Chapter 6

Human Microbiome and Aging

Seema Joshi and Melissa Navinskey,    Dwight D. Eisenhower Veterans Affairs Medical Center, Leavenworth, KS, United States

Abstract

The past decade has seen an increasing interest in the role of the microbiome on human health. Advances in molecular biology have shed light on trillions of microorganisms living in a stable and mutually beneficial relationship with the human host. In addition, there has been increasing evidence that the gut microbiome has an impact on the host immune system. The structure of the gut microbiome appears to be altered by the aging process with an associated increased inflammatory status known as inflammaging that may be predictive of disease. This article discusses recent evidence related to the microbiome, its role in some common age-related disorders and diseases, along with microbially based strategies for possible treatment and prevention of diseases in the elderly.

Keywords

Microbiome; longevity; aging; sarcopenia; probiotics; prebiotics

Introduction

The role of microorganisms in disease causation has been well established, and the scientific emphasis until recently has been on the prevention and cure of diseases caused by microbes. A dramatic improvement in mortality and morbidity has been seen through improved hygiene, immunization, and antibiotic therapy. However, most interactions between humans and microorganisms do not result in disease. Humans and their microbiome have coevolved over the millennia and live intimately to their mutual benefit (Steves et al., 2016). Recent advances in molecular biology have changed the pathogen-dominated view of human-associated microorganisms, and there has been an increasing interest in the role of the microbiome in human health. Approaches based on gene sequencing have recently allowed complex microbial communities to be characterized more comprehensively and have removed the constraint of being able to identify only microorganisms that can be cultured, greatly increasing knowledge about commensal microorganisms and the mutualistic microorganisms of humans (Dethlefsen et al., 2007).

Joshua Lederberg coined the term human microbiome to describe the ecological community of symbiotic and pathogenic microorganisms that inhabit the human body (Lederberg and McCray, 2001). The human intestinal tract is a nutrient-rich environment packed with as many as 100 trillion microbes, whose collective genome is termed the microbiome (Ley et al., 2006). Collectively, gut microorganisms encode 150-fold more unique genes than the human genome. The gut microbiome may be conceptualized as an additional organ undertaking a vast amount of metabolic reactions that influence the normal physiology and host metabolism (Steves et al., 2016).

Human Microbiome

Advances in bacterial deoxyribonucleic acid sequencing have allowed for characterization of the human commensal bacterial community (microbiota) and its corresponding genome (microbiome). Surveys of healthy adults reveal that a signature composite of bacteria characterizes each unique body habitat (e.g., gut, skin, oral cavity, and vagina) (Zapata and Quagliarello, 2015). Although host-associated microbes are presumably acquired from the environment, the composition of the mammalian microbiota, especially in the gut, is surprisingly different from free-living microbial communities. In the human gut and across human-associated habitats, bacteria comprise the bulk of the biomass and diversity, although archaea, eukaryotes, and viruses are also present in smaller numbers and cannot be neglected (Ursell et al., 2012).

Estimates of the human gene catalog and the diversity of the human genome pale in comparison to estimates of the diversity of the microbiome. The MetaHIT consortium reported a gene catalog of 3.3 million nonredundant genes in the human gut microbiome alone as compared to the 22,000 genes present in the entire human genome (Qin et al., 2010; Consortium IHGS, 2004). Similarly, the diversity among the microbiome of individuals is immense compared to genomic variation: individual humans are about 99.9% identical to one another in terms of their host genome but can be 80–90% different from one another in terms of the microbiome of their hand or gut (Ursell et al., 2012).

The Human Microbiome Project (HMP), a multidisciplinary international effort, was launched in 2007 to characterize the microbial community within the human body. In 2012, the consortium reported a large study that recruited 242 healthy US adults of both sexes aged 18–40 years to further characterize the microbiota and microbiome. Subjects underwent sampling from various body sites, including the skin, nose, mouth, throat, vagina, and feces. The study confirmed previous findings that each body habitat had a distinct microbial community with a signature composite of taxa. Most metabolic pathways were uniformly distributed across individuals and body habitats, indicating a redundancy in bacterial metabolism. The oral cavity and the stool had the most diverse bacterial communities (the most alpha diversity). Conversely, the vaginal microbial community showed the lowest alpha diversity, with domination by Lactobacillus species. The oral cavity had the lowest diversity between subjects (beta diversity), whereas the skin had the highest beta diversity. In the gut, microbiota showed an inverse relationship between the phyla Bacteroidetes and Firmicutes; subjects dominant in Bacteroidetes had a minority of Firmicutes (Zapata and Quagliarello, 2015; Human Microbiome Project Consortium, 2012).

Microbiome Through the Human Life Cycle

The establishment of a stable microbial population involves complex processes such as bacterial succession and host microbe interactions (Lakshminarayanan et al., 2014). Newborns have bacterial communities that reflect the mode of delivery. Vaginally delivered newborns have bacterial communities dominated by vaginal flora such as Lactobacillus species. Conversely, newborns delivered by cesarean section have microbiota dominant in skin flora, such as Staphylococcus species. The microbiota of the infant gut become more diverse over time with dietary changes. Ingestion of solid food results in an increase in gut Bacteroidetes. By age three, composition of the gut microbiota in children approximates that seen in adults (Dominguez-Bello et al., 2010; Koenig et al., 2011; Yatsunenko et al., 2012).

It has been noted that species diversity of the intestinal microbiota changes with age. Bifidobacterium species are decreased while Bacteroides increase in the elderly when compared to younger adults (Hopkins et al., 2002). Factors such as clinical changes associated with aging and exposure to multiple medications, including antibiotics, may contribute to changes in the microbiota. A study that analyzed stool samples from more than 35,000 adults reported that colony-forming units remained stable and showed no age- or sex-related changes. However, individual bacterial species such as Escherichia coli and Enterococcus species constantly and significantly increased with age; Bacteroides spp. decreased with increasing age, while Lactobacilli and Bifidobacteria remained stable through the lifespan. The colonic microbiota demonstrated the most profound changes during the last decades of life (age >60 years). It remains to be shown whether these changes reflect direct changes of the gut microbiota, the mucosal innate immunity, or indirect consequences of age-related altered nutrition (Enck et al., 2009).

The study reported by the HMP consortium in 2012 suggested that the bacterial communities from various human habitats were relatively stable from baseline to repeat sampling within the same subject, but there was large variation between subjects. The stability of the microbiome within an individual therefore suggests a mutually beneficial stable coexistence between the microbiota and the human host. This may imply that any disturbance in the microbiota may be predictive of disease (Human Microbiome Project Consortium, 2004; Zapata and Quagliarello, 2015).

Microbiome and the Immune Response

The study by Biagi et al. to explore the age-related differences in both the inflammatory status and the gut ecosystem composition of not only young adults (20–40 years old) and elderly (60–80 years old) but also centenarians revealed that centenarians harbor a less diverse microbiota. Bacteroidetes and Firmicutes still constitute the dominant phyla with enrichment of potentially pathogenic Proteobacteria. The microbiota show a marked decrease in Faecalibacterium prausnitzii and relative symbiotic species with reported antiinflammatory properties (Biagi et al., 2010). A subsequent functional microbiome profiling of selected, well-characterized samples from this cohort indicated increased abundance of genes involved in aromatic amino acid metabolism, decreased abundance of those involved in short-chain (≤6) fatty acid production and an enrichment of pathobionts, low-abundance microbiota that promote and sustain proinflammatory conditions (Rampelli et al., 2013).

The aging process thus deeply affects the structure of the human gut microbiota as well as their homeostasis with the host’s immune system. The presence of a compromised microbiota is associated with an increased inflammatory status, which is also known as inflammaging. This is reflected by an increase in proinflammatory cytokines (IL-6 and IL-8) in the peripheral blood and correlates with changes in the gut microbiota profile of centenarians (Biagi et al., 2010).

This study by Biagi et al. revealed a rearrangement in the population of butyrate-producing bacteria in centenarians. Butyrate is a short-chain fatty acid mainly produced in the gut by Firmicutes of the Clostridium clusters IV and XIVa, which is receiving a growing interest in the gut ecology because it represents a major energy source for the enterocytes and has been implicated in the protection against inflammatory bowel diseases. Several butyrate producers were found in lower amounts in centenarians than in other age groups (Biagi et al., 2010).

The microbiota play a crucial role in the host physiology and health status, thus age-related differences in the gut microbiota composition may contribute to inflammaging or itself be affected by the systemic inflammatory status. It may also be related to the progression of diseases and frailty in the elderly population (Biagi et al., 2010).

Impact of Diet on Microbiota

Several factors—including age, genetics, and diet—may influence the microbiome composition. Of these, diet is the easiest to modify and presents the simplest route for therapeutic intervention. A high fat–low fiber Western diet contributes to a Bacteroides-dominant gut microbiome, whereas a low fat–high fiber diet is associated with a Firmicutes-dominant microbiome. There appears to be a strong correlation between long-term diet and enterotypes (gut microbial variants) (Wu et al., 2011).

A study by David et al. examined the impact of dietary interventions on gut microbial communities and revealed that an animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila, and Bacteroides) and decreased the levels of Firmicutes (Roseburia, Eubacterium rectale, and Ruminococcus bromii) that metabolize dietary plant polysaccharides. Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation (David et al., 2014).

By promoting changes in host bile acid composition, dietary fats can dramatically alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. Increases in the abundance and activity of Bilophila wadsworthia on an animal-based diet support a link between dietary fat, bile acids, and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. Current data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases such as inflammatory bowel diseases in genetically susceptible hosts (Devkota et al., 2012). Ultimately, the impact of diet on the human gut microbiota may be an important environmental factor involved in the pathogenesis of disease states that are rapidly growing in industrialized nations (Bushman et al., 2013).

Therapeutic Interventions for Microbial Manipulation

Functional Foods: Prebiotics and Probiotics

Prebiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of one or a limited number of bacterial species already resident in the colon and thus attempt to improve host health. Gibson et al. defined three criteria for classifying a food ingredient as a prebiotic. These include (1) resistance to gastric acidity, hydrolysis by mammalian enzymes, and gastrointestinal absorption; (2) fermentation by intestinal microflora; and (3) selective stimulation of the growth or activity of intestinal bacteria associated with health and well-being (Gibson and Roberfroid, 1995; Gibson et al., 2004). Currently, the prebiotics that fulfill these three criteria are fructooligosaccharides, galactooligosaccharides (GOS), lactulose, and nondigestible carbohydrates (inulin, resistant starches, cellulose, hemicellulose, pectins, and gums) (Yoo and Kim, 2016).

Aging is associated with various changes to the human colonic microbiota. Most relevant is a reduction in Bifidobacteria, which is a health-positive genus. Prebiotics such as GOS are dietary ingredients that selectively fortify beneficial gut microbial groups. Therefore, they have the potential to reverse the age-related decline in Bifidobacteria and modulate associated health parameters. Vulevic et al. assessed the effect of a Bimuno and GOS (B-GOS) on gut microbiota, markers of immune function, and metabolites in 40 older (age 65–80 years) volunteers in a randomized, double-blind, placebo-controlled, crossover study. The intervention periods consisted of 10 weeks with daily doses of 5.5 g/day with a 4-week washout period in between. Blood and fecal samples were collected for the analyses of fecal bacterial populations and immune and metabolic biomarkers. B-GOS consumption led to significant increases in Bacteroides and Bifidobacteria, the latter correlating with increased lactic acid in fecal waters. Higher IL-10, IL-8, natural killer cell activity, and C-reactive protein and lower IL-1β were also observed. The authors suggested that administration of B-GOS to elderly volunteers may be useful in positively affecting the microbiota and some markers of immune function associated with aging (Vulevic et al., 2015).

The term probiotic originates from the Greek and means “for life.” Probiotics have been defined as live microbial feed supplements that beneficially affect the host animal by improving its intestinal balance (Fuller, 1989). At the beginning of the 20th century, Metchnikoff associated healthy aging with a specific type of gut microbiota. He observed that populations with a high yogurt consumption also showed increased longevity. He proposed that the consumption of yogurt containing Lactobacillus would result in a decrease in toxin-producing bacteria in the gut and increase in host longevity (Mackowiak, 2013). Subsequent studies noted a reduction in serum cholesterol following consumption of copious amounts of milk fermented with Lactobacillus or Bifidobacterium or both (Sharp et al., 2008; Mann, 1977). A randomized, double-blind, placebo-controlled, 4-week crossover study using a synbiotic (synergistic combinations of a probiotic and prebiotic) was done on healthy volunteers ages 65–90 years. The synbiotic comprised the probiotic Bifidobacterium longum and an inulin-based prebiotic. Treatment group was noted to have increased numbers of Bifidobacteria, Actinobacteria, and Firmicutes (p<.0001) and a reduction in Proteobacteria (p<.0001). Synbiotic feeding was associated with increased butyrate production and significantly reduced proinflammatory cytokine TNF-α in the peripheral blood at 2 and 4 weeks postsynbiotic consumption. The study suggested that short-term synbiotic use may be effective in improving the composition and metabolic activities of colonic bacterial communities and immune parameters in older people (Macfarlane et al., 2013).

Bacteriotherapy

Fecal microbial transplantation (FMT) to restore the normal microbiome of the colon is performed for recurrent and severe Clostridium difficile infection (CDI). A meta-analysis that included two randomized controlled trials and multiple case series covering 516 patients found an 85% success rate with FMT compared with only 20% success for vancomycin for the treatment of CDI (Drekonja et al., 2015). A recent randomized trial was stopped early because of the overwhelming superiority of FMT: 90% success rate compared with 26% for vancomycin (Cammarota et al., 2015).

FMT or bacteriotherapy is now routinely offered in 500 centers across the United States. It is possible that donor or engineered microbial transplantation could also be used to treat other microbe-associated diseases. However, there is a need for firm evidence supporting its efficacy, along with a better understanding of the mechanism of action and safety in other disease processes. Intervention studies targeting the gut microbiome in age-related diseases might provide an insight and help determine whether there is a clinical window for microbiome manipulations to reduce severity of diseases in the elderly (Spector and Knight, 2015; Petrof and Khoruts, 2014).

Implications for Health and Disease

The role of host-associated microbiota, especially the gut microbiome, has received tremendous interest for their potential association with health. Age-associated changes in the colonic microbiota are profound, especially in the last decades of life. An important concern exists regarding the biological significance of alterations in the microbiota and their impact on disease causation.

The gut microbiota have a large impact on the immune system and deal with a large number of bacterial antigenic substances on a daily basis. In fact, there is no larger immune organ in the body than the gut. Thus the gut–microbe interaction is critical for the establishment of a healthy immune system. It is possible that the gut microbiota have a role in stimulating production of the inflammatory molecules that are a hallmark of persistent inflammation in the elderly and lead to chronic health conditions and modulation of the aging process (Lynch et al., 2015; Zapata and Quagliarello, 2015).

Currently, definitive evidence for disease causation by the microbiota is lacking. However, there seems to be an alteration of the microbiota with age and disease processes. The following is a review of some disease states and possible associations with the microbiome.

Frailty

The medical community has not agreed on one specific definition of frailty, but the general consensus is that frailty is a term used to describe multisystem physiological changes (cognition, energy, health, and physical ability) that can render an individual vulnerable (Rockwood Mitnitski, 2007; Rockwood et al., 2005). Jackson et al. describes frailty as a useful indicator of overall health deficit, describing a physiological loss of reserve capacity and reduced resistance to stressors (Jackson et al., 2016). An assessment of an individual’s frailty is thought to predict unfavorable outcomes such as mortality and hospitalization better than chronological age (Jackson et al., 2016; Mitnitski et al., 2001).

A study of 23 elderly individuals reviewed the composition of the fecal microbiota and the link between the composition and an individual’s frailty score. This study revealed that the anaerobic microorganisms Lactobacilli, Bacteroides, and Faecalibacterium prausnitzii were significantly reduced in the individuals with high frailty scores (Van Tongeren et al., 2005). The same study also concluded that members of the Enterobacteriaceae family were present in higher amounts in individuals with high frailty scores (Van Tongeren et al., 2005). Lactobacilli, Bacteroides, and Faecalibacterium species are known producers of butyrate, a beneficial short-chain fatty acid required for a healthy colon (Meehan et al., 2015; Hague et al., 1997). The decrease of these species in elderly individuals may have an inverse effect on the health of the gut and could have implications for an individual’s frailty score (Claesson et al., 2012). The potential link between frailty and an individual’s microbiota is evident from past research, but other factors associated with aging may also contribute to frailty such as diet, changes in living conditions, permanent moves to long-term care facilities, and more frequent visits to hospitals (Claesson et al., 2012). When assessing frailty in an individual, one cannot rule out the importance the microbiome may play on an individual’s overall health and wellness. Further studies are needed to determine if altering an elderly individual’s microbiome with the addition of probiotics and diet positively impact the frailty index and improve perceived health.

Sarcopenia

Sarcopenia is the loss of muscle mass in an older person. The scientific definition is a measure of muscle mass loss that is two standard deviations less than the mean for young persons (Morley, 2008; Morley, 2012). Disability is regularly associated with sarcopenia, and it occurs in approximately one in every 20 persons ages 65 years and can occur in 50% of those greater than 80 years of age (Morley, 2012). The associated disability related to sarcopenia can lead to increased risk of falls, loss of independence, impaired ability to perform activities of daily living, and increased risk of death (Steves et al., 2016). A proposed link between the gut microbiome and muscle wasting was studied by Bindles and colleagues. This study conducted research on the gut microbiota in mouse models with leukemia, which in later stages can display muscle atrophy, anorexia, inflammation, and loss of fat mass. The study revealed an imbalance and a selective modulation in Lactobacillus species in the mice inoculated with leukemia when compared with the control group. The leukemia group was then orally supplemented with Lactobacillus species (L. reuteri and L. gasseri) and doing so produced reduced expression of atrophy markers (Bindels et al., 2012). While human studies are needed to further explore the link between the human gut microbiome and its relationship to sarcopenia, the study by Bindels and colleagues does suggest that a potential link exists.

Clostridium Difficile Infection

Clostridium difficile is a gram-positive, spore-forming, anaerobic bacillus, first discovered in 1978 as the leading bacterial cause of pseudomembranous colitis and antibiotic-associated diarrhea (AAD) (Mylonakis et al., 2001; Bartlett et al., 1978; De Pestel and Aronoff, 2013). Clostridium difficile is the most commonly recognized cause of infections diarrhea in health-care settings and accounts for 20–30% of cases of AAD (Cohen et al., 2010). Incidence rates of C. difficile infection are highest among those 65 and older compared to other age groups. Hospitalization rates for CDI are highest for those 85 and older (1089 per 100,000 population) (Lucado et al., 2012). Clostridium difficile does not cause major disease unless there is a disruption of the intestinal flora, which can happen with antibiotic use. Associated proliferation of C. difficile can lead to inflammation and damage to the lining of the intestine with resulting life-threatening illness (Bien et al., 2013; Wilson, 1993). Research was conducted by Rea and colleagues on C. difficile carriage in elderly subjects and associated changes in the intestinal microbiota. Their findings revealed large variabilities in the composition of the microbiota among subjects in the C. difficile negative and positive groups (Rea et al., 2012). Research related to the manipulation of the gut microbiota and the potential link between the prevention of C. difficile–associated diarrhea has revealed varied results with regard to probiotic therapy. A pilot study of 150 subjects by Plummer and colleagues researched the effect of probiotic supplementation on the incidence of C. difficile diarrhea during antibiotic treatment in the elderly. In the subjects who developed diarrhea, C. difficile–associated toxin was found to be less in the probiotic group compared to the placebo group. Also samples from the probiotic group had less occurrence of being toxinpositive when compared to the placebo group (Plummer et al., 2004). Recently, the PLACIDE trial conducted by Allen and colleagues studied 2981 subjects and the effect of administering Lactobacilli and Bifidobacteria in the prevention of AAD and C. difficile diarrhea (CDD) in older inpatients. The trial found no significant difference in prevention of AAD or CDD between the microbial preparation group and the placebo group (Allen et al., 2013). FMT, another manipulation strategy of the gut microbiota, has been studied in patients suffering from recurrent CDI. Preliminary results related to FMT for the treatment of CDI have been promising with reported cure rates of more than 80% (Youngster et al., 2014; Van Nood et al., 2013). A meta-analysis of two randomized controlled trials and multiple case series found an 85% success rate with FMT as opposed to a 20% success rate with vancomycin for CDI. Another randomized trial was stopped early because of the overwhelming superiority of FMT when compared with to vancomycin for the treatment of CDI (Drekonja et al., 2015; Cammarota et al., 2015).

Larger, randomized controlled trials are needed to determine if FMT can be generalized across different patient subtypes or if this option provides long-term cure rate for those suffering from recurrent CDI.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by symptoms of abdominal pain or discomfort that is associated with disturbed defecation (Drossman et al., 2002). Patients with IBS typically present in the third or fourth decade of life; IBS is characteristically more prevalent in females (Saito et al., 2002; Bennett and Talley, 2002; Ruigomez et al., 1999). A systematic review of IBS in North America revealed that the prevalence of IBS did not change significantly with age and occurs in approximately one in 10 individuals across all ages. However, research conducted by Ruigomez and colleagues concluded that newly diagnosed cases of IBS occur less frequently in people greater than 60 years old when compared to other age groups (Bennett and Talley, 2002; Ruigomez et al., 1999). Evidence suggests there is a reduction in IBS prevalence in the elderly due to reduced pain perception with age (Lagier et al., 1999). Also bear in mind that the geriatric population has a higher prevalence of other diseases such as colon cancer and mesenteric ischemia, which can be displayed as intermittent IBS symptoms on presentation (Bennett and Talley, 2002). Research conducted by Tana and colleagues studied the correlation between gastrointestinal microbiota and their contribution to IBS symptoms through increased levels of organic acids. Twenty-six IBS patients were matched with 26 age- and sex-matched controls. The results of the study revealed IBS patients showed significantly higher counts of Veillonella and Lactobacillus when compared to controls. Study participants with IBS also had higher levels of acetic acid and propionic acid than did the controls. Acetic acid and propionic acid are known by-products of Veillonella and Lactobacillus, and high levels of these acids may be associated with abdominal symptoms, impaired quality of life, and negative emotions in those who suffer from IBS (Tana et al., 2010).

Based on current research, there appears to be a preliminary link between a disruption in intestinal microbiota and development of IBS. However, one must also consider the complex pathophysiology of IBS and other factors such as dietary indiscretions, lifestyle changes, and psychological stress that may also trigger symptoms (Drossman et al., 2002). Pharmacologic modalities are available to treat IBS, but cure and complete resolution of symptoms are perplexing due to the poorly defined pathophysiology related to IBS (Distrutti et al., 2016). Distrutti and colleagues discussed several systematic reviews that have been conducted related to the use of probiotics and have reported improvement in IBS symptoms. They concluded the evidence related to the manipulation of gut microbiota as an effective cure for IBS is increasing, and probiotic supplementation is a promising strategy for treatment. However, adequate randomized controlled trials of proper length are still needed to definitively determine whether addition of probiotics would be a primary treatment strategy for patients with IBS (Distrutti et al., 2016).

Anxiety and Depression

The US Centers for Disease Control and Prevention estimate that the rate of occurrence of major depression in older adults ranges from less than 1% to 5% for those living in the community, 11.5% in older hospitalized patients, and 13.5% among those who require home healthcare. In 2014, older adults were at an increased risk of depression and associated morbidity with a suicide risk as high as 16.6% among individuals 65 years and older (Drapeu and McIntosh, 2015).

Historically, research related to depression and anxiety has largely focused on neurotransmitters in the brain, and researchers have concentrated on the central nervous system (CNS) and how it controls exhibited behaviors and moods. Recently, a change in this approach and new research has illuminated the distinctive role of gut microbes and their effect on emotional and stress responses (Friedrich, 2015; Foster and McVey Neufeld, 2013). Research on the gut microbes and their effect on mood has been conducted in animals such as mice. A review by Carabotti et al. looked at the research related to the gut–brain axis and the bidirectional communication between the central and enteric nervous system. This review suggests that the gut microbiome plays an important role in the two-way interaction between the CNS and the gut. The gut microbiome interacts with CNS by regulating brain chemistry and influencing neuroendocrine systems associated with stress response, anxiety, and memory function (Carabotti et al., 2015).

Bravo and colleagues tested the manipulation of the gut microbiome on mouse models with the ingestion of Lactobacillus and the effect it had on emotional behavior and central gamma-aminobutyric acid receptor expression. The findings resulted in reduced stress-induced corticosterone and anxiety- and depression-related behavior in the group that ingested Lactobacillus. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain (Bravo et al., 2011).

Most studies related to the microbiome–gut–brain axis have been conducted on mice. Validation of the role of the gut–brain axis on modulation of human behavior is still needed. Current studies offer intriguing opportunities to develop microbially based strategies such as pre- or probiotics for the treatment of stress-related behavioral disorders.

Conclusion

Interest in the role of the human microbiome in health has been increasing over the years. Recent advances in molecular biology have shifted our pathogen-dominated view of microorganisms to their role in human health. There has been a dramatic increase in knowledge related to the mutually beneficial stable coexistence between microbiota and the human host. Aging affects the structure of the human gut microbiota, as well as their homeostasis with the host’s immune system. Presence of a compromised microbiota has been associated with an increased inflammatory status, which is known as inflammaging. The implications of this knowledge are intriguing and suggest that a disturbance in the microbiota may be predictive of disease.

There also appears to be a strong correlation between long-term diet and microbial variants in the gut. Thus, diet may impact the human microbiota by making them an important environmental factor in the pathogenesis of diseases that are rapidly increasing in incidence in industrialized nations.

The impact of fecal transplants in C. difficile infections has highlighted the possible role of microbiome manipulation in treatment and prevention of disease. Although more human trials will be needed, there appears to be a tremendous potential for developing microbially based strategies for the treatment and prevention of diseases in the elderly.

Acknowledgment

This material is the result of work supported with resources and the use of facilities at the Dwight D. Eisenhower Veterans Affairs Medical Center, Leavenworth, KS, USA.

References

1. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multicenter trial. Lancet. 2013;382:1249–1257.

2. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298:531–534.

3. Bennett G, Talley NJ. Irritable bowel syndrome in the elderly. Clin Gastroenterol. 2002;16(1):63–76.

4. Biagi E, Nylund L, Candela M, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One. 2010;5(5):e10667.

5. Bien J, Palagani V, Bozko P. The intestinal microbiota dysbiosis and clostridium difficile infection: is there a relationship with inflammatory bowel disease? Ther Adv Gastroenterol. 2013;6(1):53–68.

6. Bindels LB, Beck R, Schakman O, et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLoS One. 2012;7(6):e37971.

7. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS. 2011;108(38):16050–16055.

8. Bushman FD, Lewis JD, Wu GD. Diet, gut enterotypes and health: is there a link? Nestle Nutr Inst Workshop Ser. 2013;77:65–73.

9. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharm Ther. 2015;41:835–843.

10. Carabotti M, Scirocco MMA, Severi M. The gut-brain axis: interactions between enteric microbiota, centeral and enteric nervous systems. Ann Gastroenterol. 2015;28:203–209.

11. Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–185.

12. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society of Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431–455.

13. Consortium IHGS. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–945.

14. David LA, Maurice CF, Carmody RN, Gootenberg DB, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559–563.

15. DePestel DD, Aronoff DM. Epidemiology of Clostridium difficile infection. J Pharm Pract. 2013;26(5):464–475.

16. Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on human–microbe mutualism and disease. Nature. 2007;449:811–818.

17. Devkota S, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/−mice. Nature. 2012;487:104–108.

18. Distrutti E, Monaldi L, Ricci P, Fiorucci S. Gut microbiota role in irritable bowel syndrome: new therapeutic strategies. World J Gastroenterol. 2016;22(7):2219–2241.

19. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107:11971–11975.

20. Drapeu, C.W., McIntosh, J.L., 2015. U.S.A. suicide 2014: Official final data. Washington, DC: American Association of Suicidology, dated December 22, 2015, downloaded from http://www.suicidology.org. Accessed March 15, 2016.

21. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med. 2015;162:630–638.

22. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108–2131.

23. Enck P, Zimmermann K, Rusch K, et al. The effects of ageing on the colonic bacterial microflora in adults. Z Gastroenterol. 2009;47:653–658.

24. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–312.

25. Friedrich MJ. Unraveling the influence of gut microbes on the mind. JAMA. 2015;313(17):1699–1701.

26. Fuller R. Probiotics in man and animals. J Appl Bacteriol. 1989;66:365–378.

27. Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev. 2004;17:259–275.

28. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;1995(125):1401–1412.

29. Hague A, Singh B, Paraskeva C. Butyrate acts as a survival factor for colonic epithelial cells: further fuel for the in vivo in vitro debate. Gastroenterology. 1997;112(3):1036–1040.

30. Hopkins MJ, Sharp R, Macfarlane GT. Variation in human intestinal microbiota with age. Dig Liver Dis. 2002;34(Suppl. 2):S12–S18.

31. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207–214.

32. Jackson M, Jeffery IB, Beaumont M, et al. Signatures of frailty in the gut microbiota. Genome Med. 2016;8(8):1–11.

33. Koenig JE, Spor A, Scalfone N, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA. 2011;108(Suppl. 1):4578–4585.

34. Lagier E, Delvaux M, Vellas B, et al. Influence of age on rectal tone and sensitivity to distension in healthy subjects. Neurogastroenterol Mot. 1999;11:101–107.

35. Lakshminarayanan B, Stanton C, O’Toole PW, Ross RP. Compositional dynamics of the human intestinal microbiota with aging: implications for health. J Nutr Health Aging. 2014;18(9):773–786.

36. Lederberg, J., Mccray, A., 2001. Ome Sweet’Omics—a genealogical treasurey of words. Scientist. 15(8). http://lhncbc.mlm.nih.gov/publication/lhncbc-2001-047.

37. Ley RE, Peteresen DA, Gordon JL. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124(4):837–848.

38. Lucado, J., Gould, C., Elixhauser, A., 2012. Clostridium difficile Infections (CDI) in Hospital Stays, 2009. HCUP Statistical Brief #124. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrg.gove/reports/statbriefs/sb124.pdf. Accessed April 16, 2016.

39. Lynch DB, Jeffery IB, O’Toole PW. The role of the microbiota in ageing: current state and perspectives. WIREs Syst Biol Med. 2015;7:131–138.

40. Macfarlane S, Cleary S, Bahrami B, Reynolds N, Macfarlane GT. Synbiotic consumption changes the metabolism and composition of the gut microbiota in older people and modifies inflammatory processes: a randomised, double-blind, placebo-controlled crossover study. Aliment Pharm Ther. 2013;38:804–816.

41. Mackowiak PA. Recycling Metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front Public Health. 2013;1:52.

42. Mann GV. A factor in yogurt which lowers cholesteremia in man. Atherosclerosis. 1977;26:335–340.

43. Meehan CJ, Langille MGI, Beiko RG. Frailty and the microbiome. Interdiscipl Top Gerontol Geriatr. 2015;41:54–65.

44. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging. Sci World J. 2001;1:323–336.

45. Morley JE. Sarcopenia: diagnosis and treatment. J Nutr Health Aging. 2008;12(7):452–456.

46. Morley JE. Sarcopenia in the elderly. Family Pract. 2012;29:i44–i48.

47. Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficle-associated diarrhea: a review. Arch Intern Med. 2001;161:525–533.

48. Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology. 2014;146(6):1573–1582.

49. Plummer S, Weaver MA, Harris JC, Dee P, Hunter J. Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficlie diarrhea. Intern Microbiol. 2004;7:59–62.

50. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–465.

51. Rampelli S, Candela M, Turroni S, et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging. 2013;5:902–912.

52. Rea MC, O’Sullivan I, Shanahan F, et al. Clostridium difficile carriage in elderly subjects and associated changes in the intestinaal microbiota. J Microbiol. 2012;50(3):867–875.

53. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol. 2007;62A(7):722–727.

54. Rockwood K, Xiaowei S, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173(5):489–495.

55. Ruigomez A, Wallander MA, Johansson S, Rodriguez AG. One-year follow up of newly diagnosed irritable bowel syndrome patients. Aliment Pharm Ther. 1999;13:1097–1102.

56. Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97(8):1910–1915.

57. Sharp MD, McMahon DJ, Broadbent JR. Comparative evaluation of yogurt and low-fat cheddar cheese as delivery media for probiotic lactobacillus casei. J Food Sci. 2008;73:M375–M377.

58. Spector T, Knight R. Faecal transplants. BMJ. 2015;351:h5149.

59. Steves CJ, Bird S, Williams FMK, Spector TD. The microbiome and the musculoskeletal conditions of aging: a review of evidence for impact and potential therapeutics. J Bone Miner Res. 2016;2:261–269.

60. Tana C, Umesaki Y, Imaoka A, et al. Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol Mot. 2010;22 512-e115.

61. Ursell KL, Metcalf JL, Wegener Parfrey L, Knight R. Defining the human microbiome. Nutr Rev. 2012;70(Suppl. 1):S38–S44.

62. Van Nood E, Vrieze A, Nieuwdrop M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407–415.

63. Van Tongeren SP, Slaets JPJ, Harmsen HJM, Welling GW. Fecal microbiota composition and frailty. Appl Environ Microbiol. 2005;71(10):6438–6442.

64. Vulevic J, Juric A, Walton GE, et al. Influence of galacto-oligosaccharide mixture (B-GOS) on gut microbiota, immune parameters and metabonomics in elderly persons. Br J Nutr. 2015;114(4):586–595.

65. Wilson KH. The microecology of Clostridium difficile. Clin Infect Dis. 1993;16:214–218.

66. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–108.

67. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–227.

68. Yoo JY, Kim SS. Probiotics and prebiotics: present status and future perspectives on metabolic disorders. Nutrients. 2016;8:173.

69. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58(11):1515–1522.

70. Zapata HJ, Quagliarello VJ. The microbiota and microbiome in aging: potential implications in health and age-related diseases. J Am Geriatr Soc. 2015;63(4):776–781.

..................Content has been hidden....................

You can't read the all page of ebook, please click here login for view all page.
Reset