Gut-Immune Interplay: Decoding the Microbiome’s Impact on Immunity and Diseases

Abstract

The gut microbiome is a critical regulator of local and systemic immunity with downstream consequences on immune functions and health of the host. Coevolution with the host bolsters the development and performance of the immune system, particularly during early life, and also plays roles in immune responses in adulthood. Alterations in the gut microbiome, whether as a result of antibiotics, diet, or environmental manipulation, can also drive inappropriate immune responses and predisposition to infections and inflammatory and autoimmune diseases. Since the microbiome impacts systemic immunity, microbial products stemming from the gut can alter immunity in far-flung tissues. Recent studies have emphasized the therapeutic promise of probiotics due to their ability to modulate gut microbiota and improve immune system activity and symptoms as well as prognosis of different diseases. Aging is one of the key risk factors for several age-related conditions, where the immune system and gut microbiome are major culprits, further explaining the importance of microbiome health across the life course. This emerging approach of microbiome modulation is opening up new pathways for combating infectious diseases, including both antibiotic-resistant infections and viral disease. This review highlights the interdependent nature of the gut microbiome and immune health, with significant ramifications for disease prevention and treatment.

INTRODUCTION

The human body, including the gut, skin, and other mucosal surfaces, harbors a diverse array of microorganisms referred to as the microbiome.[1]

The past 20 years have witnessed the advent of rapid culture-independent genomic technologies allowing the genomes of these microorganisms—including bacteria, fungi, viruses, and parasites—to be interrogated.

New findings in microbiome science have revealed that the gut microbiome is involved in regulating host phenotypes, including circadian rhythms, nutrient responses, metabolism, and immune system activity.[2,3,4]

A significant cellular and molecular component of mammalian immunity, innate and adaptive elements together form an intricate immune network dispersed across all tissues, enabling the host to respond to a multitude of environmental insults as well as disturbances to homeostasis.[5]

Specialized study and balance: Ecological balance—mammals and commensals have coevolved to establish mutualistic relationships. This close relationship depends on the immune system working correctly to avoid commensal microbes from consuming host resources to excess and developing tolerance toward innocuous stimuli.[6,7]

Yet, disturbances to the gut microbiome—resulting from environmental factors such as the use of antibiotics, changes in diet, and changes to geography—exacerbated by host–microbiome interaction disturbances or immunological modifications, can lead to an expansion of commensal microorganisms, increased susceptibility to pathogens, and maladaptive immune responses. Beyond the control of infectious pathogens and commensal spread, the interaction between the microbiome and the immune system is associated with a range of noncommunicable intestinal diseases, such as inflammatory bowel disease (IBD) and celiac disease, as well as extraintestinal pathologies including rheumatoid arthritis, metabolic syndrome, neurodegenerative diseases, and cancer.[8,9,10,11,12,13]

The association between gut microbiota and host immunity is complex, context-dependent, and dynamic. Here, we present key findings and concepts showing the relationship between microbiome and the development and functional maturation of the immune system. We further discuss mechanistic insights into the intricate communication between the microbiome and immunity during states of health and disease. This review further discusses recent challenges and future perspectives on microbiome-centered strategies to investigate disease mechanisms and to create new clinical applications.

Although no single review can address all facets of host immune–microbiome interactions, we hope to highlight concepts and examples that have potential relevance in human health and disease risk. It also offers short references to more up-to-date reviews that concentrate on particular elements of these exciting interactions.[14,15,16]

The Microbiome’s Contribution to Immune System Development

The presence of microbes on mucosal surfaces in mammalian hosts shapes the immune system early in life. Much of host immunity maturation occurs in the first few years of life, a time frame during which microbiota composition shows the highest intra- and interindividual differences. By approximately 3 years of age, the microbiota becomes established in a stable, adult-like configuration.[17,18,19,20] Yet, this “window of opportunity” also renders infants more susceptible to loss of their microbiota in response to environmental perturbations, with potential long-term consequences for immunity.[21]

In fact, the physiological immaturity of the immune system has been well documented in this age group, evidenced by their increased risk of infectious disease, the most common cause of child mortality.[22,23] Premature babies also have a tendency for heightened excessive inflammation such as in necrotizing enterocolitis.[24]

Reproducible microbial colonization occurring in utero has most often not been observed to date,[25] and it is commonly assumed that the majority of colonization happens postnatally, providing maternal microbiota in most instances of colonization.[26] Early colonization is influenced by a variety of factors, including delivery mode, which influences the composition of initial microbiota across multiple body habitats.[27]

As has been clearly shown for neonates, maternal antibodies provided through breast milk provide essential passive protection against infection from pathogens.[28] Note that work from this year in fact has demonstrated that the commensal microbiota of pregnant mice regulates antibody-driven protective immunity through breastfeeding.[29]

By providing a unique approach to study the mechanistic causative relation between commensal microbiota and host immunity, germ-free (GF) animal models are well suited for investigating the interplay between commensal microbiota and host immunity. In initial studies on GF animals, extensive intestinal defects of lymphoid tissue architecture and immune function were observed following the independent habits of commensal microbes.[30] Notably, levels of αβ and γδ IEL in GF mice are markedly decreased compared with conventionally colonized animals but can be robustly induced with de novo colonization.[31]

IgA antibodies, central to the protective humoral mucosal immunity, are dramatically decreased in newborns and GF animals but regained rapidly following microbial colonization.[32] Colonization of the maternal gut during pregnancy enhances intestinal group 3 innate lymphoid cells (ILC3s) and F4/80+ CD11c+ circulating mononuclear cells in offspring.[26] IL-17 producing T helper (Th17) cells are abundant in the lamina propria of the small intestine and are a powerful class of immunomodulatory effector cells.[33] GF mice lack Th17 cells, which can be induced by microbial colonization, notably by segmented filamentous bacteria (SFB) and other commensal bacteria.[33,34,35] SFB adheres to epithelial cells and induces Th17 cells.[36]

A bacterial polysaccharide of the ubiquitous commensal *Bacteroides fragilis* promotes maturation of the immune system in mice, including rectification of systemic T cell deficits and Th1/Th2 deviations in lymphoid tissues.[37]

There is an early B cell lineage in the intestine mucosa that is controlled by microbe-derived extracellular signals shaping gut immunoglobulin repertoires.[38] The optimal diversity of gut microbiota shape during early-life colonization drives the establishment of an immunoregulatory network that protects against the promotion of mucosal IgE, which is linked to allergy susceptibility.[39] Innate immune receptor Toll-like receptor 5 (TLR5) functions as a sentinel of bacterial flagellin. In mice, TLR5-mediated counterselection of flagellated bacteria is limited to the neonatal period, but this process is critical for shaping gut microbiota composition and impacting immune homeostasis and health in adulthood.[40]

Defending against infections: How the gut microbiota influences systemic immunity

Furthermore, it is increasingly clear that not only the gut microbiome exercises control over the local mucosal immune system but also these organisms impact the innate and adaptive cell-mediated systemic immune response through multiple avenues.[41]

One such mechanism is related to the release of microbial soluble products into the bloodstream that influence the activation of immune cells in distant tissues. Indeed, immune cells in organs distant from the gut directly recognize circulating microbial-derived factors, and the absence of these microbiota-derived signal molecules leads to immune dysfunction and enhanced susceptibility to systemic infections.[42,43]

Among the strongest characterizations of how the gut microbiome affects the systemic immune response, one mechanism is its influence on the T cell compartment of the adaptive immune system.[44]

Studies have shown that the gut microbiota is capable of skewing T-cell subsets toward either T-helper (Th) Th1, Th2, and Th17 populations, or toward a regulatory T-cell phenotype.[45,46]

In particular, butyrate is an SCFA that enhances the differentiation of peripherally induced regulatory T cells to stifle the onset of systemic inflammation.[47]

SCFAs also have the potential to reprogram the metabolic activity of cells, such as the induction of regulatory B cells and inhibition of pentanoate-induced Th17 generation, which could be relevant in IBD and autoimmune diseases.[48]

Moreover, ATP derived from the microbiota can favor Th17 cell amplification, tryptophan metabolites can enhance intraepithelial CD4+ CD8αα+ T cells, and polysaccharides produced by bacteria can prepare regulatory T cells.[49]

The microbiome promotes the suppression of inflammatory responses via its capacity to induce regulatory populations.[50] However, it has been demonstrated in studies of host–pathogen interactions that resistance to bacterial infections requires the commensal activation of memory T cells and their trafficking to inflamed sites.[51]

Importantly, the active modulation of IL-10-dependent immunosuppressive signals by commensal species is required to prevent infectious challenges. These effects could also be reproduced using TLR agonists, which are well known to inhibit IL-10 production, reducing susceptibility to infection via improved bacterial clearance and correct inflammatory response.[52]

Because signaling molecules released from the microbiota can access the bloodstream, resident gut bacteria may impact the immune system during hematopoiesis and impact the immune response to pathogens.[53,54]

For instance, the short-chain fatty acid butyrate is known to support the differentiation of bone marrow-derived monocytes from an inflammatory phenotype to a more tolerogenic phenotype.[55]

Bone marrow cells express multiple pattern recognition receptors (PRRs) and are responsive to circulating microbe-associated molecular patterns (MAMPs), the effects of which are governed by PRR expression and MAMP availability.[56]

As an example, the stimulation of the C-type lectin receptor (CLR) dectin-1 on hematopoietic stem and progenitor cells (HSPCs) induces trained immunity.[57,58]

Another example includes activation of TLR2 on HSPCs, which results in tolerized macrophages that have improved antigen presentation and costimulatory ability.[59]

Additionally, AhR ligands can induce the accumulation of immunosuppressive myeloid-derived suppressor cells from HSPCs.[60]

All the abovementioned mechanisms clearly show that gut microbiota dysbiosis can lead to the loss of the capacity to mount normal, appropriate local and systemic immune responses, leading to the development of local inflammatory diseases and affecting distal sites as well. Among these sites of interest are the airways, and the gut–lung axis is the specific relationship between the gut and the lung.[61,62,63] Preclinical and clinical studies have shown that antibiotic-induced alterations of gut microbiota are associated with the development of atopic manifestations, allergic airway disease, and subsequently increased asthma risk.[21,64,65,66,67]

Besides its impact on allergic airway disease development, gut microbiota protects against bacterial and viral respiratory infections via direct modulation of both innate and adaptive immune responses.[68,69,70] Several human clinical trials demonstrate that probiotics use is associated with a reduced incidence and better clinical outcomes of respiratory infections.[71,72,73] A complementary pathway in which events in the gut impact lung disease occurs via the common mucosal immune system, whereby antigen-specific B cells primed in the gut may traffic to distant sites via the thoracic duct.[62]

That said, however, in gut–lung microbiota research, similar to many other microbiota studies, establishing whether gut microbiota changes are either a cause or a consequence of a disease is still complex. In addition, longitudinal studies are required to further unravel the role of the gut microbiota in the severity and progression of established lung diseases.[61]

Probiotics: Modulating gut microbiota and enhancing immune function

The term probiotic was introduced by Metchnikoff in the early 1900s, who suggested that Bulgarian peasants’ longevity was associated with high consumption of fermented milk with beneficial living microorganisms (now known as probiotics).[74]

A working group of the WHO/FAO in 2001 and 2002 defined probiotics as “live microorganisms that, when administered in appropriate amounts, confer a health benefit on the host”.[75]

According to Hill et al. (2014), probiotics must be “safe for their intended purpose” and have “of specified contents, with a suitable live number at end of shelf life, and proof that supports their health benefit”.

The International Scientific Association of Probiotics and Prebiotics (ISAPP) 74 reaffirmed these guidelines in 2018.

Currently, 35 probiotic species or subspecies—which are divided into three categories—are authorized for consumption as food:

1) bacteria that produce lactic acid (Bifidobacterium, Enterococcus, and Lactobacillus), 2) yeast, and 3) Bacillus species that generate spores.

Lactobacillus species and Bifidobacterium species are commonly isolated from dairy products or healthy human colons.[76]

A healthy gastrointestinal microbiota is essential since it is closely linked to numerous illnesses. The initial line of defense between the host and microbes is the gastrointestinal epithelium. The intestinal mucosa is contacted by harmful microorganisms during invasion or infection, which triggers an immunological reaction.[77]

Changes in gut microbiota composition and diversity are associated with gastrointestinal diseases, including IBD, colorectal cancer, and irritable bowel syndrome, as well as systemic diseases such as allergies, bronchial asthma, and cystic fibrosis. Probiotics have been demonstrated to modulate gut microbiota in studies with animals and clinical trials with humans.[9,10]

Bifidobacterium species are important beneficial bacteria in the human intestine, and the imbalance of microbiota is generally found in various diseases, such as Crohn’s disease,[24] ulcerative colitis,[25] respiratory infections,[11] and autism.[26]

One of the approaches used by probiotics is to inhibit pathogenic bacteria through the enhancement of intestinal protective mechanisms (e.g, blood flow and mucus secretion) and by inhibiting pathogenic organisms such as Desulfovibrio, while enhancing the growth of protective strains, such as lactate-producing bacteria. One study found that pretreatment with the probiotic Bifico (which contains Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus) reduced the risk of colitis-related cancer and tumor formation in mice. That was done by reducing levels of colitogenic bacteria such as Desulfovibrio, Mucispirillum, and Odoribacter, but increasing levels of Lactobacillus.[12]

PRRs, available on immune cells, which can identify probiotics, are toll-like receptors (TLRs). Once recognized, probiotics regulate the major signaling pathways and, consequently, trigger signaling cascades that activate nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) and communicate with their hosts.[78]

Moreover, intrinsic immunity might also be stimulated by the NLRP3 complex, which activates the pathways of proinflammatory and anti-inflammatory cytokines or chemokines.[77]

Four strains [Lactobacillus rhamnosus (L. rhamnosus) GG, L. rhamnosus KLSD, Lactobacillus helveticus (L. helveticus) IMAU70129, and Lacticaseibacillus casei (L. casei) IMAU60214] were evaluated in an in vitro study and enhanced monocyte-derived macrophage innate immunity by increasing reactive oxygen species (ROS) and NF-κB p65 and TLR2 signaling.[79]

In another in vivo experiment, post-preemptive with Lactobacillus johnsonii (L. johnsonii) NBRC 13952 enhanced the phagocytosis action of RAW264.7 macrophage cell line against different pathogens, as well as enhanced the expression of interleukin-1β (IL-1β) and CD80. Both human and animal studies further explored the regulatory effects.[80]

In an animal study, oral administration of Lactobacillus gasseri (L. gasseri) SBT2055 (LG2055) increased IgA production and the number of IgA+ cells in Peyer’s patches and lamina propria in the intestine of mice because of their stimulated expression of transforming growth factor β (TGF-β) and the TLR2 signaling pathway.[81]

Kwon et al.[82] used an animal model and found that probiotic mixtures containing L. acidophilus, L. casei, Limosilactobacillus reuteri (L. reuteri), Bifidobacterium bifidum (B. bifidum), and Streptococcus thermophilus (5 × 10^8 cfu/day) increased the number of CD4+ Foxp3+ regulatory T cells (Tregs) and reduced the levels of Th1, Th2, and Th17 cytokines, which helped inhibit the progression of immune disorders in IBD, atopic dermatitis, and rheumatoid arthritis.

Additionally, Bifidobacterium breve (B. breve) AH1205 and Bifidobacterium longum (B. longum) AH1206 were shown to promote the expression of the transcription factor Foxp3 to induce Tregs in infant mice, which was associated with a protective effect against allergies.[83]

The influence of aging on gut microbiota and immune system health

Older adults will also have a less effective immune system, a process called “immunosenescence.” This immune system aging is irreversible and leads to a gradual decline in both innate and adaptive immunities. Aging-related changes in the signal transduction pathways of DC-associated aging influence the function of DC, resulting in altered cytokine secretion patterns in response to pathogens.[84] This leads to reduced phagocytosis, decreased antigen-presenting ability, and impaired migration ability of DCs.[85]

Moreover, monocytes, macrophages, and neutrophils have impaired phagocytosis in older people.[86] The expression and function of TLRs in monocytes, DCs, and neutrophils decline with age,[87,88,89] and deficient localization of TLRs can affect cytokine production as well. However, one notable exception was the increased expression of TLR5 on monocytes of the elderly when compared to younger individuals, which was associated with more cytokine production in older individuals.[90,91]

T cells also undergo age-related changes, including epigenetic and metabolic changes that impact naïve, memory, and effector T cells.[92,93] Furthermore, the T cell receptor (TCR) repertoire narrows, while functionally inactive senescent or exhausted T cells accumulate. This age-induced modulation of T cell immunity can be explained by the altered production of effector molecules such as cytokines—critical mediators of T cell responses. Between the elderly, the T cells are characterized primarily by a Th2-like phenotype[94]; in addition, the ratio of Th17 to regulatory T cells appears to be elevated, which might lead to impaired response to infectious agents in elderly individuals. One possible underlying factor is a less diverse B cell repertoire in older people, which could explain their greater risk for infections.[95]

Immunosenescence is related to a chronic, low-grade, sterile inflammation which defines the term inflammaging.[96] Chronic infection associated with persistent viral and bacterial agents, as well as cell breakdown products and misfolded proteins, are several triggers of innate immune activation that may contribute to inflammaging.[97,98,99] The aging process in immune system components, including both decrease and hyperactivity, results in a higher prevalence of infections, cancer, and autoimmune and chronic diseases, and a lower response to vaccinations in the elderly.[100]

Although the role of gut microbiota in infants and its impact on the immune system has been widely studied, a limited number of studies have investigated the gut microbiota and what changes occur along aging. Despite high inter-subject variability, the gut microbiota of healthy adults remains relatively stable until aging initiates a disturbance of the microbiota equilibrium.[101] This disruption frequently leads to decreased biodiversity, particularly a reduction in SCFA-producing bacteria and gut microbiota stability, often correlated with increased infection susceptibility.[102]

Clinical implications of infectious diseases and the gut microbiome

Infectious disease specialists have historically focused more on diagnosing and treating particular pathogens. Antibiotics have been among the most useful therapeutic methods, but the constantly increasing problem of pathogens resistant to antibiotics has made the need for alternative methods greater.[42,103]

In addition to fostering antibiotic-resistant pathogenic bacteria, antibiotics disrupt the architecture and function of the microbial community, paving the way for the colonization, growth, and persistence of pathogenic organisms. This novel understanding of the interplay among the immune system, gut microbiota, and pathogens is currently reshaping the field of infectious diseases and clinical microbiology. This knowledge is starting to be integrated into the clinician’s work.[103]

Our gut microbiota are used to having certain pathogens walking around our gut, but some of them, in certain situations, can lead to infectious diseases. Antibiotics eliminate antibiotic-sensitive bacteria, which leaves microbiota signaling impaired along with reduced immune responses to C. difficile. Also, with no competing organisms, C. difficile can take advantage of the targeted nutrient availability in the cleared region, consequently colonizing to a higher extent. This particularly strong association between antibiotic consumption and Clostridium difficile infection renders it a high-profile target for microbiome-targeted therapies.[104]

Similarly, numerous enteric viruses (e.g., rotavirus, norovirus, and poliovirus) have been shown to utilize the bacterial microbiome for immune evasion that supports their entry and replication during intestinal infections, leading to increased infectivity.[103,105]

It is therefore established that the gut microbiome has a direct potential influence in systemic viral infections through the aforementioned systemic immune mechanisms. For example, the microbiota-derived short-chain fatty acids (SCFAs) confer protection against influenza through modulation of T cell responses.[106]

Also, a higher level of the Lactobacillales order has been associated with a lower viral load in the gut of HIV patients, indicating that microbiota may modulate the progression of HIV infections either directly or indirectly.[107]

CONCLUSION

The connection between the gut microbiome and the immune system is complex and can have significant effects on both health and disease. Emerging research highlights the importance of the microbiome in the development of the immune system, especially early in life. Regulatory synapses that arise from microbes present in the intestinal mucosa help shape immune system development, and dysregulation around the effects of microbes on immunity during this critical period of development can result in increased vulnerability to infectious disease, allergic disease, and autoimmunity. Moreover, the gut microbiota not only helps to regulate local immunity but also impacts systemic immune responses by modulating T cell differentiation, regulatory pathways, and immune memory.

Dysbiosis of gut microbiota due to environmental factors, including diet, antibiotics, or aging, perturbs immune homeostasis and has been associated with numerous diseases like IBD, metabolic syndrome, and cancer. These complex interactions between the microbiome and immune system govern local defense mechanisms while also modulating systemic immunity, influencing distant organs and tissues ranging from the lungs to the brain and joints. This synergetic interaction highlights the power of microbiome therapies, for example, probiotics, in modulating immune response with potential therapeutic applications across a spectrum of diseases, from respiratory infections to autoimmunity. The progression of aging leads to a decline in immune function (immunosenescence) that is also affected by microbiota as older adults have a less diverse gut microbiome that contributes to heightened inflammation and increased susceptibility to infections.

Moreover, gut microbiota is also involved in the host’s immune defense, regulating T cell activation and cytokine production against bacterial and viral pathogens. Recognizing the influence of the gut microbiome on immune function in the context of clinical practice is changing the paradigm of infectious disease treatment and suggests promising new directions toward microbiome-centered therapies. These treatments have the potential to rebalance the microbial community and enhance immune resilience when antibiotic resistance and chronic infections are involved. So far, there is a growing recognition of the importance of a healthy and diverse microbiome for immune health, disease prevention, and overall wellbeing, and ongoing research continues to explore this complex relationship.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.