mechanism of the virus infection observed by previously [34,58], the presence of toxins produced by bacteria continuously after viral aggression can be blocked using an appropriate combination of antibiotics in vitro models. ...
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Citation: Brogna, C.; Cristoni, S.; Brogna, B.; Bisaccia, D.R.; Marino, G.; Viduto, V.; Montano, L.; Piscopo, M. Abstract: It has been 3 years since the beginning of the SARS-CoV-2 outbreak, however it is as yet little known how to care for the acute COVID-19 and long COVID patients. COVID-19 clinical manifestations are of both pulmonary and extra-pulmonary types. Extra-pulmonary ones include extreme tiredness (fatigue), shortness of breath, muscle aches, hyposmia, dysgeusia, and other neurological manifestations. In other autoimmune diseases, such as Parkinson's disease (PD) or Alzheimer's Disease (AD), it is well known that role of acetylcholine is crucial in olfactory dysfunction. We have already observed the presence of toxin-like peptides in plasma, urine, and faecal samples from COVID-19 patients, which are very similar to molecules known to alter acetylcholine signaling. After observing the production of these peptides in bacterial cultures, we have performed additional pro-teomics analyses to better understand their behavior and reported the extended data from our latest in vitro experiment. It seems that the gut microbiome continues to produce toxin-like peptides also after the decrease of RNA SARS-CoV-2 viral load at molecular tests. These toxicological interactions between the gut/human microbiome bacteria and the virus suggest a new scenario in the study of the clinical symptoms in long COVID and also in acute COVID-19 patients. It is discussed that in the bacteriophage similar behavior, the presence of toxins produced by bacteria continuously after viral aggression can be blocked using an appropriate combination of certain drugs.
... 7,54 At old age, there is reportedly a decline in microbiota diversity, with reduced numbers of Bifidobacteria and an increase in Enterobacteriaceae. 57,58 Likewise, the abundance of Bacteroidetes increases, whereas the Firmicutes becomes less abundant in elderly adults (>65 years). 59 Apart from age, gut microbiome composition is also greatly influenced by the environment in different anatomical locations. ...
Article
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The human microbiome is composed of a collection of dynamic microbial communities that inhabit various anatomical locations in the body. Accordingly, the coevolution of the microbiome with the host has resulted in these communities playing a profound role in promoting human health. Consequently, perturbations in the human microbiome can cause or exacerbate several diseases. In this Review, we present our current understanding of the relationship between human health and disease development, focusing on the microbiomes found across the digestive, respiratory, urinary, and reproductive systems as well as the skin. We further discuss various strategies by which the composition and function of the human microbiome can be modulated to exert a therapeutic effect on the host. Finally, we examine technologies such as multiomics approaches and cellular reprogramming of microbes that can enable significant advancements in microbiome research and engineering.
... However, various external factors may influence the in vivo colonization ability of GEBs. The key influencing factor is the location of GEBs in the body because each bacterium in our body has a corresponding colonization area in which the microenvironment formed by longperiod interactions with other bacteria and mammalian cells provides a safe place for them to proliferate with high genetic stability (O'Toole and Claesson, 2010;Zou et al., 2019;Tochitani, 2021). Therefore, the disease location in the body determines the species of chassis bacterium, thus enhancing their colonization and reducing the off-target effects of their secreted substances (Dosoky et al., 2020). ...
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Advances in synthetic biology and the clinical application of bacteriotherapy enable the use of genetically engineered bacteria (GEB) to combat various diseases. GEB act as a small ‘machine factory’ in the intestine or other tissues to continuously produce heterologous proteins or molecular compounds and, thus, diagnose or cure disease or work as an adjuvant reagent for disease treatment by regulating the immune system. Although the achievements of GEBs in the treatment or adjuvant therapy of diseases are promising, the practical implementation of this new therapeutic modality remains a grand challenge, especially at the initial stage. In this review, we introduce the development of GEBs and their advantages in disease management, summarize the latest research advances in microbial genetic techniques, and discuss their administration routes, performance indicators and the limitations of GEBs used as platforms for disease management. We also present several examples of GEB applications in the treatment of cancers and metabolic diseases and further highlight their great potential for clinical application in the near future.
... age of onset, duration of use) would shed light on certain gaps and discrepancies in the literature. More importantly, the gut microbiota changes throughout the lifespan (O'Toole & Claesson, 2010) and is dependent on sex (Valeri & Endres, 2021). However, despite the clear association between endogenous sex hormones and gut composition, far too little is known regarding how synthetic sex hormones affect the gut microbiome (Valeri & Endres, 2021). ...
Article
Combined oral contraceptives (containing synthetic forms of estradiol and progestins) are one of the most commonly used drugs among females. However, their effects on the gut-brain axis have not been investigated to a great extent despite clear evidence that suggest bi-directional interactions between the gut microbiome and endogenous sex hormones. Moreover, oral contraceptives are prescribed during adolescence, a critical period of development during which several brain structures and systems, such as hypothalamic-pituitary-gonadal axis, undergo maturation. Considering that oral contraceptives could impact the developing adolescent brain and that these effects may be mediated by the gut-brain axis, further research investigating the effects of oral contraceptives on the gut-brain axis is imperative. This article briefly reviews evidence from animal and human studies on the effects of combined oral contraceptives on the brain and the gut microbiota particularly during adolescence.
... However, since CVA shows a circadian rhythm, 24-h measurements could provide more precise insights into microbiota-brain communication (Valladares et al. 2008). Moreover, HRV and microbiota patterns seem to be age-dependent and change throughout the lifespan (Umetani et al. 1998;Lehofer et al. 1999;O'Toole and Claesson 2010). Additionally, both, gut microbiota and vagal nerve function seem to be closely interconnected with inflammation (Pavlov and Tracey 2012;Soares-Miranda et al. 2012;Al Bander et al. 2020). ...
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Introduction: A functional reciprocity between the gut microbiome and vagal nerve activity has been suggested, however, human studies addressing this phenomenon are limited. Methods: Twenty-four-hour cardiac vagal activity (CVA) was assessed from 73 female participants (aged 24.5 ± 4.3 years). Additionally, stool samples were subjected to 16SrRNA gene analysis (V1-V2). Quantitative Insights Into Microbial Ecology (QIIME) was used to analyse microbiome data. Additionally, inflammatory parameters (such as CRP and IL-6) were derived from serum samples. Results: Daytime CVA correlated significantly with gut microbiota diversity (r sp = 0.254, p = 0.030), CRP (r sp = -0.348, p = 0.003), and IL-6 (r sp = -0.320, p = 0.006). When the group was divided at the median of 24 h CVA (Mdn = 1.322), the following features were more abundant in the high CVA group: Clostridia (Linear discriminant analysis effect size (LDA) = 4.195, p = 0.029), Clostridiales (LDA = 4.195, p = 0.029), Lachnospira (LDA = 3.489, p = 0.004), Ruminococcaceae (LDA = 4.073, p = 0.010), Faecalibacterium (LDA = 3.982, p = 0.042), Lactobacillales (LDA = 3.317, p = 0.029), Bacilli (LDA = 3.294, p = 0.0350), Streptococcaceae (LDA = 3.353, p = 0.006), Streptococcus (LDA = 3.332, p = 0.011). Based on Dirichlet multinomial mixtures two enterotypes could be detected, which differed significantly in CVA, age, BMI, CRP, IL-6, and diversity. Conclusions: As an indicator of gut-brain communication, gut microbiome analysis could be extended by measurements of CVA to enhance our understanding of signalling via microbiota-gut-brain-axis and its alterations through psychobiotics.
... Human gut microbiota is unique, stable, and change-resistant [13] . Despite this, their composition changes over time [14] . Birth method [15,16] , host age, lifestyle, medications, and diet all affect the gut microbiota [17][18][19][20] . ...
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Malabsorption is a very important topic that impacts the health of people all over the world. The main objective of the present study is to review the literature regarding malabsorption and the role of microbes in malabsorption. Malabsorption can be attributed by several factors such as bacteria, vitamins, and disturbance of intestinal mucosa. The present study focused on microbial reasons due to their species diversity including bacteria and parasites. It seems that microbial origin has become hidden with time and not well considered in clinical practice. In some parts of the world, parasites are still existing and their role in malabsorption can not be ignored.
... It is well-known that the pro-inflammatory response shows a progressive increase with an increase in age [48,49]. During inflammatory aging, the balance of the gut microbiota is gradually lost, and the composition and diversity of the gut microbiota are altered, causing chronic systemic low-level inflammation [50][51][52] and resulting in the deterioration of intestinal tissue function and an intensified inflammatory response of the body [53]. After dietary intervention, APF, APS, and APRS significantly downregulated the relative mRNA expression of the p53 aging gene in aging mice and significantly upregulated expression of anti-aging gene SIRT1, suggesting that RS dietary intervention had potential anti-aging effects and APRS had the best effect, followed by APS and APF. ...
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This study aimed to compare the regulatory effects of Arenga pinnata retrograded starch (APRS), Arenga pinnata starch (APS), and whole Arenga pinnata flour (APF) on gut microbiota and improvement of intestinal inflammation in aged mice. APF, APS, and APRS altered gut microbiota composition and exhibited different prebiotic effects. Bifidobacterium showed the greatest increase in feces of aged mice fed APF. The abundance of genus Lachnospiraceae_NK4A136 was highest in the APS group. APRS supplementation led to a greatest increasement in abundance of Lactobacillus, Roseburia, and Faecalibacterium prausnitzii. APRS induced significantly more short-chain fatty acid (SCFAs) production than APF and APS. APF, APS, and APRS treatments improved intestinal inflammation in aged mice and the order of ameliorative effect was APRS > APS > APF. APRS significantly decreased relative mRNA expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and increased anti-inflammatory cytokines (IL-10). In addition, APF, APS, and APRS significantly downregulated the relative mRNA expression of senescence-associated gene p53 and upregulated the expression of anti-aging gene Sirt1. These results provide potentially useful information about the beneficial effects of Arenga pinnata products on human health.
... Furthermore, gut microbiota composition is often imbalanced (i.e., dysbiosis) in older adults, especially in those who are frail and/or who have been institutionalized (13,14). Compared to healthier individuals, these populations frequently have lower microbial diversity, larger numbers of opportunistic pathogens, and lower levels of species that produce anti-inflammatory and insulinsensitizing metabolites (e.g., Faecalibacterium prausnitzii) (14,15). Recent studies have found that the gut microbiota and skeletal muscle engage in cross-talk (5,(16)(17)(18)(19)(20), which leads us to hypothesize that strategies targeting gut community composition and function could help frail elderly individuals improve their skeletal muscle health. ...
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The aim of this study was to identify a probiotic-based strategy for maintaining muscle anabolism in the elderly. In previous research, we found that individuals experiencing short bowel syndrome (SBS) after an intestinal resection displayed beneficial metabolic adjustments that were mediated by their gut microbes. Thus, these bacteria could potentially be used to elicit similar positive effects in elderly people, who often have low food intake and thus develop sarcopenia. Gut bacterial strains from an SBS patient were evaluated for their ability to (1) maintain Caenorhabditis elegans survival and muscle structure and (2) promote protein anabolism in a model of frail rodents (18-month-old rats on a food-restricted diet: 75% of ad libitum consumption). We screened a first set of bacteria in C. elegans and selected two Lacticaseibacillus casei strains (62 and 63) for further testing in the rat model. We had four experimental groups: control rats on an ad libitum diet (AL); non-supplemented rats on the food-restricted diet (R); and two sets of food-restricted rats that received a daily supplement of one of the strains (∼10⁹ CFU; R+62 and R+63). We measured lean mass, protein metabolism, insulin resistance, cecal short-chain fatty acids (SCFAs), and SCFA receptor expression in the gut. Food restriction led to decreased muscle mass [−10% vs. AL (p < 0.05)]. Supplementation with strain 63 tempered this effect [−2% vs. AL (p > 0.1)]. The mechanism appeared to be the stimulation of the insulin-sensitive p-S6/S6 and p-eIF2α/eIF2α ratios, which were similar in the R+63 and AL groups (p > 0.1) but lower in the R group (p < 0.05). We hypothesize that greater SCFA receptor sensitivity in the R+63 group promoted gut-muscle cross talk [GPR41: +40% and GPR43: +47% vs. R (p < 0.05)]. Hence, strain 63 could be used in association with other nutritional strategies and exercise regimes to limit sarcopenia in frail elderly people.
... The experimental study of gut microbiota requires culturing methods that are adapted to their specific requirements. The gut microbiota is mainly comprised of strict and facultative anaerobic members with complex nutritional demands, making these micro-organisms difficult to cultivate with common microbiological techniques (O'Tool & Claesson, 2010;Vacca, 2017). Initially, an anaerobic environment is required, which is generally created by oxygen replacement with anoxic gases, such as nitrogen (N 2 ), hydrogen (H 2 ) and carbon dioxide (CO 2 ). ...
Article
Aims: This research aimed to develop and validate a cultivation and monitoring protocol that is suitable for a surrogate microbial community that accounts for the gut microbiota of the ileum of the small intestine. Methods and results: Five bacterial species have been selected as representatives of the ileal gut microbiota and a general anaerobic medium (MS-BHI, as minimally supplemented BHI) has been constructed and validated against BCCM/LGM recommended and commercial media. Moreover, appropriate selective/differential media have been investigated for monitoring each ileal gut microbiota surrogate. Results showed that MS-BHI was highly efficient in displaying individual and collective behavior of the ileal gut microbiota species, when compared with other types of media. Likewise, the selective/differential media managed to identify and describe the behavior of their targeted species. Conclusions: MS-BHI renders a highly efficient, inexpensive and easy-to-prepare cultivation and enumeration alternative for the surrogate ileal microbiota species. Additionally, the selective/differential media can identify and quantify the bacteria of the surrogate ileal microbial community. Significance and impact of study: The selected gut microbiota species can represent an in vitro ileal community, forming the basis for future studies on small intestinal microbiota. MS-BHI and the proposed monitoring protocol can be used as a standard for gut microbiota studies that utilize conventional microbiological techniques.
... Ageing and age-related diseases are frequently associated to a modification of the overall number and species diversity of the complex ecosystem of bacteria, fungal, and viral species living as symbiotic companions in our body from birth to death. 16 Moreover, there is increasing awareness of the association between gut microbiota and brain functions, which has come to be known as the gut-brain axis, 17,18 affecting cognitive outcomes and decline. 19 All these physiological changes, which are associated with possible concomitant presence of chronic diseases (e.g. ...
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Ageing is an unavoidable progressive process causing many changes of the individual life. However, if faced in an efficient way, living longer in a healthy status could be an opportunity for all. In this context, food consumption and dietary patterns are pivotal factors in promoting active and healthy ageing. The development of food products tailored for the specific needs of the elderly might favour the fulfilment of nutritionally balanced diets, while reducing the consequences of malnutrition. To this aim, the application of a food structure design approach could be particularly profitable, being food structure responsible to the final functionalities of food products. In this narrative review, the physiological changes associated to food consumption occurring during ageing were firstly discussed. Then, the focus shifted to the possible role of food structure in delivering target functionalities, considering food acceptability, digestion of the nutrients, bioactive molecules and probiotic bacteria.
... The human gut microbiota is unique and relatively stable, and thus highly resilient to change [14]. In spite of this, they are also dynamic, and their composition is remodelled during different stages of our lifespan [15]. Several factors, such as the birth method of a child [16,17]; the age of the host [18]; lifestyle; medications; and, most importantly, diet [19][20][21], significantly modulate the composition of the gut microbiota. ...
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B vitamins act as coenzymes in a myriad of cellular reactions. These include energy production, methyl donor generation, neurotransmitter synthesis, and immune functions. Due to the ubiquitous roles of these vitamins, their deficiencies significantly affect the host's metabolism. Recently, novel roles of B vitamins in the homeostasis of gut microbial ecology and intestinal health continue to be unravelled. This review focuses on the functional roles and biosynthesis of B vitamins and how these vitamins influence the growth and proliferation of the gut microbiota. We have identified the gut bacteria that can produce vitamins, and their biosynthetic mechanisms are presented. The effects of B vitamin deficiencies on intestinal morphology, inflammation, and its effects on intestinal disorders are also discussed.
Chapter
The human microbiome is a dynamic area of research that continues to reveal new insights into human health and the intricate relations between microorganisms and their human host. It has a pivotal role in human health by contributing to various physiological processes and influencing immune system function. Microbiomes in a variety of body organs and its association with human health have been discussed. Moreover, the importance of the digestive (oral cavity, stomach, and intestine), respiratory (nasal cavity, pharynx, larynx, trachea, and lungs), skin, urinary, and reproductive systems on human health has been discussed. The human microbiomes play a crucial role in the pathogenesis and progression of various diseases. This chapter will provide a comprehensive overview of the human microbiome and its impact on human health. We provide an overview of the potential therapeutic applications of microbiome manipulation through probiotics and prebiotics, particularly in the context of obesity, gastrointestinal diseases, and cancer treatment.
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Obesity is recognized as a global epidemic that can result in changes in the human body and metabolism. Accumulating evidence indicates that gut microbiota (GM) can affect the development of obesity. The GM not only plays a crucial role in digesting and absorbing nutrients, but also in maintaining the overall health of the host. Dietary supplements such as non-starch polysaccharides are mainly fermented by the GM in the colon. Recent findings suggest that shaping the GM through the prebiotic function of non-starch polysaccharides may be a viable strategy against obesity. In this paper, the effects of non-starch polysaccharides on host health, together with their prebiotic function influencing the GM to control obesity via the gut-target organ axis, are reviewed. Potential perspectives of non-starch polysaccharides exhibiting anti-obesity effects via the gut-target organ axis are proposed for future research.
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The human gut is a complex ecosystem that supports billions of living species, including bacteria, viruses, archaea, phages, fungi, and unicellular eukaryotes. Bacteria give genes and enzymes for microbial and host-produced compounds, establishing a symbiotic link between the external environment and the host at both the gut and systemic levels. The gut microbiome, which is primarily made up of commensal bacteria, is critical for maintaining the healthy host’s immune system, aiding digestion, synthesizing essential nutrients, and protecting against pathogenic bacteria, as well as influencing endocrine, neural, humoral, and immunological functions and metabolic pathways. Qualitative, quantitative, and/or topographic shifts can alter the gut microbiome, resulting in dysbiosis and microbial dysfunction, which can contribute to a variety of noncommunicable illnesses, including hypertension, cardiovascular disease, obesity, diabetes, inflammatory bowel disease, cancer, and irritable bowel syndrome. While most evidence to date is observational and does not establish direct causation, ongoing clinical trials and advanced genomic techniques are steadily enhancing our understanding of these intricate interactions. This review will explore key aspects of the relationship between gut microbiota, eubiosis, and dysbiosis in human health and disease, highlighting emerging strategies for microbiome engineering as potential therapeutic approaches for various conditions.
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An altered gut microbiome is a feature of many multifactorial diseases, and microbiome effects on host metabolism, immune function, and possibly neurological function are implicated. Increased biological age is accompanied by a change in the gut microbiome. However, age-related health loss does not occur uniformly across all subjects but rather depends on differential loss of gut commensals and gain of pathobionts. In this article, we summarize the known and possible effects of the gut microbiome on the hallmarks of aging and describe the most plausible mechanisms. Understanding and targeting these factors could lead to prolonging health span by rationally maintaining the gut microbiome.
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Introduction Galacto-oligosaccharides (GOS) are well-substantiated prebiotic substrates. Multiple studies have demonstrated a positive impact of GOS on gut microbiota composition and activity, so-far mainly related to Bifidobacterium. However, data on the beneficial impact at lower dosages in a healthy female population are limited. The primary aim of the current study was to reveal the effect of low dosages (1.3 and 2.0 g) of GOS on fecal Bifidobacterium abundance in healthy women. Other outcomes included the effect of low dosage of GOS on overall fecal microbiota composition and on self-perceived GI comfort, sleep quality and mental wellbeing. Method Eighty-eight healthy women (42–70 years, BMI 18.7–30 kg/m²) were included in this randomized, parallel, double-blind study of 6 weeks. The participants were stratified for fiber intake, BMI and age and randomized to consume either 1.3 or 2.0 g of GOS per day for 3 weeks after a control period of 3 weeks without any intervention. Fecal samples were collected for shotgun metagenomics sequencing at the start (t = −3) and end (t = 0) of the control period and at the end of the intervention period (t = 3). Self-perceived gut comfort, sleep quality, and mental wellbeing were assessed weekly. Hierarchical clustering of principal components was applied to data collected from study participants. Results The relative abundance of Bifidobacterium in feces increased significantly after 3 weeks of daily consumption of both 1.3 g (p < 0.01) and 2.0 g GOS (p < 0.01). This was accompanied by a significant shift in the overall microbiota composition for the dosage of 2.0 g GOS (p < 0.01). Participants that showed a larger increase in Bifidobacterium in the intervention period compared to the change in Bifidobacterium in the control period, defined as responders, showed a significant overall difference in initial fecal microbiota composition as compared to non-responders (p = 0.04) and a trend towards lower baseline levels of Bifidobacterium in responders (p = 0.10). Conclusion Daily consumption of a low dose of GOS can lead to an increase in the relative abundance of Bifidobacterium in feces of healthy women. Additionally, with 2.0 g GOS, the enrichment of Bifidobacterium is accompanied with a shift in the overall microbiota composition. Clinical trial registration: clinicaltrials.gov, identifier NCT05762965.
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Introduction: Renal interstitial fibrosis is an important pathological basis for kidney ageing and the progression of ageing nephropathy. In the present research, we established an aged mouse model of faecal microbiota transplantation (FMT), identified the rejuvenation features of the kidney in aged male mice, and preliminarily analysed the possible mechanism by which the rejuvenation of the intestinal microbiota reduces renal interstitial fibrosis and delays senescence in aged male mice. Methods: We established an aged male mice model that was treated with FMT (FMT-Old) and a normal aged male mice control group (Old). Differentially expressed cytokines were identified using a cytokine array, and changes in protein expression related to signal transduction pathways in renal tissues were detected using a signalling pathway array. Senescence-associated β-galactosidase and Masson staining were performed to observe the degrees of renal senescence and tubule interstitial fibrosis. Immunohistochemistry was utilized to detect changes in the expression of the ageing markers p53 and p21 and the inflammation-related protein nuclear factor (NF-κB) subunit (RelA/p65). Results: The pathological features of renal senescence in the FMT-Old group were significantly alleviated, and the levels of the ageing indicators p53 and p21 were decreased (p < 0.05). Ingenuity Pathway Analysis revealed that six differentially expressed cytokines, MIP-3β (CCL-19), E-selectin (SELE), Fas ligand (Fas L/FASLG), CXCL-11 (I-TAC), CXCL-1 and CCL-3 (MIP-1α) were related to a common upstream regulatory protein, RelA/p65, and the expression of this protein was significantly different between groups according to the signalling pathway array. Conclusion: Our findings suggest that the intestinal microbiota regulates the renal microenvironment by reducing immune inflammatory responses through the inhibition of the NF-κB signalling pathway, thereby delaying renal senescence in aged male mice.
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While rapid demographic changes in Asia are driving the incidence of chronic diseases related to aging, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging the availability of a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun metagenomic sequencing to do high-resolution taxonomic and functional characterization of their gut microbiomes (n=234). Joint species-level analysis with other Asian cohorts identified a distinct age-associated shift in Asian gut metagenomes, characterized by a reduction in microbial richness, and enrichment of specific Alistipes and Bacteroides species (e.g. Alistipes shahii and Bacteroides xylanisolvens ). Functional pathway analysis confirmed that these changes correspond to a metabolic potential expansion in aging towards alternate pathways that synthesize and utilize amino-acid precursors, relative to the dominant microbial guilds that typically produce butyrate in the gut from pyruvate (e.g. Faecalibacterium prausnitzii, Roseburia inulinivorans ). Extending these observations to key clinical markers helped identify >10 robust gut microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species such as Parabacteroides goldsteinii and pathobionts such as Klebsiella pneumoniae , highlighting the role of the microbiome as biomarkers and potential intervention targets for promoting healthy aging.
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The human gut microbiome is well‐recognized as a key player in maintaining health. However, it is a dynamic entity that changes across the lifespan. How the microbial changes that occur in later decades of life shape host health or impact age‐associated inflammatory neurological diseases such as multiple sclerosis (MS) is still unclear. Current understanding of the aging gut microbiome is largely limited to cross‐sectional observational studies. Moreover, studies in humans are limited by confounding host‐intrinsic and extrinsic factors that are not easily disentangled from aging. This review provides a comprehensive summary of existing literature on the aging gut microbiome and its known relationships with neurological diseases, with a specific focus on MS. We will also discuss preclinical animal models and human studies that shed light on the complex microbiota–host interactions that have the potential to influence disease pathology and progression in aging individuals. Lastly, we propose potential avenues of investigation to deconvolute features of an aging microbiota that contribute to disease, or alternatively promote health in advanced age.
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The human gut microbiome is a modifier of the risk for many non‐communicable diseases throughout the lifespan. In ageing, the effect of the microbiome appears to be more pronounced because of the lower physiological reserve. Microbial metabolites and other bioactive products act upon some of the key physiological processes involved in the Hallmarks of Ageing. Dietary interventions that delay age‐related change in the microbiome have also led to delayed onset of ageing‐related health loss, and improved levels of cognitive function, inflammatory status and frailty. Cross‐sectional analysis of thousands of gut microbiome datasets from around the world has identified key taxa that are depleted during accelerated health loss, and other taxa that become more abundant, but these signatures differ in some geographical regions. The key challenges for research in this area are to experimentally prove that particular species or strains directly contribute to health‐related ageing outcomes, and to develop practical ways of retaining or re‐administering them on a population basis. The promotion of a health‐associated gut microbiome in ageing mirrors the challenge of maintaining planetary microbial ecosystems in the face of anthropogenic effects and climate change. Lessons learned from acting at the individual level can inform microbiome‐targeting strategies for achieving Sustainable Development Goals at a global level.
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Background: Aging is a progressive decline of cellular functions that ultimately affects whole-body homeostasis. Alterations in the gut microbiota associated with aging have been reported, however, these studies were mainly based on the simple comparison of young and old subjects. In this study, we longitudinally analyzed fecal microbial community composition, together with fecal and plasma metabolomes, in C57BL/6J mice over a period of 72 weeks. Result: By using longitudinal microbiome and metabolome analyses, we found aging-related alterations in fecal microbiota and metabolome profiles. There was a significant reduction in gut microbial diversity with ageand, in addition, the fecal metabolome showed a significant decrease in monosaccharides and an increase in the metabolites of energy metabolism. In the age-related change of plasma metabolites, amino acids were significantly increased. The features of age-related changes in the fecal bacteria and metabolites were consistent with those observed in obesity and diabetes studies. Consistently, fecal microbiota transplantation from agedspecific pathogen-free (SPF) mice into young germ-free (GF) mice resulted in increased weight gain and impaired glucose tolerance. Conclusion: Our findings provide new insights into the relationships between host aging and gut environmental changes and may contribute to the development of a solution to aging-related diseases such as obesity.
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This part of the review focuses on the proposed involvement of the gut microbiota in the realization of the genetic risk of multiple sclerosis, the formation of the intestinal microbiome in early life, and provides data supporting the hypothesis that aberrant formation of the intestinal microbiota in early life may be a predisposing factor to multiple sclerosis.
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Ruminococcus gnavus was first identified in 1974 as a strict anaerobe in the gut of healthy individuals, and for several decades, its study has been limited to specific enzymes or bacteriocins. With the advent of metagenomics, R. gnavus has been associated both positively and negatively with an increasing number of intestinal and extra-intestinal diseases from inflammatory bowel diseases to neurological disorders. This prompted renewed interest in understanding the adaptation mechanisms of R. gnavus to the gut, and the molecular mediators affecting its association with health and disease. From ca. 250 publications citing R. gnavus since 1990, 94% were published in the last 10 years. In this review, we describe the biological characterisation of R. gnavus, its occurrence in the infant and adult gut microbiota and the factors influencing its colonisation of the gastrointestinal tract; we also discuss the current state of our knowledge on its role in host health and disease. We highlight gaps in knowledge and discuss the hypothesis that differential health outcomes associated with R. gnavus in the gut are strain and niche specific.
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The design of the probes is based on bioluminescence imaging, which has been widely adopted in studies of many important biological processes. Traditional Chinese Medicine (TCM) fitness could improve the state of health of adults' intestinal flora. The research aims at analyzing the impact of TCM fitness on the intestinal probiotics (Bifidobacterium, Lactobacillus) and opportunistic pathogen (Enterococcus, Enterobacteriaceae) by the noninvasive imaging. In accordance with the searching results, the researchers have found that TCM fitness has a significant impact on improving Bifidobacterium (SDM = 1.55; P = 0.02) and Lactobacillus (SDM = 1.26; P <0.01), while the impact could not be seen on Enterococcus (SDM = 0.29;P = 0.68) and Enterobacteriaceae (SDM = 0.05;P = 0.94). And there is no significant difference between the two interventions of Tai Chi and Fitness Qigong. The results of the present review show that TCM fitness could significantly better the probiotics of intestinal flora while the influence on opportunistic pathogen needs to be further investigated with the precise and reasonable proof of scientific studies.The findings suggest that TCM fitness can be used as an effective intervention, and there is no significant difference between the two interventions on the improvement of the intestinal flora. The using of optical tool based on ultrasensitive bioluminescent imaging may lead to better precision medicine treatments in the future.
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Dietary fiber intake by humans is nowadays substantially decreasing as compared to the communities of ancestral populations. Accompanying that, the incidences of inflammatory bowel disease (IBD), allergy, and other autoimmune diseases are steadily increasing over the past 60 years, especially in high-income countries, which is partly attributed to the changing dietary habit in modern societies. Chronic inflammation triggered by Immune disorders is the central part of the pathophysiology of various non-communicable diseases. Dietary fiber intake is inexorably linked to the gut microbiome leading to the reduction of inflammation. This review explores how dietary fiber modulates the gut microbiota composition and function leading to the alteration of host physiology. High-fiber dietary regime has been consistently shown to increase the microbiome alpha diversity and short-chain fatty acids (SCFAs)-producing bacteria in the human gut. SCFAs are the main players in the interplay between diet, microbiota, and host health. In clinical settings, therapies with high fiber or SCFAs supplementations are proposed for inflammatory diseases. However, due to greater variations in the dosage, types, and durations of dietary fiber intervention in different clinical trials, the effect is controversial. Unraveling the mechanisms exerted by dietary fiber in synergy with the gut microbiome in human pathophysiology holds a promising prospect in guiding next-generation precision therapies.
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Background Statins have been widely used to prevent cardiovascular disease in middle-aged and elderly populations; however, the effect of long-term treatment on cognitive function is controversial. To simulate clinical conditions, middle-aged rats were given atorvastatin for 9 consecutive months to investigate the effect on natural cognitive decline and the possible mechanisms. Results The results showed that compared with the control group, long-term atorvastatin treatment naturally improved cognitive decline. Furthermore, long-term treatment regulated intestinal retinoic acid (RA) metabolism and storage by altering retinol dehydrogenase 7 (Rdh7) expression in the intestine, while RA metabolism affected the proliferation of intestinal T reg cells and inhibited IL-17 ⁺ γδ T-cell function. In addition, long-term atorvastatin increased intestinal flora richness and decreased IL-17 expression in hippocampal tissue. Conclusion Collectively, these findings provide the first evidence that long-term atorvastatin intervention may prevent cognitive decline in naturally ageing rats by inhibiting neuroinflammation via the gut-brain axis.
Chapter
Life expectancy has increased steadily among older adults over the last century, raising concerns that aging populations will face inevitable challenges to age healthily. Maintenance of organ homeostasis throughout the adult lifespan is crucial to longevity and healthy aging. Advancing age is associated with the decline in adaptive homeostatic responses at molecular, cellular, and tissue-levels, and altered intestinal microbiota that deteriorates psychological and physiological functions, which together predisposes one to an elevated risk of age-related diseases, such as dementia, osteoporosis, macular degeneration, diabetes, and cardiovascular disease. However, human aging is a malleable process that could be influenced by lifestyle-modifiable factors, such as diet. It is also becoming evident that dietary supplementation with probiotics may promote healthy aging and have a positive impact on the onset and progression of age-related diseases. Therefore, this chapter provides an overview of the updated preclinical and clinical evidence on the antiaging potential of probiotics and discusses their possible mechanisms of action.
Chapter
The most popular approach to measure key functions of any living entity is to remove it and then study the consequences of its removal. Microorganisms influence their host in several manners and their role can be studied by eliminating them from their host and observe the host’s response, in their absence. Numerous studies have justified the vital role of microbiota in human health and disease development. Germ-free (GF) animal models are useful tools to improve our understanding of the host–microbiota relationship in vivo. Although different animal models, lacking microbiota (partially or completely) have been extensively used in research but germ-free (GF) mice are the most widely used rodent model in human research due to its close proximity to humans. In modern research, GF technology is one of the most attractive and informative tools for getting insights into host’s microbial community. Each body part harbors unique microorganisms with unique functions. Because of the advancement of microbial characterization techniques, the human microbiota community is expanding day by day. GF mice model can efficiently reveal the role of these valuable partners of humans. In spite of its high cost and obligation of skilled experts, GF research is a hot field for investigators and has a huge possibility for future applications. The present book chapter is a summary of the basics of GF technology and its main applications with future prospects.
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Early-life stress (ELS) leads to increased vulnerability for mental and metabolic disorders. We have previously shown that a low dietary ω-6/ω-3 polyunsaturated fatty acid (PUFA) ratio protects against ELS-induced cognitive impairments. Due to the importance of the gut microbiota as a determinant of long-term health, we here study the impact of ELS and dietary PUFAs on the gut microbiota and how this relates to the previously described cognitive, metabolic, and fatty acid profiles. Male mice were exposed to ELS via the limited bedding and nesting paradigm (postnatal day (P)2 to P9 and to an early diet (P2 to P42) with an either high (15) or low (1) ω-6 linoleic acid to ω-3 alpha-linolenic acid ratio. 16S rRNA was sequenced and analyzed from fecal samples at P21, P42, and P180. Age impacted α- and β-diversity. ELS and diet together predicted variance in microbiota composition and affected the relative abundance of bacterial groups at several taxonomic levels in the short and long term. For example, age increased the abundance of the phyla Bacteroidetes, while it decreased Actinobacteria and Verrucomicrobia; ELS reduced the genera RC9 gut group and Rikenella, and the low ω-6/ ω-3 diet reduced the abundance of the Firmicutes Erysipelotrichia. At P42, species abundance correlated with body fat mass and circulating leptin (e.g., Bacteroidetes and Proteobacteria taxa) and fatty acid profiles (e.g., Firmicutes taxa). This study gives novel insights into the impact of age, ELS, and dietary PUFAs on microbiota composition, providing potential targets for noninvasive (nutritional) modulation of ELS-induced deficits.
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Humans host complex microbial communities believed to contribute to health maintenance and, when in imbalance, to the development of diseases. Determining the microbial composition in patients and healthy controls may thus provide novel therapeutic targets. For this purpose, high-throughput, cost-effective methods for microbiota characterization are needed. We have employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing. In silico modeling demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level. Here we applied the technique to analyze microbial communities in throat, stomach and fecal samples. Our results demonstrate the applicability of barcoded pyrosequencing as a high-throughput method for comparative microbial ecology.
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Abstract The bacterial species diversity of three colonic tissue samples from elderly people was investigated by sequence analysis of randomly cloned eubacterial 16S rDNA. The majority of sequences (87%) clustered within three bacterial groups: (1) Bacteroides; (2) low G+C content Gram-positives related to Clostridium coccoides (cluster XIVa); (3) Gram-positives related to Clostridium leptum (cluster IV). These groups have been shown to dominate the human faecal flora. Only 25% of sequences were closely related (>97%) to current species type strains, and 28% were less than 97% related to any database entry. 19% of sequences were most closely related to recently isolated butyrate-producing bacteria belonging to clusters XIVa and IV, with a further 18% of the sequences most closely related to Ruminococcus obeum and Ruminococcus torques (members of cluster XIVa). These results provide the first molecular information on the microbial diversity present in human colonic samples.
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Ageing has been suggested to cause changes in the intestinal microbial community. In the present study, the microbiota of a previously well-defined group of elderly subjects aged between 70 and 85 years, both non-steroidal anti-inflammatory drugs (NSAID) users (n 9) and non-users (n 9), were further compared with young adults (n 14) with a mean age of 28 years, by two DNA-based techniques: percentage guanine+cytosine (%G+C) profiling and 16S rDNA sequencing. Remarkable changes in microbiota were described with both methods: compared with young adults a significant reduction in overall numbers of microbes in both elderly groups was measured. Moreover, the total number of microbes in elderly NSAID users was higher than in elderly without NSAID. In 16S rDNA sequencing, shifts in all major microbial phyla, such as lower numbers of Firmicutes and an increase in numbers of Bacteroidetes in the elderly were monitored. On the genus level an interesting link between reductions in the proportion of known butyrate producers belonging to Clostridium cluster XIVa, such as Roseburia and Ruminococcus, could be demonstrated in the elderly. Moreover, in the Actinobacteria group, lower numbers of Collinsella spp. were evident in the elderly subjects with NSAID compared both with young adults and the elderly without NSAID, suggesting that the use of NSAID along with age may also influence the composition of intestinal microbiota. Furthermore, relatively high numbers of Lactobacillus appeared only in the elderly subjects without NSAID. In general, the lowered numbers of microbial members in the major phyla, Firmicutes, together with changes in the epithelial layer functions can have a significant effect on the colon health of the elderly.
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Variations in the composition of the human intestinal microbiota are linked to diverse health conditions. High-throughput molecular technologies have recently elucidated microbial community structure at much higher resolution than was previously possible. Here we compare two such methods, pyrosequencing and a phylogenetic array, and evaluate classifications based on two variable 16S rRNA gene regions. Over 1.75 million amplicon sequences were generated from the V4 and V6 regions of 16S rRNA genes in bacterial DNA extracted from four fecal samples of elderly individuals. The phylotype richness, for individual samples, was 1,400-1,800 for V4 reads and 12,500 for V6 reads, and 5,200 unique phylotypes when combining V4 reads from all samples. The RDP-classifier was more efficient for the V4 than for the far less conserved and shorter V6 region, but differences in community structure also affected efficiency. Even when analyzing only 20% of the reads, the majority of the microbial diversity was captured in two samples tested. DNA from the four samples was hybridized against the Human Intestinal Tract (HIT) Chip, a phylogenetic microarray for community profiling. Comparison of clustering of genus counts from pyrosequencing and HITChip data revealed highly similar profiles. Furthermore, correlations of sequence abundance and hybridization signal intensities were very high for lower-order ranks, but lower at family-level, which was probably due to ambiguous taxonomic groupings. The RDP-classifier consistently assigned most V4 sequences from human intestinal samples down to genus-level with good accuracy and speed. This is the deepest sequencing of single gastrointestinal samples reported to date, but microbial richness levels have still not leveled out. A majority of these diversities can also be captured with five times lower sampling-depth. HITChip hybridizations and resulting community profiles correlate well with pyrosequencing-based compositions, especially for lower-order ranks, indicating high robustness of both approaches. However, incompatible grouping schemes make exact comparison difficult.
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In this paper we present the in silico assessment of the diversity of variable regions of the small subunit ribosomal RNA (SSU rRNA) gene based on an ecosystem-specific curated database, describe a probe design procedure based on two hypervariable regions with minimal redundancy and test the potential of such probe design strategy for the design of a flexible microarray platform. This resulted in the development and application of a phylogenetic microarray for studying the human gastrointestinal microbiota--referred as the human intestinal tract chip (HITChip). Over 4800 dedicated tiling oligonucleotide probes were designed based on two hypervariable regions of the SSU rRNA gene of 1140 unique microbial phylotypes (< 98% identity) following analysis of over 16,000 human intestinal SSU rRNA sequences. These HITChip probes were hybridized to a diverse set of human intestinal samples and SSU rRNA clones to validate its fingerprinting and quantification potential. Excellent reproducibility (median Pearson's correlation of 0.99) was obtained following hybridization with T7 polymerase transcripts generated in vitro from SSU rRNA gene amplicons. A linear dose-response was observed with artificial mixtures of 40 different representative amplicons with relative abundances as low as 0.1% of total microbiota. Analysis of three consecutively collected faecal samples from ten individuals (five young and five elderly adults) revealed temporal dynamics and confirmed that the adult intestinal microbiota is an individual-specific and relatively stable ecosystem. Further analysis of the stable part allowed for the identification of a universal microbiota core at the approximate genus level (90% sequence similarity). This core consists of members of Actinobacteria, Bacteroidetes and Firmicutes. Used as a phylogenetic fingerprinting tool with the possibility for relative quantification, the HITChip has the potential to bridge the gaps in our knowledge in the quantitative and qualitative description of the human gastrointestinal microbiota composition.
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The human intestinal tract harbors a complex microbial ecosystem which plays a key role in nutrition and health. Although this microbiota has been studied in great detail by culture techniques, microscopic counts on human feces suggest that 60 to 80% of the observable bacteria cannot be cultivated. Using comparative analysis of cloned 16S rRNA gene (rDNA) sequences, we have investigated the bacterial diversity (both cultivated and noncultivated bacteria) within an adult-male fecal sample. The 284 clones obtained from 10-cycle PCR were classified into 82 molecular species (at least 98% similarity). Three phylogenetic groups contained 95% of the clones: the Bacteroides group, the Clostridium coccoides group, and the Clostridium leptum subgroup. The remaining clones were distributed among a variety of phylogenetic clusters. Only 24% of the molecular species recovered corresponded to described organisms (those whose sequences were available in public databases), and all of these were established members of the dominant human fecal flora (e.g., Bacteroides thetaiotaomicron, Fusobacterium prausnitzii, and Eubacterium rectale). However, the majority of generated rDNA sequences (76%) did not correspond to known organisms and clearly derived from hitherto unknown species within this human gut microflora.
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This study aimed at determining ageing-related shifts in diversity and composition of key members of the fecal microbiota by comparing institutionalized elderly (n = 17, 78-94 years) and young volunteers (n = 17, 18-31 years). A combination of molecular methods was used to characterize the diversity and relative abundance of total gastro-intestinal flora, along with relevant subsets within the genera Bacteroides, bifidobacteria and Clostridium cluster IV. The institutionalized elderly harbored significantly higher numbers of Bacteroides cells than control (28.5 +/- 8.6%; 21.4 +/- 7.7%; p = 0.016) but contained less bifidobacteria (1.3 +/- 0.9, 2.7 +/- 3.2%, p = 0.026) and Clostridium cluster IV (26.9 +/- 11.7%, 36.36 +/- 11.26%, p = 0.036). The elderly also displayed less total Bacteria diversity and less diversity with the Clostridium cluster IV (p < 0.016) and Bacteroides. Despite high individual variations, our analyses indicate the composition of microbiota in the elderly comprises a less diverse subset of young healthy microbiota. A better understanding of the individual composition of the human microbiota and the effects of ageing might result in the development of specifically targeted supplementation for elderly citizens in order to support healthy ageing.
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Recent reports suggest that the metabolic activity of the gut microbiota may contribute to the pathogenesis of obesity and hepatic steatosis. The objective was to determine whether the fat composition of host tissues might be influenced by oral administration of commensal bifidobacteria previously shown by us to produce bioactive isomers of conjugated linoleic acid (CLA). Murine trials were conducted in which linoleic acid-supplemented diets were fed with or without Bifidobacterium breve NCIMB 702258 (daily dose of 10(9) microorganisms) to healthy BALB/c mice and to severe combined immunodeficient mice for 8-10 wk. To ensure that the observations were not peculiar to mice, a similar trial was conducted in weanling pigs over 21 d. Tissue fatty acid composition was assessed by gas-liquid chromatography. In comparison with controls, there was an increase in cis-9, trans-11 CLA in the livers of the mice and pigs after feeding with linoleic acid in combination with B. breve NCIMB 702258 (P < 0.05). In addition, an altered profile of polyunsaturated fatty acid composition was observed, including higher concentrations of the omega-3 (n-3) fatty acids eicosapentaenoic acid and docosahexaenoic acid in adipose tissue (P < 0.05). These changes were associated with reductions in the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma (P < 0.05). These results are consistent with the concept that the metabolome is a composite of host and microbe metabolic activity and that the influence of the microbiota on host fatty acid composition can be manipulated by oral administration of CLA-producing microorganisms.
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Probiotics have a range of proposed health benefits for the consumer, which may include modulating the levels of beneficial elements in the microbiota. Recent investigations using molecular approaches have revealed a human intestinal microbiota comprising over 1000 phylotypes. Mechanisms whereby probiotics impact on the intestinal microbiota include competition for substrates, direct antagonism by inhibitory substances, competitive exclusion, and potentially host-mediated effects such as improved barrier function and altered immune response. We now have the microbial inventories and genetic blueprints to begin tackling intestinal microbial ecology at an unprecedented level of detail, aided by the understanding that dietary components may be utilized differentially by individual phylotypes. Controlled intervention studies in humans, utilizing latest molecular technologies, are required to consolidate evidence for bacterial species that impact on the microbiota. Mechanistic insights should be provided by metabolomics and other analytical techniques for small molecules. Rigorous characterization of interactions between the diet, microbiota, and probiotic bacteria will provide new opportunities for modulating the microbiota towards improving human health.
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Gut Bifidobacterium microbiota of the elderly has been suggested to differ from that of adults, possibly promoting the risk of infections and gut barrier dysfunction. Specific probiotics may improve the gut barrier. In this randomized, placebo-controlled intervention study, 66 elders consumed a fermented oat drink containing probiotic Bifidobacterium longum 46 and B. longum 2C or a non-fermented placebo oat drink for 6 months. Faecal samples were collected before, during and after the intervention. Levels of faecal bifidobacteria were determined using species-specific quantitative PCR and plate counting. The Bifidobacterium levels in the elderly were high and the species composition diverse. Probiotic intervention increased the levels bifidobacteria significantly. Specifically, the levels of B. catenulatum, B. bifidum and B. breve were enhanced. Consumption of the fermented oat drink itself was also associated with certain changes in microbiota. In conclusion, Bifidobacterium microbiota of elderly subjects may be modulated by probiotic administration. In some healthy elderly populations, Bifidobacterium microbiota may be more abundant and diverse than previously suggested.
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Recent evidence suggests that the microbial community in the human intestine may play an important role in the pathogenesis of obesity. We examined 184,094 sequences of microbial 16S rRNA genes from PCR amplicons by using the 454 pyrosequencing technology to compare the microbial community structures of 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric-bypass surgery. Phylogenetic analysis demonstrated that although the Bacteria in the human intestinal community were highly diverse, they fell mainly into 6 bacterial divisions that had distinct differences in the 3 study groups. Specifically, Firmicutes were dominant in normal-weight and obese individuals but significantly decreased in post-gastric-bypass individuals, who had a proportional increase of Gammaproteobacteria. Numbers of the H(2)-producing Prevotellaceae were highly enriched in the obese individuals. Unlike the highly diverse Bacteria, the Archaea comprised mainly members of the order Methanobacteriales, which are H(2)-oxidizing methanogens. Using real-time PCR, we detected significantly higher numbers of H(2)-utilizing methanogenic Archaea in obese individuals than in normal-weight or post-gastric-bypass individuals. The coexistence of H(2)-producing bacteria with relatively high numbers of H(2)-utilizing methanogenic Archaea in the gastrointestinal tract of obese individuals leads to the hypothesis that interspecies H(2) transfer between bacterial and archaeal species is an important mechanism for increasing energy uptake by the human large intestine in obese persons. The large bacterial population shift seen in the post-gastric-bypass individuals may reflect the double impact of the gut alteration caused by the surgical procedure and the consequent changes in food ingestion and digestion.
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The objective of this work was to elucidate if breast milk contains bifidobacteria and whether they can be transmitted to the infant gut through breastfeeding. Twenty-three women and their respective infants provided samples of breast milk and feces, respectively, at days 4 to 7 after birth. Gram-positive and catalase-negative isolates from specific media with typical bifidobacterial shapes were identified to the genus level by F6PPK (fructose-6-phosphate phosphoketolase) assays and to the species level by 16S rRNA gene sequencing. Bifidobacterial communities in breast milk were assessed by PCR-denaturing gradient gel electrophoresis (PCR-DGGE), and their levels were estimated by quantitative real-time PCR (qRTi-PCR). Bifidobacteria were present in 8 milk samples and 21 fecal samples. Bifidobacterium breve, B. adolescentis, and B. bifidum were isolated from milk samples, while infant feces also contained B. longum and B. pseudocatenulatum. PCR-DGGE revealed the presence of one to four dominant bifidobacterial bands in 22 milk samples. Sequences with similarities above 98% were identified as Bifidobacterium breve, B. adolescentis, B. longum, B. bifidum, and B. dentium. Bifidobacterial DNA was detected by qRTi-PCR in the same 22 milk samples at a range between 40 and 10,000 16S rRNA gene copies per ml. In conclusion, human milk seems to be a source of living bifidobacteria for the infant gut.
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The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).
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The human body is colonized by an enormous population of bacteria (microbiota) that provides the host with coding capacity and metabolic activities. Among the human gut microbiota are health-promoting indigenous species (probiotic bacteria) that are commonly consumed as live dietary supplements. Recent genomics-based studies (probiogenomics) are starting to provide insights into how probiotic bacteria sense and adapt to the gastrointestinal tract environment. In this Review, we discuss the application of probiogenomics in the elucidation of the molecular basis of probiosis using the well-recognized model probiotic bacteria genera Bifidobacterium and Lactobacillus as examples.
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The human intestinal microbiota is essential to the health of the host and plays a role in nutrition, development, metabolism, pathogen resistance, and regulation of immune responses. Antibiotics may disrupt these coevolved interactions, leading to acute or chronic disease in some individuals. Our understanding of antibiotic-associated disturbance of the microbiota has been limited by the poor sensitivity, inadequate resolution, and significant cost of current research methods. The use of pyrosequencing technology to generate large numbers of 16S rDNA sequence tags circumvents these limitations and has been shown to reveal previously unexplored aspects of the "rare biosphere." We investigated the distal gut bacterial communities of three healthy humans before and after treatment with ciprofloxacin, obtaining more than 7,000 full-length rRNA sequences and over 900,000 pyrosequencing reads from two hypervariable regions of the rRNA gene. A companion paper in PLoS Genetics (see Huse et al., doi: 10.1371/journal.pgen.1000255) shows that the taxonomic information obtained with these methods is concordant. Pyrosequencing of the V6 and V3 variable regions identified 3,300-5,700 taxa that collectively accounted for over 99% of the variable region sequence tags that could be obtained from these samples. Ciprofloxacin treatment influenced the abundance of about a third of the bacterial taxa in the gut, decreasing the taxonomic richness, diversity, and evenness of the community. However, the magnitude of this effect varied among individuals, and some taxa showed interindividual variation in the response to ciprofloxacin. While differences of community composition between individuals were the largest source of variability between samples, we found that two unrelated individuals shared a surprising degree of community similarity. In all three individuals, the taxonomic composition of the community closely resembled its pretreatment state by 4 weeks after the end of treatment, but several taxa failed to recover within 6 months. These pervasive effects of ciprofloxacin on community composition contrast with the reports by participants of normal intestinal function and with prior assumptions of only modest effects of ciprofloxacin on the intestinal microbiota. These observations support the hypothesis of functional redundancy in the human gut microbiota. The rapid return to the pretreatment community composition is indicative of factors promoting community resilience, the nature of which deserves future investigation.
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A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-κB activity, F. prausnitzii had no effect on IL-1β-induced NF-κB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-γ production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-κB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment. • IBD • microbiota • probiotic
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The aerobic and anaerobic intestinal microflora of 60 newborn infants in Addis Ababa was studied. As opposed to earlier published studies from Stockholm, there were no consistent changes of the microflora attributable to antibiotic treatment. The reason why antimicrobial agents caused quantitatively smaller changes of the intestinal microflora in newborn infants in Addis Ababa than in Stockholm is not known, but may be due to antimicrobial inactivation, or marked, continuous ingestion of bacteria. Colonisation by potentially pathogenic gram-negative bacteria was coupled to a low isolation rate of bifidobacterium, but not of lactobacillus. This is consistent with the hypothesis that bifidobacterium might convey some kind of resistance to colonisation by and overgrowth of gram-negative bacteria in newborn infants. Similar results have previously been obtained in Stockholm. In comparison to 45 healthy infants in Stockholm, the Ethiopian infants had more enterococcus and lactobacillus and less staphylococcus and bacteroides during the first 2 weeks of life. After that time, the only difference was more frequent colonisation by lactobacillus in Addis Ababa.
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The frequent discrepancy between direct microscopic counts and numbers of culturable bacteria from environmental samples is just one of several indications that we currently know only a minor part of the diversity of microorganisms in nature. A combination of direct retrieval of rRNA sequences and whole-cell oligonucleotide probing can be used to detect specific rRNA sequences of uncultured bacteria in natural samples and to microscopically identify individual cells. Studies have been performed with microbial assemblages of various complexities ranging from simple two-component bacterial endosymbiotic associations to multispecies enrichments containing magnetotactic bacteria to highly complex marine and soil communities. Phylogenetic analysis of the retrieved rRNA sequence of an uncultured microorganism reveals its closest culturable relatives and may, together with information on the physicochemical conditions of its natural habitat, facilitate more directed cultivation attempts. For the analysis of complex communities such as multispecies biofilms and activated-sludge flocs, a different approach has proven advantageous. Sets of probes specific to different taxonomic levels are applied consecutively beginning with the more general and ending with the more specific (a hierarchical top-to-bottom approach), thereby generating increasingly precise information on the structure of the community. Not only do rRNA-targeted whole-cell hybridizations yield data on cell morphology, specific cell counts, and in situ distributions of defined phylogenetic groups, but also the strength of the hybridization signal reflects the cellular rRNA content of individual cells. From the signal strength conferred by a specific probe, in situ growth rates and activities of individual cells might be estimated for known species. In many ecosystems, low cellular rRNA content and/or limited cell permeability, combined with background fluorescence, hinders in situ identification of autochthonous populations. Approaches to circumvent these problems are discussed in detail.
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We have studied the effects of a life-long antigen stimulation on the clonal heterogeneity of human peripheral T cell subsets, as defined by their CD45 isoform expression. CD4+ or CD8+ T cells were obtained from healthy donors ranging in age from 20 to 100 years, and sorted into CD45RA+ and CD45RO+ populations. A modified PCR-heteroduplex analysis was then used to directly compare the TCR Vbeta clonal make up of either compartment pair. We find that the CD4+ T cell repertoire remains largely polyclonal throughout life, since CD4+ expanded clones are rare and accumulate predominantly in the CD45RO+ compartment of exceptionally old donors (100 years old). In contrast, the CD8+ T cell subset contains expanded clones which are already detectable in young adults and become very frequent in 70- to 75-year-old donors in both CD45RA+ and CD45RO+ compartments analyzed. Interestingly, some expanded clones are detectable in the CD45RA+ or in both CD45RA+ and CD45RO+ compartments of either CD4+ or CD8+ T cells. These results indicate that the age-dependent accumulation of expanded clones starts earlier and is more pronounced in the CD8+ than in the CD4+ T cell subset, reinforcing the concept that clonal expansion in the two subsets is controlled by substantially different mechanisms. Furthermore, whereas the finding of expanded CD45RO+ T cell clones is explained by antigen-driven proliferation, the detection of expanded clones in the CD45RA+ or in both CD45RA+ and CD45RO+ compartments would support the hypothesis of reversion from the CD45RO+ to the CD45RA+ phenotype after antigen encounter.
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The Escherichia coli flora of infants in developed countries is dominated by one or a few strains which persist for prolonged periods of time, but no longitudinal studies have been performed in developing countries. To this end, we studied the rectal enterobacterial flora in 22 home-delivered Pakistani infants during their first 6 months of life. Three colonies were isolated and species typed on each of 11 sampling occasions. E. coli isolates were strain typed using electromorphic typing of cytoplasmic enzymes, and their O serogroups were determined. There was a very rapid turnover of enterobacterial strains in the rectal flora of individual infants. On average, 8.5 different E. coli strains were found per infant, and several biotypes of other enterobacteria. Less than 50% of the infants were colonized with E. coli from their mothers, but strains of maternal origin were four times more likely to persists in the infants' flora than other E. coli strains. Enterobacteria other than E. coli were always of non-maternal origin, and Enterobacter cloacae and Klebsiella pneumoniae biotypes recovered from contaminated feeds were later identified in the infants' rectal flora. An early colonization with klebsiella or enterobacter was significantly associated with diarrhoea during the neonatal period, although these bacteria were not likely to be the cause of the disease. The results suggest that poor hygienic conditions result in an unstable and diverse enterobacterial flora, which may influence infant health.
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In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
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The frequent discrepancy between direct microscopic counts and numbers of culturable bacteria from environmental samples is just one of several indications that we currently know only a minor part of the diversity of microorganisms in nature. A combination of direct retrieval of rRNA sequences and whole-cell oligonucleotide probing can be used to detect specific rRNA sequences of uncultured bacteria in natural samples and to microscopically identify individual cells. Studies have been performed with microbial assemblages of various complexities ranging from simple two-component bacterial endosymbiotic associations to multispecies enrichments containing magnetotactic bacteria to highly complex marine and soil communities. Phylogenetic analysis of the retrieved rRNA sequence of an uncultured microorganism reveals its closest culturable relatives and may, together with information on the physicochemical conditions of its natural habitat, facilitate more directed cultivation attempts. For the analysis of complex communities such as multispecies biofilms and activated-sludge flocs, a different approach has proven advantageous. Sets of probes specific to different taxonomic levels are applied consecutively beginning with the more general and ending with the more specific (a hierarchical top-to-bottom approach), thereby generating increasingly precise information on the structure of the community. Not only do rRNA-targeted whole-cell hybridizations yield data on cell morphology, specific cell counts, and in situ distributions of defined phylogenetic groups, but also the strength of the hybridization signal reflects the cellular rRNA content of individual cells. From the signal strength conferred by a specific probe, in situ growth rates and activities of individual cells might be estimated for known species. In many ecosystems, low cellular rRNA content and/or limited cell permeability, combined with background fluorescence, hinders in situ identification of autochthonous populations. Approaches to circumvent these problems are discussed in detail.
Article
The frequent discrepancy between direct microscopic counts and numbers of culturable bacteria from environmental samples is just one of several indications that we currently know only a minor part of the diversity of microorganisms in nature. A combination of direct retrieval of rRNA sequences and whole-cell oligonucleotide probing can be used to detect specific rRNA sequences of uncultured bacteria in natural samples and to microscopically identify individual cells. Studies have been performed with microbial assemblages of various complexities ranging from simple two-component bacterial endosymbiotic associations to multispecies enrichments containing magnetotactic bacteria to highly complex marine and soil communities. Phylogenetic analysis of the retrieved rRNA sequence of an uncultured microorganism reveals its closest culturable relatives and may, together with information on the physicochemical conditions of its natural habitat, facilitate more directed cultivation attempts. For the analysis of complex communities such as multispecies biofilms and activated-sludge flocs, a different approach has proven advantageous. Sets of probes specific to different taxonomic levels are applied consecutively beginning with the more general and ending with the more specific (a hierarchical top-to-bottom approach), thereby generating increasingly precise information on the structure of the community. Not only do rRNA-targeted whole-cell hybridizations yield data on cell morphology, specific cell counts, and in situ distributions of defined phylogenetic groups, but also the strength of the hybridization signal reflects the cellular rRNA content of individual cells. From the signal strength conferred by a specific probe, in situ growth rates and activities of individual cells might be estimated for known species. In many ecosystems, low cellular rRNA content and/or limited cell permeability, combined with background fluorescence, hinders in situ identification of autochthonous populations. Approaches to circumvent these problems are discussed in detail.