Can probiotics mitigate age-related neuroinflammation leading to improved cognitive outcomes?
R. C. Anderson- Te Ohu Rangahau Kai, AgResearch, Palmerston North, New Zealand
Changes in brain structure and cognitive function are a natural part of aging; however, in some cases these changes are more severe resulting in mild cognitive impairment (MCI) or Alzheimer's disease (AD). Evidence is mounting to show that neuroinflammation is an underlying risk factor for neurodegenerative disease progression. Age-related neuroinflammation does not appear to occur in isolation and is part of increased systemic inflammation, which may in turn be triggered by changes in the gut associated with aging. These include an increase in gut permeability, which allows immune triggering compounds into the body, and alterations in gut microbiota composition leading to dysbiosis. It therefore follows that, treatments that can maintain healthy gut function may reduce inflammation and protect against, or improve, symptoms of age-associated neurodegeneration. The aim of this mini review was to evaluate whether probiotics could be used for this purpose. The analysis concluded that there is preliminary evidence to suggest that specific probiotics may improve cognitive function, particularly in those with MCI; however, this is not yet convincing and larger, multilocation, studies focus on the effects of probiotics alone are required. In addition, studies that combine assessment of cognition alongside analysis of inflammatory biomarkers and gut function are needed. Immense gains could be made to the quality of life of the aging population should the hypothesis be proven to be correct.
Introduction
As part of the natural process of aging, changes in brain pathology occur, which lead to a gradual decline in cognitive function. In some cases, this process is accelerated, leading to a condition known as mild cognitive impairment (MCI). In people with MCI, cognitive ability is decreased to a greater extent than in normal aging, but the ability to function in everyday life is not lost (1). In contrast, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by an on-going decline in cognition that limits the person's ability to function independently. Although MCI is a risk factor for AD, this development is not inevitable, and in fact recent evidence indicates that MCI can be reversed (2).
The pathogenesis of MCI and AD are multifaceted, but one of drivers thought to influence the progression of normal aging to MCI, and MCI to AD, is the presence of neuroinflammation (3), which is chronic inflammation of the central nervous system. Aging is also associated with chronic mild systemic inflammation (4), and changes in gut function, including alterations in gut microbiota composition and increased gut permeability (5). It has been suggested that these age-related physiological changes are interconnected, and that gut dysfunction may be a driver of systemic inflammation, and in turn neuroinflammation (6, 7). If this is indeed the case, then treatments that can maintain proper gut function, may reduce neuroinflammation and protect against, or improve symptoms of, age-associated neurodegeneration. One potential treatment is probiotics, which are beneficial bacteria, that in some cases can reduce intestinal permeability and have anti-inflammatory effects (8, 9).
This mini review briefly summarizes current knowledge on the role of neuroinflammation in age-related cognitive decline and how age-related changes in gut function may lead to neuroinflammation. Then, the mini review focuses on clinical studies assessing the ability of probiotics to improve measures of cognition during aging or as a treatment for MCI or AD.
The role of neuroinflammation in age-related cognitive decline
Neuroinflammation is an inflammatory response in the brain or spinal cord. Although an inflammatory response is vital to fight infections, the term neuroinflammation is generally used to describe an unnecessary and detrimental immune response (3). Chronic neuroinflammation is thought to be a key factor in the progression of neurodegenerative diseases (10).
During the normal aging process in healthy adults, changes in cognition and brain structure occur, which are more pronounced in those with MCI. Cognitive changes include the progressive decrease in reasoning, spatial visualization, memory and speed, alongside retained, or possibly improved, vocabulary knowledge (11). People with MCI have isolated cognitive impairment, commonly in verbal episodic memory, that does not interfere with their ability to carry out everyday tasks (12). Changes in brain structure with aging include reduced brain volume and increase in ventricular size, as well as cortical thinning and white matter volume reduction that is most apparent in the frontal lobe (13). A meta-analysis showed that across studies brain atrophy was 0.46% per year higher in those with MCI compared to normal aging (14). In addition, the volume loss in key memory and cognition regions, the hippocampus and enroehinal cortex, were both 1.35% per year higher in people with MCI.
The underlying cellular and molecular causes of the age-associated changes in brain structure and the resulting loss of cognition are multifaceted. Mattson and Arumugam (15) describe the nine hallmarks of an aging brain, one of which is neuroinflammation. As discussed by Norden and Godbout (16), aged-related neuroinflammation is characterized by an increase in levels of proinflammatory cytokines, such as interleukin (IL)-1β, and a decrease in levels of anti-inflammatory cytokines, such as IL-10 and IL-4. This inflammatory profile appears to be the result of both glial cells and astrocytes being activated in the aged brain. This activation coincides with increased systematic inflammation which may trigger the neuroinflammation in turn impair cognition (17). In support of this, a recent systematic review indicates that there is an association between an increase in peripheral inflammation markers and poorer cognition in aging (18). However, further research is required to understand prove the cause and effect.
In the case of AD, which is a progressive degenerative brain disorder, where cognition is reduced to the extent that it interferes normal daily tasks, the molecular characteristics are well-studied. These are the build-up of β-amyloid plagues formed by the aggregation of β-amyloid peptides outside the neurons and the build-up of neurofibrillary tangles formed by hyperphosphorylated tau proteins inside the neurons (19). β-amyloid plaques interfere with neuronal communication at synapses which triggers cell death, whereas tau tangles block the transport of molecules inside neurons. These two abnormalities interact in such a way that once a critical amount of β-amyloid plaques are formed, abnormal tau tangles spread throughout the brain, causing the disease progression (19). This eventually leads to excessive brain atrophy and severe dementia.
Although the appearance of β-amyloid plaques and tau tangles are often not apparent until neurodegeneration is observed, the aberrant processes, including excessive neuroinflammation, are thought to start 20 years before symptom onset (20). Initially, the toxic β-amyloid plaques and tau tangles proteins can be cleared by the microglial cells in the brain. However, this causes the microglia to be activated and release pro-inflammatory cytokines. This then makes it more difficult for the microglia to keep up with removing the unwanted proteins, leading to excessive neuroinflammation which when it reaches a threshold initiates glial cells to destroy neurons. The ability for glial cells to adequately keep up with the removal of β-amyloid plagues and tau tangles is likely related to the underlying neuroinflammation present which determines the leeway before the threshold is reached. It is proposed that this baseline neuroinflammation level is influenced by the systemic inflammation in the body (21).
Associations between age-related changes in the gut and neuroinflammation
As described above, systemic inflammation, which leads to neuroinflammation, is likely a risk factor for the progression of neurodegenerative diseases. Although systemic inflammation can be the result of numerous processes and diseases, one key trigger during aging is changes in the gut, such as the increase in gut permeability and alterations in microbiota composition (22).
During aging, the gut naturally becomes more permeable (23). The gastrointestinal tract, with a surface area of approximately 32 m2 in an adult human, is the second largest interface between the host and the outside world (24). Therefore, this reduction in its barrier function associated with aging has follow-on consequences, such as allowing unwanted components (antigens and opportunistic pathogenic bacteria) to enter the body, leading to the production of proinflammatory cytokines in the blood. These cytokines can then cross the blood brain barrier to cause neuroinflammation, which impacts brain function (25).
Whether age-associated increases in gut permeability are a cause or a consequence of other gut related changes is currently unknown. However, a recent study showed that the development of gut barrier dysfunction during aging is not consistent across all people (26). People with irritable bowel syndrome (IBS) are more susceptible to gut hyperpermeability in later life than healthy individuals (26). Interestingly, those with IBS are also more at risk at developing AD (27), supporting the idea that gut hyperpermeability is a risk factor for AD.
Current data on the association of gut barrier dysfunction with age-related neurodegeneration is conflicting. In one study, the blood biomarker zonulin, which is a group of structurally and functionally related proteins that are required for maintaining intestinal barrier integrity, was quantified. Zonulin was higher in people with MCI compared to healthy controls, and higher again in people with AD compared to those with MCI (28). Zonulin concentration was also associated with lower scores in the Mini-Mental State Examination (MMSE). In contrast, another study did not detect any difference in gut permeability between healthy controls, and participants with MCI and AD (29). However, as the authors acknowledge, the blood biomarkers used were lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (IFABP), which are measures of acute inflammation and therefore more indirect measures of intestinal permeability than zonulin.
Another aspect of the gut that changes with aging is the gut microbiota composition. The human gut is host to approximately 1013 bacterial cells which are collectively referred to as the gut microbiota (30). Over 2000 species of bacteria have been isolated from human gut samples, with the majority of these belonging to four main phyla (31). The composition of gut microbiota varies among individuals, based factors such as diet, lifestyle, geographical location, and health status, as well as age.
Recent studies have sought to define a microbiota profile associated with healthy aging, but this varies between the study populations (32, 33). However, as reviewed by Wu et al. (34), gut microbiota composition of people with AD has been shown to differ from that of healthy older adults in a number of studies. Recent studies have also shown there is a difference in the composition of the gut microbiota between people with MCI and those without (35), and that these differences are similar to those seen in people with AD (36). This implies that microbiota dysbiosis proceeds AD development and, therefore, may be a driver in the disease progression.
A key consequence of microbiota dysbiosis is changes in microbial metabolite production, and in particular a reduction in beneficials short-chain fatty-acids (SCFAs). For example, some SCFAs are known to support intestinal barrier function, and these SCFAs, as well as the microbes that produce them, have been found to be in higher abundance in healthy older adults vs. those who are frail or experiencing cognitive impairment (37). In addition, in older adults with cognitive performance from average to AD, anti-inflammatory SCFA concentrations were positively correlated with cognitive performance; whereas as pro-inflammatory microbial lipopolysaccharide concentrations were associated with poorer cognition (38). SCFAs downregulate the expression of pro-inflammatory cytokines, such as IL-1β which is associated with not only increased intestinal barrier permeability (39), but also blood brain barrier permeability (40) and a glial cell inflammatory state (41). Therefore, changes in microbiota composition that result in a decrease in SCFA production impact inflammation systemically.
Microbial-derived SCFAs impact host inflammatory pathways via epigenetic mechanisms because they are inhibitors of histone deacetylases (HDACs) (42). HDACs repress transcription by removing acetyl-groups from histones in DNA; therefore, conversely SCFA enable transcription of these genes. Rodent studies indicate that HDAC activity increases with age and in models of AD, and that this is associated with decreases synaptic plasticity (43); therefore, HDAC inhibitors, such as SCFAs, may have a protective effect. Indeed, the SCFA acetate has been shown to reduce histone acetylation and decrease IL-1β expression in a rodent model of neuroinflammation (44). Together this shows that the products of the gut microbiota can affect neuroinflammation via epigenetic mechanisms independent of their effects on gut barrier function.
The use of probiotics to mitigate age-related cognitive decline
Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” (45). Probiotics are thought to be able to improve gut barrier function, alter microbiota composition and reduce systemic inflammation, all of which may lead to a reduction in neuroinflammation. The concept of using probiotics in the prevention or treatment of age-related neurodegenerative diseases is discussed widely in the literature in review articles and opinion pieces, however, to date there are few original research articles to support this. A Scopus search of [(“ageing” OR “mild cognitive impairment” OR “Alzheimer's disease”) AND “probiotics”] resulted in 420 articles which was limited to 187 based on screening the titles to exclude articles that were off topic. These abstracts were reviewed to select primary research on probiotic intervention with older adults. Review articles and research articles using animal or cell models were excluded. Nine human clinical studies for which there is sufficient information to critique the findings are discussed below. Studies with quasi-experimental designs were excluded from this review.
Probiotic treatment for healthy older adults
There are two published studies that investigated the effects of mixes of bifidobacteria on cognition in healthy older adults. Although the first study had some limitations, the second provided preliminary evidence that probiotics may improve cognitive function in older adults via modulation of the gut microbiota.
In the first study, all participants (66–78 years) underwent a 12-week resistance training programme. One group (n = 20) also received a multi-strain probiotic mixture (Bifidobacterium longum subsp. longum BB536, B. longum subsp. infantis M-63, Bifidobacterium breve M-16V and B. breve B-3) and the other group did not (n = 18) (46). Both groups had an increase in cognitive function, as measured by the Japanese version of the Montreal Cognitive Assessment (MoCA-J), but there was no difference in the improvement of those receiving the probiotics verses those who did not. There was potentially a larger improvement in the number of correct responses in the Flanker test in the probiotic group, however, this was not statistically significant (P = 0.056). This study focused on the combination of exercise and probiotics, therefore there was not a treatment group where participants received the probiotic without the resistance training, and no control group that did not receive either the resistance training or probiotic. The study did not assess any gut-related parameters, however, this probiotic combination has previously been shown to be effective in children with IBS (47), so it is plausible that it is having its cognitive effects via alterations in gut function.
In the second study, participants (≥65 years) took placebo (n = 31) or probiotic (n = 32) (Bifidobacterium bifidum BGN4 and B. longum BORI) capsules twice a day for 12 weeks (48). B. bifidum BGN4 has anti-inflammatory properties and has been shown to be beneficial for infants with eczema and adults with (IBS) (49). In the study by Kim et al. (48), participants in the probiotic group had an increase in mental flexibility (attention and executive function) after 12 weeks compared to baseline, and at 12 weeks compared to the placebo group, as measured by the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K) test. In addition, after 12 weeks the probiotic group had higher blood serum levels of brain-derived neurotrophic factor (BDNF), which is a protein known to protect against neuroinflammation. BDNF levels correlated with increased in abundance of particular gut bacteria subpopulations (Eubacterium and Clostridiales), which indicates that the neuroprotective effects may have originated in the gut.
Probiotic treatment for mild cognitive impairment
There are four published studies that assessed the effects of probiotics in people with age-related MCI and all indicated that the probiotic treatments resulted in improved cognitive function. Two studies used B. breve A1 and the other two studies used strains of lactobacilli. There are some indicators that improvements in cognition were related to a reduction in inflammation, however, no gut-related parameters were measured in any of the studies.
Evidence for the effectiveness of the probiotic B. breve A1 for improving cognitive function in people with MCI has been accumulated over three publications by the same group. In the first study, participants (≥65 years) with memory complaints were recruited and were given either a probiotic supplement containing B. breve A1 (n = 32) or a placebo (n = 31) for 12 weeks (50). Initial analysis of the data did not show any differences in the improvement in cognitive function compared to baseline scores between treatments groups. However, when the participants were stratified, based on their initial scores in the Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), those with MCI had greater improvements in MMSE scores after taking the probiotic compared to the placebo.
To build on the previous results, in the second study participants (50–79 years) were selected based on their pre-screening RBANS score being in the range expected for MCI and then assigned to either the probiotic supplement B. breve A1 (n = 40) or a placebo (n = 40) group for 16 weeks (51). After the treatment, the probiotic group had a significant increase in RBANS score compared to baseline and compared to the placebo group, which was driven by improvements in immediate memory, visuospatial/constructional and delayed memory domain scores. The probiotic group also had an increase in MCI screen score. Further analysis of blood biomarkers found that RBANS scores were negatively correlated with hemoglobin A1c (HbA1c) levels (52). This is consistent with the idea that HbA1c levels are associated with the development of neuroinflammation and cognitive decline (53). Interestingly, in the analysis by Bernier et al. (52), participants with higher baseline HbA1c levels had more marked improvement in RBANS scores across more domains of the battery when treated with B. breve A1, indicating that the probiotic was able to mitigate some of the negative impacts of HbA1c. In a study using a mouse model of AD, B. breve A1 improved cognition and reduced neuroinflammation, however, it did not alter microbiota composition (54). Therefore, further research is needed to understand the mechanisms by which the probiotic present in the gut affects the brain.
In the first study with a lactobacilli, participants (55–85 years) with MCI were treated with a nutritional supplement containing Lactobacillus plantarum C29-fermented soybean (n = 50) or a placebo (n = 50) for 12 weeks (55). L. plantarum C29-fermented soybean was previously shown to improve cognition in a mouse model of AD, and that this correlated with changes in brain and blood inflammatory biomarkers and microbiota composition (56). In the study by Hwang et al. (55), the group receiving the nutritional supplement had a greater increase in combined cognitive function after the treatment period than those in the control group, which was largely driven by an increase in attention. For the group receiving the nutritional supplement, there was a positive correlation between BNDF levels and increase in cognitive function, whereas there was no relationship between the two measures for the placebo group, which indicates a potential mechanism of action of the supplement. Unfortunately, due to the study design, it is not possible to discern whether the benefits were due to the probiotic, the soybean or the combination of the two.
In the second study with a lactobacilli, the effects of the well-known probiotic Lactobacillus rhamnosus GG on cognition in middle-aged and older adults (52–75 years) was assessed (57). Participants were randomly assigned to consume placebo (n = 68) or probiotic (n = 77) capsules daily for 3 months, and cognitive ability was assessed before and after the treatment using the NIH Toolbox of Neurological and Behavior Function. Similar to the results of the Kobayashi et al. (50) study, greater cognitive improvement was observed in participants with MCI taking the probiotic than those with MCI taking the placebo, and this treatment effect was not apparent for those with intact cognition. The physiological mechanisms for the change in cognition were not explored in this study. However, L. rhamnosus GG is a well-studied probiotic with 30 years of research to illustrate it gut health benefits and anti-inflammatory properties (58), so it is plausible that it acts via the gut-brain axis.
Probiotic treatment for Alzheimer's disease
There are three published studies that investigate the effects of probiotics on cognitive function in people with AD. These studies were all conducted by the same research group and used mixed probiotic cultures containing both bifidobacteria and lactobacilli. All of the studies have limitations, and the results were varying. Like the MCI studies, some indicators of systemic inflammation were measured, but the link to gut function was not explored. Furthermore, the strain names for the probiotics used were not given so it was not possible to determine if they had known gut health benefits.
In the first study, participants (age range not given) received either a probiotic milk drink containing Lactobacillus acidophilus, Lactobacillus casei, B. bifidum, and Lactobacillus fermentum (n = 30) or standard milk (n = 30) for 12 weeks (59). The authors reported a 28% increase in MMSE score after the probiotic treatment compared to no increase in the control group. In addition, they reported changes in a range of metabolism related biomarkers, but no changes in biomarkers related to oxidative stress and inflammation. Unfortunately, the validity of this study is currently under review by the institute in which it was conducted, so the results should be viewed with caution until this matter is resolved (60).
In a follow up study, participants (65–90 years) in the probiotic treatment group (n = 25) received two different supplements on alternate days for 12 weeks; one containing L. fermentum, L. plantarum, and Bifidobacterium lactis and one containing L. acidophilus, B. bifidum, and B. longum (61). There was also a placebo group (n = 23) which received maltodextrin capsules. Unlike the previous study, the probiotic treatment group did not have a significant increase in cognitive function after the treatment. The authors proposed that this was due to the severity of AD in the participants, which was higher than in the previous study. It is also worth noting that cognitive function was assessed using a different measure - the Test Your Memory (TYM) brief test instead of the MMSE - which may also have also accounted for the difference in results.
In the third AD study, Tamtaji et al. (62) compared participants (55–100 years) treated with a placebo (n = 26), a selenium supplement (n = 26), or a selenium supplement plus a probiotic mixture containing L. acidophilus, B. bifidum and B. longum (n = 27) for 12 weeks. The group receiving the selenium plus probiotic supplement had a significant increase in MMSE score, whereas the placebo and selenium only groups did not. Differences in some inflammatory and oxidative stress-related biomarkers were also observed in the group receiving the probiotic supplement compared to the other groups. These included an increase in blood plasma concentrations of glutathione (GSH), which is important in reducing oxidative stress, as well as total antioxidant capacity (TAC), and a reduction in the lymphocyte gene expression of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFβ). As the focus of this study was on probiotic and selenium co-supplementation, there was not a group which received the probiotic mixture only.
Conclusions
The concept that neuroinflammation is a critical driver of neurogenerative disease progression is discussed widely in the scientific literature and the idea that systematic inflammation is a risk factor for this is gaining traction. However, cognitive impairment during aging is a complicated and multifaceted process, and the contribution of various factors and their interplay is yet to be fully understood. There is another layer of complexity when considering the hypothesis that systemic inflammation that triggers neuroinflammation is initiated in the gut and that this process may be mitigated using probiotics. There is much discussion and conjecture in the literature, but very little original research.
The answer to the question this minireview sought to investigate—Can probiotics mitigate age-related neuroinflammation leading to improved cognitive outcomes?—remains unknown. There is preliminary evidence to suggest that specific probiotics may improve cognitive function, particularly in those with MCI; however, the results are not just conclusive. Larger, multilocation studies designed specific to assess the effect of probiotics on cognition alongside the analysis of biomarkers of systemic inflammation, gut permeability and microbiota composition are needed.
Author contributions
RA completed the literature search and wrote the mini review.
Funding
This mini review was partially funded by the New Zealand Ministry of Business, Innovation & Employment as part of the Endeavor Research Programme entitled Smarter Lives: New Opportunities for Dairy Products Across the Lifespan (Contract C10X1706).
Acknowledgments
The author thanks Josh Faulkner (Massey University), Julie Dalziel (AgResearch) and Dulantha Ulluwishewa (AgResearch) for critical review of the manuscript.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Tuokko HA, Hultsch DF. Mild Cognitive Impairment: International Perspectives. 1st ed. Psychology Press (2020). doi: 10.4324/9781003020301
2. Shimada H, Doi T, Lee S, Makizako H. Reversible predictors of reversion from mild cognitive impairment to normal cognition: a 4-year longitudinal study. Alzheimer's Res Ther. (2019) 11:24. doi: 10.1186/s13195-019-0480-5
3. DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. (2016) 139 (Suppl 2):136–53. doi: 10.1111/jnc.13607
4. Chung HY, Kim DH, Lee EK, Chung KW, Chung S, Lee B, et al. Redefining chronic inflammation in aging and age-related diseases: Proposal of the senoinflammation concept. Aging Dis. (2019) 10:367–82. doi: 10.14336/AD.2018.0324
5. Soenen S, Rayner CK, Jones KL, Horowitz M. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care. (2016) 19:12–8. doi: 10.1097/MCO.0000000000000238
6. Bairamian D, Sha S, Rolhion N, Sokol H, Dorothée G, Lemere CA, et al. Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer's disease. Mol Neurodegener. (2022) 17:19. doi: 10.1186/s13024-022-00522-2
7. Lin L, Zheng LJ, Zhang LJ. Neuroinflammation, gut microbiome, and Alzheimer's disease Mol Neurobiol. (2018) 55:8243–50. doi: 10.1007/s12035-018-0983-2
8. Gou HZ, Zhang YL, Ren LF, Li ZJ, Zhang L. How do intestinal probiotics restore the intestinal barrier? Front Microbiol. (2022) 13:929346. doi: 10.3389/fmicb.2022.929346
9. Liu Q, Yu Z, Tian F, Zhao J, Zhang H, Zhai Q, et al. Surface components and metabolites of probiotics for regulation of intestinal epithelial barrier. Microb Cell Fact. (2020) 19:23. doi: 10.1186/s12934-020-1289-4
10. Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: current evidence and future directions. Alzheimers Dement. (2016) 12:719–32. doi: 10.1016/j.jalz.2016.02.010
11. Salthouse TA. Selective review of cognitive aging. J Int Neuropsychol Soc. (2010) 16:754–60. doi: 10.1017/S1355617710000706
12. Nordahl CW, Ranganath C, Yonelinas AP, DeCarli C, Reed BR, Jagust WJ. Different mechanisms of episodic memory failure in mild cognitive impairment. Neuropsychologia. (2005) 43:1688–97. doi: 10.1016/j.neuropsychologia.2005.01.003
13. MacDonald ME, Pike GB. MRI of healthy brain aging: a review. NMR Biomed. (2021) 34:e4564. doi: 10.1002/nbm.4564
14. Tabatabaei-Jafari H, Shaw ME, Cherbuin N. Cerebral atrophy in mild cognitive impairment: a systematic review with meta-analysis. Alzheimers Dement. (2015) 1:487–504. doi: 10.1016/j.dadm.2015.11.002
15. Mattson MP, Arumugam TV. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. (2018) 27:1176–99. doi: 10.1016/j.cmet.2018.05.011
16. Norden DM, Godbout JP. Review: Microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol. (2013) 39:19–34. doi: 10.1111/j.1365-2990.2012.01306.x
17. Corona AW, Fenn AM, Godbout JP. Cognitive and behavioral consequences of impaired immunoregulation in aging. J Neuroimmune Pharmacol. (2012) 7:7–23. doi: 10.1007/s11481-011-9313-4
18. Fard MT, Savage KM, Stough CK. Peripheral inflammation marker relationships to cognition in healthy older adults – a systematic review. Psychoneuroendocrinology. (2022) 144:105870. doi: 10.1016/j.psyneuen.2022.105870
19. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. (2014) 71:505–8. doi: 10.1001/jamaneurol.2013.5847
20. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. (2015) 14:388–405. doi: 10.1016/S1474-4422(15)70016-5
21. Boyd RJ, Avramopoulos D, Jantzie LL, McCallion AS. Neuroinflammation represents a common theme amongst genetic and environmental risk factors for Alzheimer and Parkinson diseases. J Neuroinflammation. (2022) 19:223. doi: 10.1186/s12974-022-02584-x
22. Megur A, Baltriukien, e D, Bukelskien, e V, Burokas A. The microbiota–gut–brain axis and Alzheimer's disease: Neuroinflammation is to blame? Nutrients. (2021) 13:1–24. doi: 10.3390/nu13010037
23. Man AL, Bertelli E, Rentini S, Regoli M, Briars G, Marini M, et al. Age-associated modifications of intestinal permeability and innate immunity in human small intestine. Clin Sci. (2015) 129:515–27. doi: 10.1042/CS20150046
24. Helander HF, Fändriks L. Surface area of the digestive tract – revisited. Scand J Gastroenterol. (2014) 49:681–9. doi: 10.3109/00365521.2014.898326
25. Ambrosini YM, Borcherding D, Kanthasamy A, Kim HJ, Willette AA, Jergens A, et al. The gut-brain axis in neurodegenerative diseases and relevance of the canine model: a review. Front Aging Neurosci. (2019) 11. doi: 10.3389/fnagi.2019.00130
26. Wilms E, Troost FJ, Elizalde M, Winkens B, de Vos P, Mujagic Z, et al. Intestinal barrier function is maintained with aging – a comprehensive study in healthy subjects and irritable bowel syndrome patients. Sci Rep. (2020) 10:475. doi: 10.1038/s41598-019-57106-2
27. Chen CH, Lin CL, Kao CH. Irritable bowel syndrome is associated with an increased risk of dementia: a nationwide population-based study. PLoS ONE. (2016) 11:e0144589–e0144589. doi: 10.1371/journal.pone.0144589
28. Wang X, Liu GJ, Gao Q, Li N, Wang R. C-type lectin-like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease. Acta Neurol Scand. (2020) 141:250–5. doi: 10.1111/ane.13196
29. Voigt RM, Raeisi S, Yang J, Leurgans S, Forsyth CB, Buchman AS, et al. Systemic brain derived neurotrophic factor but not intestinal barrier integrity is associated with cognitive decline and incident Alzheimer's disease. PLoS ONE. (2021) 16:e0240342. doi: 10.1371/journal.pone.0240342
30. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. (2016) 14:e1002533–e1002533. doi: 10.1371/journal.pbio.1002533
31. Hugon P, Dufour JC, Colson P, Fournier PE, Sallah K, Raoult D. A comprehensive repertoire of prokaryotic species identified in human beings. Lancet Infect Dis. (2015) 15:1211–9. doi: 10.1016/S1473-3099(15)00293-5
32. Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nature Metabol. (2021) 3:274–86. doi: 10.1038/s42255-021-00348-0
33. Xu C, Zhu H, Qiu P. Aging progression of human gut microbiota. BMC Microbiol. (2019) 19:236. doi: 10.1186/s12866-019-1616-2
34. Wu S, Liu X, Jiang R, Yan X, Ling Z. Roles and mechanisms of gut microbiota in patients with Alzheimer's disease. Front Aging Neurosci. (2021) 13. doi: 10.3389/fnagi.2021.650047
35. Saji N, Murotani K, Hisada T, Tsuduki T, Sugimoto T, Kimura A, et al. The relationship between the gut microbiome and mild cognitive impairment in patients without dementia: a cross-sectional study conducted in Japan. Sci Rep. (2019) 9:19227. doi: 10.1038/s41598-019-55851-y
36. Li B, He Y, Ma J, Huang P, Du J, Cao L, et al. Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota. Alzheimers Dement. (2019) 15:1357–66. doi: 10.1016/j.jalz.2019.07.002
37. Rashidah NH, Lim SM, Neoh CF, Majeed ABA, Tan MP, Khor HM, et al. Differential gut microbiota and intestinal permeability between frail and healthy older adults: a systematic review. Ageing Res Rev. (2022) 101744. doi: 10.1016/j.arr.2022.101744
38. Marizzoni M, Cattaneo A, Mirabelli P, Festari C, Lopizzo N, Nicolosi V, et al. Short-chain fatty acids and lipopolysaccharide as mediators between gut dysbiosis and amyloid pathology in Alzheimers disease. J Alzheimers Dis. (2020) 78:683–97. doi: 10.3233/JAD-200306
39. Kaminsky LW, Al-Sadi R, Ma TY. IL-1β and the intestinal epithelial tight junction barrier. Front Immunol. (2021) 12. doi: 10.3389/fimmu.2021.767456
40. Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci. (2000) 20:8153–9. doi: 10.1523/JNEUROSCI.20-21-08153.2000
41. Liu X, Quan N. Microglia and CNS Interleukin-1: beyond immunological concepts. Front Neurol. (2018) 9. doi: 10.3389/fneur.2018.00008
42. Fellows R, Denizot J, Stellato C, Cuomo A, Jain P, Stoyanova E, et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun. (2018) 9:105. doi: 10.1038/s41467-017-02651-5
43. Chacko S, Ladiges W. Therapeutic targeting of histone deacetylation to prevent Alzheimer's disease. Emed Res. (2021) 3.
44. Soliman ML, Smith MD, Houdek HM, Rosenberger TA. Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation. J Neuroinflammation. (2012) 9:51. doi: 10.1186/1742-2094-9-51
45. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. (2014) 11:506–14. doi: 10.1038/nrgastro.2014.66
46. Inoue T, Kobayashi Y, Mori N, Sakagawa M, Xiao JZ, Moritani T, et al. Effect of combined bifidobacteria supplementation and resistance training on cognitive function, body composition and bowel habits of healthy elderly subjects. Benef Microbes. (2018) 9:843–53. doi: 10.3920/BM2017.0193
47. Giannetti E, Maglione M, Alessandrella A, Strisciuglio C, De Giovanni D, Campanozzi A, et al. A mixture of 3 bifidobacteria decreases abdominal pain and improves the quality of life in children with irritable bowel syndrome: a multicenter, randomized, double-blind, placebo-controlled, crossover trial. J Clin Gastroenterol. (2017) 51:e5–e10. doi: 10.1097/MCG.0000000000000528
48. Kim H, Kim S, Park SJ, Park G, Shin H, Park MS, et al. Administration of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI improves cognitive and memory function in the mouse model of Alzheimer's disease. Front Aging Neurosci. (2021) 13. doi: 10.3389/fnagi.2021.709091
49. Ku S, Park MS, Ji GE, You HJ. Review on Bifidobacterium bifidum BGN4: Functionality and Nutraceutical Applications as a Probiotic Microorganism. Int J Mol Sci. (2016) 17:1544. doi: 10.3390/ijms17091544
50. Kobayashi Y, Kuhara T, Oki M, Xiao JZ. Effects of bifidobacterium breve a1 on the cognitive function of older adults with memory complaints: a randomised, double-blind, placebo-controlled trial. Benef Microbes. (2019) 10:511–20. doi: 10.3920/BM2018.0170
51. Xiao J, Katsumata N, Bernier F, Ohno K, Yamauchi Y, Odamaki T, et al. Probiotic bifidobacterium breve in improving cognitive functions of older adults with suspected mild cognitive impairment: a randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. (2020) 77:139–47. doi: 10.3233/JAD-200488
52. Bernier F, Ohno K, Katsumata N, Shimizu T, Xiao J. Association of plasma hemoglobin A1c with improvement of cognitive functions by probiotic bifidobacterium breve supplementation in healthy adults with mild cognitive impairment. J Alzheimers Dis. (2021) 81:493–7. doi: 10.3233/JAD-201488
53. Marden JR, Mayeda ER, Tchetgen Tchetgen EJ, Kawachi I, Glymour MM. High hemoglobin A1c and diabetes predict memory decline in the health and retirement study. Alzheimer Dis Assoc Disord. (2017) 31:48–54. doi: 10.1097/WAD.0000000000000182
54. Kobayashi Y, Sugahara H, Shimada K, Mitsuyama E, Kuhara T, Yasuoka A, et al. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer's disease. Sci Rep. (2017) 7:13510. doi: 10.1038/s41598-017-13368-2
55. Hwang YH, Park S, Paik JW, Chae SW, Kim DH, Jeong DG, et al. Efficacy and safety of lactobacillus plantarum C29-fermented soybean (DW2009) in individuals with mild cognitive impairment: a 12-week, multi-center, randomized, double-blind, placebo-controlled clinical trial. Nutrients. (2019) 11:305. doi: 10.3390/nu11020305
56. Lee HJ, Hwang YH, Kim DH. Lactobacillus plantarum C29-Fermented Soybean (DW2009) Alleviates Memory Impairment in 5XFAD Transgenic Mice by Regulating Microglia Activation and Gut Microbiota Composition. Mol Nutr Food Res. (2018) 62:1800359. doi: 10.1002/mnfr.201800359
57. Sanborn V, Azcarate-Peril MA, Updegraff J, Manderino L, Gunstad J. Randomized clinical trial examining the impact of Lactobacillus rhamnosus GG probiotic supplementation on cognitive functioning in middle-aged and older adults. Neuropsychiatr Dis Treat. (2020) 16:2765–77. doi: 10.2147/NDT.S270035
58. Capurso L. Thirty Years of Lactobacillus rhamnosus GG: a review. J Clin Gastroenterol. (2019) 53:S1–S41. doi: 10.1097/MCG.0000000000001170
59. Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki E, Tamtaji OR, et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. (2016) 8:256–256. doi: 10.3389/fnagi.2016.00256
60. Frontiers Editorial O. Expression of concern: effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. (2020) 12:602204–602204. doi: 10.3389/fnagi.2020.602204
61. Agahi A, Hamidi GA, Daneshvar R, Hamdieh M, Soheili M, Alinaghipour A, et al. Does severity of Alzheimer's disease contribute to its responsiveness to modifying gut microbiota? A double blind clinical trial. Front Neurol. (2018) 9:662. doi: 10.3389/fneur.2018.00662
62. Tamtaji OR., Heidari-soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E, et al. Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer's disease: A randomized, double-blind, controlled trial. Clin Nutr. (2019) 38:2569–75. doi: 10.1016/j.clnu.2018.11.034
Keywords: neurodegeneration, mild cognitive impairment, Alzheimer's disease, dementia, gut permeability, microbiota, probiotics, neuroinflammation
Citation: Anderson RC (2022) Can probiotics mitigate age-related neuroinflammation leading to improved cognitive outcomes? Front. Nutr. 9:1012076. doi: 10.3389/fnut.2022.1012076
Received: 08 August 2022; Accepted: 07 November 2022;
Published: 24 November 2022.
Edited by:
David Vauzour, University of East Anglia, United KingdomReviewed by:
Andrea Fuso, Sapienza University of Rome, ItalySofia Cussotto, Université Paris-Saclay, France
Copyright © 2022 Anderson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: R. C. Anderson, rachel.anderson@agresearch.co.nz