Gut microbiota alterations and health status in aging adults: From correlation to causation (2024)

The composition of the gut microbiota changes with the increasing of the age. The changes are various in different people. The gut microbiota of some people turns into a combination of fewer beneficial bacteria and more pro‐inflammatory bacteria, which affects immune system and causes a low‐grade inflammatory state. As a result, the body becomes more susceptible to certain diseases and this is closely related to the more apparent inter‐individual differences in health status in the elderly.

2.1. The structure of the microbiota changes with age and external factors

Thirty‐nine of 95 species of gut microbiota have been shown to play a crucial role in predicting age. A study in Ireland showed that Bacteroidetes species and the Firmicutes phylum predominate in the gut microbiota of elderly individuals.⁴ Compared to younger individuals, the relative proportion of Bacteroides spp. was higher and the relative abundance of Clostridium groups was increased in the gut microbiota of elderly individuals. Older individuals also showed a reduction in the abundance of Ruminococcus, Prevotella and related genera.⁴Bacteroidetes account for more than half (53%) of the core microbiota in elderly individuals, compared with 8%‐27% in healthy young adults. The gut microbiota of elderly individuals contained a wide array of Bacteroides, Alistipes and Parabacteroides species, while that of healthy young adults also contained a unique Bacteroides species, most similar to Bacteroides vulgatus. Moreover, when the aggregated microbiota was compared, cluster IV was most predominant cluster among the elderly group, whereas cluster XIVa was more prevalent in the healthy young cohort. Gut microbiota senescence has been related to external factors, such as alcohol, antibiotics, probiotics, or diet.⁸ Thus, the accumulation of external effects may possibly explain the altered gut microbiota diversity in the elderly.

The microbiota is also affected by the outside environment at various stages of life. Before delivery, vagin*l infections can enable bacteria to invade the uterine environment of pregnant women. The microbiota of the mother's intestines is transmitted to the fetus through the blood. The mode of delivery (vagin*l delivery and caesarean section) affects the initial bacterial inoculum of the newborn. In the early stages of life, acquired factors such as diet (breastfeeding versus milk powder feeding, supplementary food supplementation), genetic factors, environmental exposure and antibiotic use, affect the formation of the microbiota.¹⁰ Such inter‐individual variation in factors may explain for the large differences in the gut microbiota of infants and young children.¹¹ By the age of three, the diet becomes more diverse, and the microbiota gradually transform into an adult‐like form.¹⁰ A core microbiota is shared between puberty and adulthood.¹² The gut microbiota of adults is quite stable, and also more flexible and complex, and can buffer exogenous invasions such as stress. However, the gut microbiota of adults can still be altered by environmental disturbances.¹³ A recent study showed that even short‐term exposure to diets consisting entirely of animal or plant products significantly change the structure of the adult gut microbial community.¹³ Therefore, inter‐individual variations in numerous factors can lead to differences in the gut microbiota both during early life and also in adults. Gut microbiota that can offset exogenous damage may accumulate the influence of these external factors through specific alternation, which may partially explain the greater diversity of the gut microbiota in the elderly.

2.2. Age‐related diseases are accompanied by significant changes in the gut microbiota

A recent study showed that the gut microbiota composition of 5XFAD transgenic (Tg) mice, which are widely used in Alzheimer's disease research, undergoes significant changes during the progression of AD, whereas the gut microbiota composition of wild‐type (WT) mice exhibited little change. At the phylum level, Bacteroides, Firmicutes and Verrucomicrobia were most abundant in 2‐month‐old Tg mice (47.3%, 33.0%, 12.2%, respectively). By seven months of age, Firmicutes had become the predominant phylum (62.8%), while the relative abundance of Bacteroidetes and Verrucomicrobia decreased significantly, indicating a change in bacterial type.¹⁴

Evidence indicates that members of the Firmicutes and Bacteroidetes phyla stimulate the inflammasome pathway in the intestine and lead to an inflammatory response.¹⁵ Based on the changes in the gut microbiota of the elderly, an inflammatory response in the gut is likely to develop during ageing This age‐related imbalance in the gut microbiota could reduce the integrity of the intestinal barrier.⁶ Subsequent leakage of microbial products may upregulate the circulating levels of pro‐inflammatory factors (such as interferons, TNFα, interleukin‐6 and interleukin‐1) and promote a persistent low‐grade inflammatory state, which has been related to cognitive decline and dementia.¹ The persistent low‐grade inflammatory state has also been observed in other chronic diseases, such as IBD,^{16, 17} diabetes type I,¹⁸ CVD¹⁹ and metabolic disorders.²⁰ The pro‐inflammatory state caused by dysbiosis of the gut microbiota is considered to play key roles in these common diseases of the elderly.

3.1. Aging and chronic inflammation

In the innate immune system, neutrophils exhibit a sharp decline in bactericidal and phagocytic function as the cells age.²⁴ Macrophage function also changes, with increased secretion of IL‐6 and IL‐8 induced by mitogens and lipopolysaccharides. Dendritic cells also significantly reduce in number, distribution, and likelihood of production and development from hematopoietic precursors.²⁵ Natural killer cells also exhibit reduced cytotoxicity as the cells age.²⁶ In terms of the adaptive immune system, the thymus atrophies and the number of naive T cells decrease, while the proportion of memory T cells increase during aging. The number and proliferation of Th1 cells also decrease. Additionally, the number and proliferation of memory Th2 cells increases; which leads to production of higher levels of IL‐10, which further inhibits the function of Th1 cells. The consequence is a decrease in Th1‐type immunity mediated by cells. Moreover, the decrease in the production of antibodies by B cells in response to antigens is thought to be primarily due to the decline in helper T cell activates for B cells.²¹ These alternations increase susceptibility to immune‐mediated diseases. In addition, the increase in pro‐inflammatory factors is characteristic of chronic inflammation,²⁷ which has been related to degenerative diseases such as diabetes and osteoporosis.²⁸

Neurons are active participants in the interaction between the central nervous system and the immune system, and regulate the activation of microglia to maintain the integrity of the central nervous system.²⁹ Aging can influence the interaction between microglia and neurons by altering the nervous environment, and results in increased microglial reactivity.³⁰ Compared with healthy microglial cells, aged microglia a more rapid induction and release the higher levels of cytokines upon activation. Primed microglia appear to be in an intermediate activation state with deamidation and upregulation of MHCII.³⁰ After further stimulation induced by activation of the peripheral or central innate immune system, primed or sensitized microglia releases pro‐inflammatory cytokines significantly and for a long time.³¹ It also shows significant enhancement of the pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α after immune stimulation with the bacterial endotoxin lipopolysaccharide in vitro.³² Also, the levels of the anti‐inflammatory cytokines IL‐10 and IL‐4 decrease with age‐related increases in the levels of the pro‐inflammatory cytokines.³³ These changes have been linked to cognitive decline and depressive behavior.³⁴

Chronic inflammation and chronic diseases, such as diabetes and cancer are associated with aging.³⁵ The underlying inflammatory response increases with age, which in turn leads to chronic, low‐grade inflammation that accelerates aging.³⁵ This process is known as "inflammaging", and is also a process of immunosenescence.³⁶ Various mechanisms are involved in inflammaging, such as the redox stress hypothesis, mitochondrial dysfunction, immunosenescence, chronic infection and homeostasis reconstruction.³⁷

3.2. Aging and intestinal immune

Induction and maintenance of the intestinal mucosal immune response is a multi‐step process. First, intestinal cavity antigens are transported across the intestinal epithelium.³⁸ In aging mice, the specific expression of E26 transformation‐specific family transcription factor Spi‐B in M cells is impaired ³⁸ and expression of CCL20 in the follicle‐associated epithelium (FAE) is reduced,³⁹ which could affect the functional maturation of M cells in FAE.³⁸ The density of mature M cells in Peyer's patches is significantly decreased in aged mice, which prevented the granuloantigen from transcytosis of FAE. In addition, the expression of zonula occludens‐1 (ZO‐1), junctional adhesion molecules (JAMs), and occludins are decreased in the intestinal epithelium of aged rats and baboons.⁴⁰ The resulting destruction of the tight junctions in the intestinal epithelium may lead to increased paracellular permeability to intraluminal antigens and pro‐inflammatory stimuli.

Mononuclear phagocytes (MNPs), consisting of macrophages and typical dendritic cells, engulf the pathogen and present antigens to T cells located in gut‐associated lymphoid tissue (GALT) and mesenteric lymph nodes (MLN).^{38, 41} T cells then polarize along the effector or tolerant pathway. In contrast, antigen‐specific IgA⁺ B cell immunoblasts undergo antibody isotype switching, differentiate, and subsequently migrate to the lamina propria. Finally, plasma cells in the lamina propria produce IgA locally, which is subsequently transported across the intestinal epithelium and secreted into the lumen. Aging affects these intestinal immune responses to varying degrees61. Immunohistochemical staining indicated that the numbers of CD11c⁺ MNP were reduced in Peyer's patch in one‐year‐old mice,⁴² and the number of macrophages was significantly decreased in the lamina propria of aged dogs.⁴³ However, the high‐sensitivity immunohistochemical analysis of Peyer's knots in aged mice revealed that the apparent M‐cellinducingCD11c ⁺ CD45R ⁺ (B220) cells in FAE was significantly reduced,⁴⁴ while the density of CD11c⁺ MNP in the sub‐epithelium dome (SED) was not adversely affected61. The ability of dendritic cells to initiate T cell responses appears to be impaired in old mice.⁴⁵ Another study also reported that aging dendritic cells are characterized by a significant decrease in IL‐12p70 and IL‐15 production, accompanied by a decrease in the expression of the CD80/CD86 co‐stimulatory signal, and that the reduced IL‐15 appears to reduce the ability to initiate T cell response of aging dendritic cells.⁴⁵ Moreover, aging intestinal‐derived dendritic cells cannot induce the differentiation and secretion of TGF‐β in CD4 + CD25 + LAP + T cells, and enable to up‐regulated the amount of IFN‐γ produced by CD4 + CD25 + LAP + T cells. In contrast, gut‐derived dendritic cells directly activate T cells by producing TGF‐β, or produces lower levels of IFN‐γ, or indirectly via TGF‐β producing T cells to activate T cells.⁴⁶ On the other hand, TGF‐β also determines the fate of B cells in Peyer's patches (PPs) and affects their homing to the lamina propria of distant mucosal sites.⁴⁷ How the levels of intestinal IgA change with aging are still unclear. Some studies have found intestinal IgA decreased,⁴⁸ whereas others found intestinal IgA was unchanged or even increased during aging.⁴⁶ However, the heterogeneity of the VH gene pool of IgA antibodies is increased in aged mice, and the affinity of IgA to antigen decreases.⁴⁹

4.1. The gut microbiota regulates the immune system

A study published in 2019 showed that patients treated with broad‐spectrum antibiotics before receiving immune checkpoint inhibitors (ICIs) for cancer treatment were nearly twice as likely to respond poorly to ICI than patient who were not treated with broad‐spectrum antibiotics. Broad‐spectrum antibiotics may lead to an imbalance in the gut microbiota that affects the treatment of cancer with ICIs.⁵⁰ Moreover, oral administration of broad‐spectrum antibiotics in mice reduced the severity of experimental autoimmune encephalomyelitis (EAE).⁵¹ Single colonization of germ‐free mice with segmented filamentous bacteria (SFB) enhanced the ability to recruit neutrophils and other immune cells of T helper 17 (Th17) cells in the intestinal lamina propria and the central nervous system, and caused severe EAE. Therefore, enhancement of Th17 cell‐mediated inflammation by SFB may exacerbate EAE.⁵² These studies indicate a possible mechanism by which the gut microbiota can promote the progression of aging related diseases by affecting the immune system.

Comparison of germ‐free and colonized mice revealed that colony colonization had a profound effect on the formation of lymphoid tissue and subsequent development of the immune system.⁵³ Thus, the microbiota affects the immune system. On one hand, the microbiota affects the development of myeloid cells.⁵⁴ The level of myeloid production is related to the complexity of the gut microbiota and mediated by the level of TLR ligands present in the serum.⁵⁵ Microbial‐derived short‐chain fatty acids (SCFA) can promote hematopoiesis in the bone marrow.⁵⁴ However, the signals produced by the microbiota do not seem to affect the lymphopoiesis of innate lymphoid cells (ILCs), as these cells develop normally in the absence of microbiota.⁵⁶ On the other hand, the microbiota affects the maturation and function of myeloid cells^{56, 57} and innate lymphoid cells.^{56, 57} The persistence of microbiota‐derived TLR ligands drives neutrophil senescence⁵⁷ and affects the number of basophils in the circulation.⁵⁸ SCFAs such as acetate and propionate produced by Bacteroides fermented polysaccharides and butyrate produced by thick‐walled fungi can promote the integrity and function of intestinal epithelium.^{15, 59} SCFAs can also inhibit the production of proinflammatory cytokines by macrophages and neutrophils,⁶⁰ promote the function of microglia,⁶¹ inhibit the maturation of dendritic cells and macrophages, promote the production of antibodies by B cells,⁶² and promote the differentiation and expansion of T regulatory cells (Tregs).⁶³ The gut microbiota decomposes dietary tryptophan to produce indole derivatives, which in turn activate the promiscuous nuclear receptor subfamily, 1 group, I member 2 (NR1I2) and the aryl hydrocarbon receptor (AhR).⁶⁴ Activation of ANR promotes the maintenance of ILC3 cells, which enhance the integrity of the intestinal mucosa by secreting IL‐22.⁶⁵ Activation of NR1I2 also enhances epithelial barrier function.^{64, 66} Polyamine, a derivative of arginine produced and secreted by gut bacteria inhibits expression of pro‐inflammatory cytokines by LPS‐induced monocytes and macrophages. Primary bile acids and secondary bile acids reduce the expression of proinflammatory cytokines in monocytes, macrophages, dendritic cells and liver macrophages.⁶⁷ Taurine produced decomposition of primary bile acids by the gut microbiota maintains and enhances epithelial barrier function by promoting IL‐18 production.^{68, 69} ATP secreted by the gut microbiota limits the number of follicular helper T cell (Tfh) cells in Peyer's patches, and thereby reduces B‐cell secretion of bacteria‐specific IgA across the intestinal epithelium.⁷⁰ ATP also promotes the differentiation of T_H17 cells in the intestinal mucosa⁷⁰ and may promote epithelial barrier function by activating NLRP3 inflammasomes and subsequently inducing secretion of IL‐18 by macrophages.⁷⁰ Polysaccharide A (PSA) secreted by Bacteroides fragilis exerts a strong anti‐inflammatory effect by inducing secretion of IL‐10 from CD4⁺ T cells and changing the T_H1: T_H2 ratio to favour T_H1.⁷¹

4.2. Immune changes regulated by the gut microbiota in elderly individuals

Changes in the gut microbiota may increase the expression of pro‐inflammatory factors and lead to chronic age‐related inflammation. For example, the permeability of the intestinal mucosa increases in the absence of sufficient SCFA production, which allows intestinal bacteria to pass through and enter the bloodstream. The pathogen‐associated molecular patterns (PAMP) of invading bacteria, such as lipopolysaccharide (LPS), bind to pattern recognition receptors (PRR) expressed by immune cells and adipocytes, and trigger the production of pro‐inflammatory cytokines to lead to widespread persistent, low‐grade inflammation.⁷² Moreover, changes in gut microbiota metabolites may also alter the function of immune cells in the immune system. For example, the reduction in B cell antibody production caused by a decrease in TH1 cells in the elderly may be related to reduced PSA secretion by Bfragilis. Related immune changes in the elderly can lead to susceptibility and vulnerability to disease, and chronic inflammation can also accelerate aging. Notably, one study found that the weakened gut germinal center responses observed in aged mice could be improved by fecal transplantation from the same stain young mice.⁷³ In addition, inter‐individual differences in aging of the immune system²¹ may explain why some elderly people have the ability to delay the occurrence of or avoid chronic diseases. The gut microbiota acts as a buffer to individual external environmental and lifestyle factors. The corresponding changes induced by external stimulus occur to accumulate the influences of these factors, thus the gut microbiota of the elderly display greater inter‐individual variations than that of younger individuals.⁴ The greater inter‐individual variations could be one mechanism underlying the inter‐individual differences in immunosenescence. Thus, the gut microbiota may lead to the emergence of health diversity in the elderly. The relationship between gut microbiota and immune system in the elderly is illustrated in Figure2.

Based on the premise that the health diversity of the elderly is related to changes and differences in the gut microbiota, a recent study showed that drug treatment inhibited the gut microbiota dysbiosis and improve neuroinflammation and reduced cognitive disorders in a mouse model of Alzheimer's disease.¹⁴ In addition, transplantation of the microbiota from patients with Parkinson's disease increased motor dysfunction in a mouse model of Parkinson's mouse compared to transplantation of microbiota from healthy controls.⁷⁴ Thus, the gut microbiota may influence the aging process of the immune related network. Therefore, we believe that the alterations to the gut microbiota caused by the internal and external environment are key factor in age‐related diseases. The alterations to the gut microbiota have shaped the differences in the health status of the elderly by affecting the human immune system for a long time. Thus, it is feasible that regulation of immune changes by modulating the gut microbiota may delay aging and improve the quality of life of the elderly.

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