Ageless harmony: decoding the microbiome–stem cell nexus in aging

Swarup K. Chakrabarti* [1] Dhrubajyoti Chattopadhyay [1,2] Academia Molecular Biology and Genomics 4 December 2024

Ronald Peters, MD – Commentary

“As above, so below.”

We humans are very good at upsetting the balance of Nature.  The ecology of Mother Earth is polluted with chemicals, heavy metals, plastics and more leading to 70% loss of species and major damage to the land, air and water.  The ecology within us, the microbiome, is also severely disturbed by the Standard Americn Diet, recurrent use of antibiotics and other medications, high levels of stress and sedentary lifestyle which leads to dysbiosis, gut barrier disruption, aka “leaky gut” and subsequent chronic inflammation. The microbiome is a “parallel organ” that is essential for our health, just like Mother Nature.

Abstract

The dynamic interplay between aging stem cells and the microbiota is a burgeoning frontier in biomedical science, unveiling key insights into systemic health maintenance. Among the myriad microbial communities inhabiting the human body, the gut microbiome emerges as a pivotal regulator, heavily influencing stem cell function through the production of an array of bioactive substances, including vitamins, secondary metabolites, and short-chain fatty acids. Delving into these microbial influences reveals their multifaceted effects on various facets of stem cell biology, such as maintenance, proliferation, and differentiation. Together these interactions shape tissue regeneration and repair highlighting the key role of the microbiota in orchestrating cellular homeostasis. Dysbiosis, marked by age-related changes in gut microbiota composition, disrupts the signals necessary for optimal stem cell activation. As a result, tissue regeneration becomes affected, resulting in reduced capacities for repair and renewal with aging. Techniques, such as spatial transcriptomics and single-cell sequencing, provide opportunities to unravel the molecular intricacies underpinning the crosstalk between gut microbes and stem cells within their tissue microenvironments, thereby governing health and longevity. While therapeutics targeting the microbiome hold promise in keeping stem cell homeostasis and tissue repair capacities, the primary focus remains on deepening our understanding of the interplay between the microbiota and stem cells. Such insights not only illuminate age-related decline but also hold great implications for improving human health, which in turn paves the way for newer treatments while laying the groundwork for a deeper evaluation of the microbiome–stem cell axis and its impact on diverse physiological processes.

  1. Introduction

The human microbiome, composed of a diverse array of microorganisms inhabiting both the body’s interior and exterior, plays a fundamental role in overall health [1–3]. Recent scientific inquiry has uncovered an intriguing link between the microbiome and the health of stem cells, which are essential for tissue repair and maintenance [4–6]. This microbial community, predominantly located within the gastrointestinal (GI) tract, significantly influences various bodily functions, including immune response, metabolism, and digestive processes [7, 8].

Furthermore, emerging evidence suggests that the microbiome exerts regulatory control over stem cells, impacting their functionality [4–6]. Dysbiosis, defined by disruptions in the composition and function of the gut microbiota, is increasingly recognized as a contributor to the aging process of stem cells [5, 9, 10]. Microbial imbalances can trigger metabolic disturbances, abnormal immune reactions, and host epigenetic instability, all of which have the potential to compromise stem cell health and functionality of stem cells [11–13].

Additionally, age-related shifts in the composition of mammalian microbiomes often involve older individuals experiencing alterations in the prevalence of specific bacterial phyla [14–16]. For example, there is typically an increase in Firmicutes, gram-positive bacteria adept at breaking down resistant starch and dietary fiber in the gut, while Bacteroidetes, gram-negative bacteria essential for producing short-chain fatty acids (SCFAs) for energy production in the large intestine, tend to decrease. These changes in microbiome composition, both in quantity and in quality, are notably distinct from those observed in middle-aged, healthy adults [14–16].

On the other hand, a prime example of how the regenerative capability of tissue stem cells deteriorates with age is the steady loss of skeletal mass, bone formation, and bone growth [17, 18]. Consistent with this finding, antibiotic treatment in animals also modifies the gut microbiota, leading to decreased bone growth and mass, likely by interfering with the differentiation of bone-resident progenitor stem cells [6, 19]. Conversely, introducing certain gut microbiota into germ-free (GF) mice increases bone mass and development, potentially through its possible impact on the bone’s resident stem cells [20, 21]. To emphasize this point further, stem cell exhaustion is now considered one of the key hallmarks of aging, supported by large-scale evidence [22, 23].

However, the intricate interplay between host microbiota and stem cell functionality in the context of aging remains largely elusive due to its multifaceted nature. A comprehensive review of the literature is essential to grasp the burgeoning significance of the microbiota across diverse domains of regenerative medicine before definitive conclusions can be drawn regarding this pivotal relationship. Accordingly, this article primarily endeavors to elucidate the complex dynamics between stem cell behavior and the microbiome, offering insights into the mechanisms underlying the influence of these microscopic inhabitants on cellular homeostasis.

  1. The intricate relationship between stem cells, aging, and the microbiome

In the realm of aging and tissue regeneration, stem cells offer immense potential due to their remarkable ability to transform into various cell types. However, as stem cells age, their capacity for self-renewal diminishes and their ability to differentiate into diverse cell types become impaired. As a result, there is growing recognition of the notion that the pathophysiology of various age-related diseases could be substantially impacted by the decline in stem cell functions induced by aging [18, 24–26].

Numerous adult stem cell types are found in the body, including neural stem cells (NSCs), hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), skin epidermal stem cells (SESCs), intestinal epithelial stem cells (IESCs), retinal stem cells (RSCs), germline stem cells (GSCs), muscle satellite cells (MuSCs), and pancreatic stem cells (PSCs) [27]. This highlights the significance of stem cell dysfunction in the etiology of various organ-specific, metabolic, and blood-related diseases.

As it turns out, stem cells share a number of common mechanistic characteristics that control their behavior. For example, all types of stem cells express telomerase to promote self-renewal and transition between static and active states; their chromatin exists in two states, euchromatic and heterochromatic, to promote renewal or differentiation; and they have specific metabolic needs that may be used to treat age-related disorders associated with stem cell dysfunction [28–30].

Meanwhile, attention is being focused on unraveling the connection between stem cells and the microbiome, with the aim of understanding how the microbiome sustains the viability and maintenance of stem cells as we age. This intricate interplay encompasses the impact of the microbiome on the stem cell niche, as well as its influence on differentiation and proliferation, ultimately affecting tissue equilibrium and repair processes [5, 6, 9–11, 14–16, 22, 25].

A deeper understanding of these interrelationships unveils novel insights into the mechanisms underlying aging. Moreover, it establishes a link between stem cell dysfunction and aging, with the microbiome acting as a pivotal modulator in this reciprocal relationship that governs human health and disease. This knowledge paves the way for innovative therapeutic approaches that harness the innate potential of stem cells for self-renewal and regeneration.

2.1. Microbial synergy in stem cell dynamics: a niche story

The early stages of human development offer compelling evidence linking gut microbiota exposure after birth to the maturation and development of intestinal stem cells (ISCs) [31, 32]. This discovery underscores the significant relationship between stem cell niches and microbiomes.

Notably, a single-cell transcriptional study revealed that antibiotic treatment in early life impacted the differentiation of stem cells into Paneth cells—specialized secretory epithelial cells situated at the base of small intestinal crypts, adjacent to ISCs [33, 34]. Paneth cells rely on Wnt (wingless-related integration site) signaling for differentiation and also secrete Wnt ligands, which are crucial factors in the stem cell niche that stimulate stem cell activity [35]. Wnt signaling is, in fact, the primary pathway regulating stem cell differentiation within the niche, fostering ISC proliferation [35].

The influence of the microbiota on stem cell characteristics is further evidenced by the observation that ISCs begin differentiating into Paneth cells during the first two weeks after birth, coinciding with exposure to gut microbiota [36, 37].

Remarkably, in order to better understand the niche effects of microbiota on ISC homeostasis, scientists are increasingly employing GF species as models, such as sterile zebra fish, mice, pigs, and Drosophila, and intestinal organoids [38, 39]. In general, these models exhibit reduced intestinal epithelial cell (IEC) proliferation resulting from ISC differentiation, along with decreased IEC proliferative capacity and a lower number of IEC cells detected in the intestinal crypt compared to normal animals (germ-exposed) [40–42]. Nevertheless, these alterations return to normal levels once bacteria have colonized GF animals [43].

To understand how microbiota influences IEC biology by modulating ISCs, studies have shown that intestinal bacteria actively collaborate with ISCs to regulate IEC biology through pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) [44–46].

Furthermore, when pathogenic organisms like Salmonella infect intestinal organoids, there is a noticeable decrease in the expression of two ISC markers that regulate ISC maintenance: BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1) and LGR5 (the leucine-rich repeat-containing G protein-coupled receptor (GPCR)) [47, 48]. Conversely, in a physiological context, the commensal, beneficial Lactobacilli activate ISCs through the generation of reactive oxygen species (ROS), which, in turn, promotes ISC self-renewal and influences the Wnt and Notch signaling pathways [49, 50].

Apart from ISC, studies have also shown that the microbiota actively influences the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow within the framework of niche regulation [6, 51, 52]. Using gnotobiotic zebra fish, the authors in this study were able to show that the microbiota is necessary for HSPC development and differentiation.

Additionally, the myeloid and lymphoid differentiation resulting from HSPCs is altered in these zebra fish [38, 51, 53]. Importantly, this investigation revealed that the microbiota uses inflammatory cytokines to mediate HSPC development. Overall, the results of this study emphasize the crucial role of a balanced microbiome in healthy HSPC development and homeostasis throughout the embryonic stage [6]. By adjusting the local production of inflammatory cytokines near the HSPC niche, several bacterial species exhibit distinct effects on HSPC development and differentiation.

2.2. Connecting metabolism to stem cell aging via the microbiome

Given that stem cell exhaustion is a hallmark of aging and that the gut microbiota’s relationship with stem cell exhaustion is pivotal, it is possible that an individual’s aging process is indirectly influenced by their gut microbiota [22, 23, 54].

First, some animal studies seem to support this hypothesis. For instance, feces from mice on a high-fat diet (HFD) can be transferred to normal animals, altering the intestinal microbiota of healthy mice and leading to a decrease in HSCs [55].

Second, studies addressed the underlying mechanisms and provided further support for the initial findings of the HFD mice study. They demonstrated that leaky microbes (microorganisms that typically cannot pass through the epithelium barrier but manage to enter the bloodstream) and their metabolites directly promote abnormal proliferation and overuse of stem cells by activating Wnt, Notch, and other signaling pathways [56–58]. Additionally, these microbes disrupt the interactions between stem cells and their microenvironment—a term used to refer to the three-dimensional structure and various signaling molecules found in the stroma, the region in which stem cells reside [59–61]. These molecules can regulate the fate of the stem cells, either by inducing proliferation or differentiation, which in turn accelerates host aging and reduces the stem cell pool.

Third, bacterial and fungal microbiota produce a diverse array of secondary metabolites, including antibiotics, such as penicillin and streptomycin; signaling molecules like acyl-homoserine lactones; and toxins such as botulinum toxin from Clostridium botulinum and aflatoxins from Aspergillus fungi [62–65]. Additionally, they generate immunomodulatory compounds, including the mycobacterial glycolipid sulfatide and fungal metabolites, such as gliotoxin. These metabolites play a crucial role in microbial survival, communication, and their interactions with host organisms [63–67]. While these bioactive metabolites are not synthesized by human cells, they can influence stem cell biology in various ways. Antibiotics, such as penicillin and streptomycin, possess the capability to affect host microbiota and immune responses, which may, in turn, modify stem cell niches [68, 69]. Moreover, signaling molecules from microorganisms, such as quorum sensing substances, have the ability to alter the behavior of stem cells by affecting how cells communicate with each other [70, 71]. This interaction, in turn, can influence the growth and development of stem cells. Additionally, the toxins and mycotoxins released by fungi can induce cellular stress and inflammation, which may also impact stem cell functions, including their ability to renew themselves and differentiate [72, 73]. On the other hand, metabolites like SCFAs, generated by intestinal bacteria, can influence immune responses and create a supportive environment for stem cells, especially during tissue repair and regeneration [4, 74].

For instance, a multitude of additional studies conducted over the years have contributed to a complex mechanistic understanding of the relationship between gut microbiota and stem cell exhaustion [10, 14, 18, 22, 23, 28, 36]. These studies generally indicate that SCFAs, including butyrate, propionate, and acetate, are microbial metabolites produced through the fermentation of dietary fibers by gut bacteria. These SCFAs, which are often produced by an imbalanced or “leaky” microbiota associated with aging, have a direct impact on stem cell metabolism by binding to their GPCRs, which, in turn, affect insulin signaling, a crucial regulator of the mitochondrial electron transport chain [75–78]. When insulin signaling is disrupted, an imbalance occurs between glycolysis and oxidative phosphorylation (OXPHOS), raising the risk of ROS accumulation and mitochondrial dysfunction [65–67]. Ultimately, these factors promote aberrant stem cell differentiation and proliferation, culminating in stem cell exhaustion [79, 80].

It is important to note in this regard that a number of theories have been put forth to explain why glycolysis is so crucial to stem cells. For example, stem cells’ long-term evolutionary adaptation to their low oxygen niche, such as the hypoxic bone marrow environment of HSCs, may be linked to their reliance on anaerobic metabolism associated with glycolysis [81, 82].

Another tenable theory is that glycolytic metabolism is crucial for providing the intermediates necessary to maintain the anabolic pathways vital for stem cell self-renewal [83]. Additionally, anaerobic metabolism can also prevent oxidative damage caused by ROS generated through the electron transport chain during OXPHOS in mitochondria.

Nevertheless, recent research has shown that during self-renewal, stem cells utilize mitochondrial fatty acid oxidation (FAO) alongside glycolysis [84, 85]. These studies collectively suggest that dysregulated glycolysis and OXPHOS, leading to the metabolic imbalance of stem cells, caused by a malfunctioning insulin signaling pathway, may impact stem cell longevity and overall health [86, 87].

  1. Unraveling connection: microbiome-driven epigenetic landscape in stem cell fate

The intersection of the microbiome and stem cell epigenetics has emerged as a captivating area of scientific exploration, revealing intricate interactions within biological systems [88–90]. Stem cells, renowned for their remarkable ability to differentiate into various cell types, play a pivotal role in tissue maintenance and regeneration, partially regulated by epigenetic mechanisms. Epigenetics, which involves heritable and nonheritable changes in gene expression without altering the DNA sequence, profoundly influences stem cell fate. Mechanisms, such as DNA methylation, histone modification, and noncoding RNA (ncRNA) molecules, delicately regulate gene expression and cellular identity [91, 92].

Investigating the potential interactions between the microbiome and host stem cells requires examining the various factors that influence this relationship. Such an exploration is essential for advancing our understanding of fundamental biological processes and could offer significant insights into human health, particularly in the context of diseases and developmental biology.

Disruptions in the balance between stem cell epigenetics and the microbiome have been linked to a variety of conditions, ranging from inflammatory diseases to neurological disorders [93–95]. Abnormal stem cell function is often associated with imbalances in the microbiome–epigenetics axis, which may contribute to the onset and progression of various disorders [96, 97].

Therefore, exploring this intricate relationship not only deepens our understanding of fundamental biology but also paves the way for groundbreaking discoveries in human health. This segment of the article explores the complex interplay between stem cell epigenetics and the microbiome, highlighting the intricate mechanisms that determine cellular fate.

3.1. Microbiome’s epigenetic symphony: steering stem cell fate

The coevolution of gut microbes and their mammalian hosts has facilitated mutualistic coexistence [98–100]. A crucial aspect is understanding the molecular mechanisms underlying the interaction between the microbiota and host cells, particularly stem cells within our bodies, to maintain homeostasis.

Epigenetic changes induced by the microbiota involve DNA or histone modifications and the regulation of ncRNAs [101]. Despite extensive descriptions of these mechanisms in peripheral tissues and local intestinal cells, the role of gut microbiota-mediated epigenetic processes in determining stem cell fate—whether toward renewal or differentiation—remains largely elusive.

Hence, this section of the article aims to shed light on the relationship between the microbiota and the epigenetic pathways that regulate stem cells, despite limited information available in the current literature. Understanding these dynamics is vital for leveraging epitherapeutics, which target the epigenome to modulate stem cells and promote healthy aging while delaying age-related diseases [101, 102].

To put it succinctly, the epigenetic basis of stem cell differentiation results from the necessity of preserving gene expression patterns, both for the self-renewal of stem/progenitor cells and for their differentiated progeny. Importantly, during stem cell differentiation, genes specific to a certain lineage are activated, while genes associated with self-renewal are downregulated [103].

The epigenetic landscape also undergoes significant shifts, exhibiting dynamic changes in regions associated with heterochromatin and euchromatin due to histone or DNA modifications, as well as ncRNA regulation [104]. This means that the inherited epigenetic marks on these genes must be reversible. The opposing activities of chromatin-modifying enzymes, which can tip the scales in favor of either stem cell fate—differentiation or renewal—are largely responsible for the dynamic regulation of epigenetic markings [105, 106].

Furthermore, epigenetic markers encode the cell’s capacity to permanently maintain and pass on its distinct gene expression patterns to offspring cells—a process known as epigenetic memory [107, 108].

Given this succinct overview of the role of epigenetics in controlling stem cell fate, it is now critical to explore how the microbiota—specifically, metabolites and/or products derived from the microbiome—can modify these essential epigenetic modifiers to directly control the fate of stem cells.

To catalyze chromatin modifications, epigenetic-modifying enzymes need the appropriate substrates. For example, methyl and acetyl donors are often required for the catalytic activity of histone acetyltransferases (HATs) and DNA/histone methyltransferases (DNMTs/HMTs) [109]. Even though the microbiota is not necessary for the generation of many of these donor substrates, it is becoming increasingly evident that the microbiota serves an additional source of these molecules and can influence the epigenetic modifications that determine stem cell fate.

For instance, butyrate, an SCFA, selectively inhibits the activity of histone deacetylases (HDACs), enzymes that are essential for converting a heterochromatic state into a euchromatic state and typically associated with the active transcription of genes. This state allows transcription factors and co-activators to access genes situated in an open conformation [110].

Apart from modifying histones to regulate gene expression, the microbiota also influences gene transcription in the host by inducing the binding of transcription factors to target genes. This process establishes an open conformation in nucleosome-depleted cis-regulatory regions within target cells, such as IECs, and upregulates specific transcription factors, including signal transducers and activators of transcription (STATs) and interferon regulatory factors (IRFs), in conjunction with epigenetic modifications [111, 112].

In particular, STATs are recognized as regulators of myogenic differentiation for the repair of muscle tissues, primarily through their action on muscle stem cells or satellite cells [113, 114]. In conditions like Duchenne muscular dystrophy (DMD), increased expression of STAT transcription factors induced by the microbiota has been observed to reduce the muscle stem cell reserve [115]. Furthermore, studies have shown that microbiota-induced increases in the expression of transcription factors (IRFs) promote senescence, impede stem cell self-renewal and differentiation, and ultimately, reduce in vivo lifespan [116].

All of these data point to the possibility that the microbiota controls the expression of genes associated with aging by stimulating transcription factors involved in stem cell development.

3.2. Probing stem cell epigenetics and microbiome metabolites

Growing evidence indicates that the microbiota can affect stem cell function directly or indirectly through a potent mechanism known as epigenetic regulation [88, 90, 91, 93, 106]. Direct pathways include microbial biosynthesis or metabolism that affects the availability of chemical donors for DNA or histone posttranslational modifications, as well as the regulation of epigenetic-modifying enzyme expression and/or activity. For instance, intestinal commensal microbes produce folate and other B vitamins (B2 and B12) that contribute methyl groups to DNA or histone methylation activities [117, 118]. Folate, through its involvement in one-carbon metabolism, produces S-adenosylmethionine (SAMe), the primary substrate for DNA and histone methylation. Commensal microorganisms can also convert dietary methionine into SAMe [119].

Significantly, SCFAs derived from the gut microbiota inhibit HDAC activity, leading to chromatin modifications that are often associated with increased target gene expression [109, 110]. Microbiota–host interactions are also linked to epigenetic regulation through ncRNAs, RNA molecules that do not encode functional proteins [88]. Significant expression of microbiota-induced long noncoding RNAs (lncRNAs) has been observed in the thymus and spleen, suggesting that microbiota-dependent lncRNAs may impact host immunological control, which in turn can influence the physiology and health of stem cells [120].

Overall, while this thematic explanation is not exhaustive, it is condensed to emphasize some of the most noteworthy instances of how stem cell fate is impacted by epigenetic regulation provided by microorganisms.

  1. The interwoven saga of the microbiome, immune regulation, and stem cell resilience

Recent research has illuminated the intricate interplay among the microbiome, immune system, and stem cells, highlighting their interconnectedness. The microbiome plays a crucial role in shaping the immune system, where the balance between beneficial and harmful microbes is pivotal for immune function [12, 121]. Maintaining a diverse and well-balanced microbiome is essential for the proper development and regulation of the immune system. Dysbiosis, characterized by microbial imbalance, is associated with immune dysregulation and chronic inflammation.

New findings indicate that the microbiome can influence immune responses, thereby impacting the behavior of stem cells [96, 122]. Dysregulated immune responses can potentially impair the regenerative capacity of stem cells, leading to tissue degeneration and dysfunction.

As an illustration of how immune cells might directly regulate stem cells, a recent study indicates that various stem cell niches have a dearth of inflammatory cells nearby, prompting researchers to wonder if these immune-privileged locations could serve as Treg (regulatory T cell) residents [123]. A subpopulation of CD4+ helper T lymphocytes, known as Tregs, are potent suppressors of the inflammatory response, identified by the expression of the transcription factor FOXP3 (forkhead box P3) [124]. Additionally, Tregs are known to reside in the bone marrow, and their particular depletion seems to indicate a function in regulating HSC quiescence and pool size. This finding is corroborated by the fact that HSCs are smaller in number and more vulnerable to oxidative stress in the absence of bone marrow Tregs [125, 126].

  1. Conclusions

Together, the intricate link between the aging of stem cells and the microbiota represents an exciting new field of study in biomedical science. With ramifications for several tissues and organ systems, including those harboring populations of stem cells, the gut microbiome, in particular, has emerged as playing a critical role in systemic health. Research has shown that microorganisms in the gut are capable of generating bioactive substances, including vitamins, secondary metabolites, and SCFAs, which can have significant impacts on the physiological processes of the host. Thus, by fully understanding the mechanisms by which gut microbes affect stem cell function, we may be able to develop innovative strategies for promoting healthy aging and averting age-related ailments. The more we learn about this intricate interaction, the more we will be able to use the microbiome’s therapeutic potential to help people live longer, healthier lives.

Furthermore, in the field of stem cell biology, exploration is underway into the effects of signals originating from microbes on the maintenance, proliferation, and differentiation of stem cells. For example, some bacterial metabolites may alter signaling pathways related to lineage commitment or stem cell self-renewal, which, in turn, affects processes of tissue regeneration and repair.

Moreover, changes in the composition and diversity of the gut microbiota have been linked to alterations in stem cell function and regenerative potential associated with aging. Dysbiosis, as we age, may disrupt homeostatic signals required for the optimal activation of stem cells, resulting in tissue degradation and diminished capacity for regeneration.

Future research could make use of cutting-edge tools like spatial transcriptomics and single-cell sequencing to analyze the molecular relationships between gut microorganisms and stem cells in their tissue microenvironments, helping to address these complications. Through the characterization of communication networks and signaling cascades, major microbial players and their functional implications for stem cell biology can be identified [127, 128].

Additionally, therapies that target the microbiome, such as dietary changes, probiotics, prebiotics, or fecal microbiota transplantation (FMT), have the potential to improve tissue repair in aging or disease contexts and restore stem cell homeostasis [129, 130]. The effectiveness of such therapies could be maximized by personalized methods that account for host genetics and unique microbiome profiles, opening the door for precision medicine approaches aimed at stem cell health.

In concert, as our understanding of the interactions between the immune system, stem cells, and microbiota, as well as the underlying mechanisms and convergence mediators, continues to develop, so too do the prospects for novel therapeutic approaches. Two strategies currently being researched to improve stem cell function and reduce immunological dysregulation by reestablishing a healthy microbiome are probiotics and FMT. Moreover, personalized approaches based on an individual’s microbiome profile hold potential for precision medicine. Mitigating the microbiome–immune–stem cell axis may result in novel therapeutic approaches for various ailments, encompassing age-related degenerative disorders and autoimmune diseases. This emphasizes the intrigue of the field biomedical research, particularly regarding the relationship between stem cell health and the microbiome.

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