Alzheimer’s disease (AD), today is the most prevalent form of dementia afflicting more than 50 million people worldwide (Queiroz et al., 2022, Varesi et al., 2022), and with a doubling time of 20 years could easily reach 150 million patients by 2050 (Bairamian et al., 2022). Care and treatment for those suffering from AD impose considerable cost, both financially (billions to perhaps trillions of USD) and societally. Addressing the paucity of disease-modifying or palliative therapies (not to mention a viable preventative or curative therapy) would seem to be paramount. Significant scientific attention has been focused – in the last decade or more – on the microbiome and its contribution to or prevention of host diseases. There is now considerable evidence to implicate microbiome disturbances with a range of neurological and neuropsychiatric diseases including Parkinson’s disease (PD), multiple sclerosis, Huntington’s disease (HD), Amyotrophic lateral sclerosis, and most significantly AD (Kandpal et al., 2022). Once considered unlikely, the microbiome has been described to be associated with the pathology of AD as demonstrated by an explosion of publications on the topic (Bairamian et al., 2022, Whitson et al., 2022). This blog attempts to elucidate the recent science in this area with an emphasis on the role of the gut microbiota-brain axis (GMBA).
Brief Alzheimer’s Disease Overview
AD is a progressive neurodegenerative disease with both neurological and immunological inputs. AD patients have progressive memory impairments and cognitive decline. These symptoms evolve from essentially undetectable to severe, advancing in parallel to the extent of neuropathology (Bairamian et al., 2022). AD’s molecular neuropathology is characterized by the extracellular accumulation of beta amyloid (Aβ) plaques and intracellular hyperphosphorylated tau-protein-based neurofibrillary tangles (NFT). These molecular formations (or lesions) are well established characteristics with the causative chain that initiates their development being less certain. While some monogenic forms of AD are known, most cases are idiopathic and complex with unresolved combinations of genetic and environmental factors contributing to the disease formation and progression (Zacharias et al., 2022). The apolipoprotein E (ApoE) gene carries the genetic changes most closely correlated to AD pathology development and a microglial shift away from homeostasis to neuroinflammation. The presence of Aβ and NFT pathologies coincides with neuroinflammation. Continued unresolved neuroinflammation, as well as direct effects of the molecular pathologies lead to aberrant activation of brain microglia and other immune cells to cause synaptic destruction and neuronal death, also known as neurodegeneration (Jungbauer et al., 2022). As AD progresses glial cell loss occurs thus further compromising Aβ clearance resulting in a pathological feed-forward cycle. Progressive loss of neurons leads to worsened cognitive impairment and degradation of motor control (Queiroz et al., 2022). Death of patients eventually follows from the extremes of neuropathology or more often by secondary conditions, like opportunistic infection, as the health-compromised state of late stage AD patients makes them quite vulnerable.
The Characteristics of Microbiomes and Metabolomes and How They Affect AD Development
The gut microbiome (GMB) is defined as the sum total of commensal organisms that colonize the human gastrointestinal (GI) tract. It’s comprised of bacterial, archaea, fungi, and protozoans along with their associated viruses and phages. The human gut microbiota has a mass greater than 2 kilogram with a genomic informational content tens to hundreds of times that of the reference human genome (Kandpal et al., 2022) . The phyla Firmicutes and Bacteriodetes constitute ninety percent of the gut microbial population (van Olst et al., 2021). There are also lesser contributions by Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia (Queiroz et al., 2022). Originally, the microbiota was defined by 16S rRNA sequencing while more recently deep metagenome shotgun sequencing is evolving as the preferred gold standard (Zacharias et al., 2022).
The metabolome is the sum of all biochemical content – both macromolecules and small molecules – within a system. In the gut, this would be the comprehensive identity and quantity of metabolic products of all the resident microorganisms as well as the host. This plays an important part in our understanding of the microbiome effect as it is the metabolites that often play a significant role in the communication with the host. The most common methods for analyzing the gut microbiome metabolites is either via mass spectrometry (MS), or nuclear magnetic resonance (NMR) measurement of relevant biological samples (Zacharias et al., 2022).
The GMB begins its assembly during pregnancy and continues to develop during the first years of life coinciding with both brain and immune system development (Dash et al., 2022). Interestingly, both of these critical processes are affected by changes in the GMB. In the brain the GMB influences are felt at both neuronal and glial levels and dysbiosis can change normal microglial maturation which is critical for setting the homeostasis of the brain (Dash et al., 2022). Dysbiosis can mean loss of beneficial bacteria, acquisition/overgrowth of pathological bacteria or changes in bacterial diversity causing loss or diminishment of critical function. The GMB assists the normal development of the host immune system and factors such as diet, infection/disease and antibiotic use can alter this process which can then lead to neurological impairment (Bairamian et al., 2022; Zhu S. et al., 2020). Even within ‘normal’ aging there is a slow increase in pro-inflammatory GMB microbes (Varesi et al., 2022) and a decrease in microbial diversity and stability (van Olst et al., 2021). GMB changes with age are associated with increased intestinal permeability and neuroinflammation (Queiroz et al., 2022).
The GMB changes associated with AD are generally decreased microbial diversity and a relative increase in pro- versus anti-inflammatory species. Many but not all studies show an increase in phylum Bacteriodetes in AD patients and also in relevant animal disease models (Bairamian et al.; 2022, Varesi et al., 2022). Bacteria of phylum Firmicutes are reduced versus controls in aging individuals, AD patients, and in mouse model of AD (Bettcher et al., 2021; Zacharias et al., 2022). To date, many of the studies on human populations with AD or precursor states are relatively small in size and/or geographically limited. It seems clear that regional differences in diet, environment and genetic background are also significant confounding factors and may explain why no unifying conclusions have been reached from all the existing studies so far (Bairamian et al., 2022). With this in mind, the Alzheimer Gut Microbiome Project (AGMP) was initiated in 2019 with eight AD research centers across the US to profile samples from 1,000 subjects using both metagenomics and various metabolomics platforms.
Potential Pathways of Communication from the GMB to the Brain
One could be forgiven for entertaining the notion that there is little communication between the gut and the brain as the brain has traditionally been viewed as an isolated organ. It is now clear that there are multiple paths of bidirectional communication possible between the gut and the brain and that the microbiome plays a central contributing role in this (Varesi et al., 2022).
The Vagus Nerve as a Major Communication Route
The major and most direct pathway of communication between the brain and gut is via the vagus nerve (Varesi et al., 2022). The vagus nerve (aka the tenth cranial nerve) is a major nerve of the parasympathetic nervous system and a crucial part of the autonomic nervous system (ANS) (Kandpal et al., 2022). The vagus nerve is composed of 80% afferent and 20% efferent fibers and stretches from the large intestine to the brain and through this architecture supports the hypothesis of bidirectional communication between the gut and the brain (Chandra et al., 2023). GMB derived molecules (neurotransmitters, hormones and short-chain fatty acids (SCFA)) have been show to stimulate the vagus nerve directly.
Microbiome Modulation of Inflammation and Neuroinflammation
Another mode of communication between the brain and the gut microbiome is via modulation of inflammation. There is considerable data demonstrating that peripheral inflammatory markers are associated with AD. For example, levels of C-reactive protein, IL-6, Tumor necrosis factor (TNF), and IL-1β are all associated with AD (Bettcher et al., 2021). In APP/PS1 mice plasma levels of CCL11, IL-1β, IL2, IL3, stem cell factor (SCF) and IL6 are all altered by GMB changes. In related APPPS1-21 mouse models, GMB perturbations altered levels of insulin-like growth factor (IGF)-binding protein (IGFBP) 3, IL6, IL10, eotaxin1, IL-1β, IL2, IL3, IL17a, and CCL5 (Chandra et al., 2023). Changes of plasma cytokine markers are associated with peripheral changes in immune cell regulation and central changes in Aβ plaque and microglial activation state. These and other mouse model data support the notion that GMB alterations of the balance between pro- and anti-inflammatory cytokines can drive changes in peripheral immune response which then propagate into neuroinflammation changes (Chandra et al., 2023).
The GMB can also more directly influence neuroinflammation via second messengers that make their way to the CNS. In mouse AD model systems, like APPPS1-21 or 5XFAD, changes of the GMB can affect microglial activation state with SCFA acting as a possible messenger conduit (Chandra et al., 2023). GMB perturbations in mouse AD models can also regulate astrocyte inflammation state possibly by tryptophan metabolites generated in the gut (Chandra et al., 2023).
The Blood Brain Barrier (BBB) and GI Tract Integrity
The blood-brain barrier (BBB) is a critical physiological structure in protecting the CNS from unwanted entities in systemic circulation. The 100 billion neurons and one trillion glial cells of the brain – which compose 2% of body weight and 20% of metabolic energy use – reside on the immune privileged side of the BBB. The defining unit of the BBB is the neurovascular unit (NVU) and is composed of brain endothelial cells, pericytes, the basement membrane, and astrocytes (Mou et al., 2022). BBB permeability and integrity can be altered by a number of molecules in circulation. BBB breakdown is a well-established hallmark of AD and therefore factors contributing to BBB regulation or disfunction can have a key role in AD emergence and progression (Chandra et al., 2023).
As such systemic inflammation can disrupt BBB integrity allowing for the passage of pro-inflammatory substances into the brain. GMB eubiosis is associated with stable intestinal permeability while GMB dsybiosis can result in increased intestinal permeability (Queiroz et al., 2022). Increased translation of bacterial endotoxins and metabolites to the blood can lead to inflammation and compromise the BBB’s integrity. Gut microbiome metabolites, like Trimethylamine N-oxide (TMAO), bile acids, and SCFA, have been shown to affect BBB’s integrity or permeability in mouse models (Bairamian et al., 2022, Chandra et al., 2023). Data such as these demonstrate the interconnectivity between the GI tract and BBB integrity.
Figure 1: Hypothetical link between the gut dysbiosis and mechanisms leading to the pathophysiology of AD as described in Bairamian et al. (2022).
A Large Number of Microbial Metabolites Can Potentially Affect the Host System
Short Chain Fatty Acids
The gut microbiome metabolites SCFAs are 2-5 carbon carboxylic acid molecules such as acetate, propionate, butyrate, and valerate. As described above, they may be produced by GMB organisms and have direct local effects via the vagus nerve, and also act distally at the BBB. In addition, these small molecules in the blood circulation can also cross the BBB and therefore can have a direct effect on the brain. SCFAs, particularly butyrate, can induce changes to microglia towards a homeostatic (M0) state and away from pro-inflammatory states triggered by bacterial lipopolysachharides (LPS) (Bairamian et al., 2022). The phylum Firmicutes selectively produces large amounts of butyrate while Bacteriodetes produce more acetate and propionate (Zhu S. et al., 2020). SCFA can also exert its influence by altering the state of chromatin acetylation and DNA methylation (Zhu S. et al., 2020; van Olst et al., 2021). While it is true that AD patients generally have decreased levels of SCFA, except for butyrate, the relative protective versus pathogenic effect of SCFA in the context of AD is still unresolved (Park and Kim, 2021).
Neurotransmitters
GMB organisms can create metabolites that act as neurotransmitters in the human host. Strains of Lactobacillus can produce acetylcholine while both Lactobacillus and Bifidobacterium can produce γ-aminobutyric acid (GABA) (Kandpal et al., 2022; Queiroz et al., 2022). In addition, there is evidence linking production of N-methyl-D-aspartate, serotonin, BDNF, and dopamine to the microorganisms within the GMB (Queiroz et al., 2022). In mouse PD models elevated levels of dopamine can be created by modulation of the GMB while in human patients elimination of H. pylori infection seems to have a sparing effect on dopamine levels generated by treatment with L-DOPA (levodopa) (Kandpal et al., 2022).
Tryptophan Metabolites
The GMB organisms metabolize tryptophan into a range of derivatives which can have effects on the host. The neurotransmitter serotonin is a tryptophan metabolite and significant synthesis (90% of the body total) is done in the host GI tract by microorganisms such as Streptococcus, Escherichia, Enterococcus, Lactococcus, and Lactobacillus (Queiroz et al., 2022). Other tryptophan derivatives such as indole, kynurenine, and tryptamine are produced by GMB organisms and can impact the anti-/pro-inflammatory balance in the intestinal mucosa (Bairamian et al., 2022). This in turn can trigger changes in regulation of various T cell populations. Some GMB derived tryptophan metabolites are known to directly modulate astrocyte reactivity (Chandra et al., 2023). In other contexts, it was found that tryptophan metabolites produced by GMB control microglial activation, influence the transcriptional program of astrocytes and their contribution to CNS inflammation (Zhu S. et al., 2020). In AD patients, the blood ratio of kyneurenine/tryptophan is elevated due to lower tryptophan levels (Park and Kim, 2021). This correlates with systemic immune activated state, present in AD and other neurodegenerative diseases, where increased indoleamine 2,3-dioxygenase (IDO) converting tryptophan to N-formylkynurenine is a hallmark.
Bacterial Lipopolysachharides (LPS)
Bacterial lipopolysachharides (LPS) are cell wall components, mostly from gram-negative organisms, which are endotoxic to the human host (Dash et al., 2022). LPS can promote release of pro-inflammatory cytokines. Some gram-negative organisms also excrete polysaccharide A (PSA) which can be anti-inflammatory (van Olst et al., 2021). LPS can activate astrocytes and is positively associated with brain amyloid deposition. The SCFA butyrate can inhibit this effect (Bairamian et al., 2022).
Bacterial Amyloid Proteins
Amyloid as a general category are proteins prone to aggregation and insolubility with characteristics resembling carbohydrate starches (Zhu S. et al., 2020). As a group they are involved in not only the pathology of AD, but also of PD (𝛼-synuclein), HD (huntingtin), and many other diseases. Some microorganisms generate proteins that bear striking similarity to human amyloid proteins. Curli, produced by E. coli, is one example of such a bacterial amyloid that may cross-seed Aβ aggregate formation in a manner similar to the prion protein (Bairamian et al., 2022; Zhu S. et al., 2020). Other work has shown Staphylococcus (Modulins), Streptococcus (Adhesin P1), Mycobacteria, Pseudomonas fluorescens (FapC), Streptomyces coelicolor (Chaplins), Salmonella (CsgA), Citrobacter, Klebsiella (MccE492), and Bacillus (TasA) species can all generate and excrete extracellular amyloids (Zhu S. et al., 2020; Kandpal et al., 2022).
Trimethylamine N-oxide (TMAO)
When L-carnitine is consumed as part of an animal protein some GMB organisms digest it to produce trimethylamine and subsequently metabolize it to TMAO (Zacharias et al., 2022). As mentioned above, TMAO can cause both intestinal and BBB functional disturbance (Mou et al., 2022; Varesi et al., 2022). TMAO has also been linked to increased beta amyloid formation, peripheral immune activation, and increased oxidative stress (Varesi et al., 2022). Furthermore, TMAO is capable of crossing the BBB and influencing the CNS directly (Bairamian et al., 2022). TMAO has also been linked to PD (Park and Kim, 2021) and atherosclerosis (Zhu S. et al., 2020).
Potential AD Therapies involving GMB
Dietary changes
Altering the diet to a Mediterranean diet (MD) can have benefits to human health and may have a beneficial effects on the GMB. Adherence to the MD has been shown to be associated with a lower risk for AD and cognitive decline in general (van Olst et al., 2021). Inherent to some definition of the MD is that it is higher in fiber compared to other diets. Indigestible fiber is partially fermented by GMB organism to produce SCFA with its concomitant health benefits. Similarly, high fiber diets in mouse models decreases expression of inflammatory cytokines like IL-1β, TNF, and IL-6 by microglia. At least some of the benefit is due to modulation of butyrate levels (van Olst et al., 2021) which has been tested in mouse models, and correlates with improved BBB integrity, lower levels of neuroinflammatory markers, and decreased Aβ deposition (van Olst et al., 2021).
The Promise of Probiotics, Prebiotics, and Synbiotics
Similar to alteration of the diet, the ingestion of probiotics and prebiotics may be beneficial in staving off AD or slowing its progress. Probiotics are formations of beneficial microorganism formulated to pass through the stomach and functionally delivered to the intestines. Some probiotic formulations aim to restore the GMB equilibrium and are being studied in the context of a plethora of neurological and neuropsychiatric disorders (Kandpal et al., 2022). Furthermore, some probiotics have been shown to have anti-inflammatory and antioxidant effects, and enhance cognitive functions (Zhu, X. et al., 2021). There are reports of AD patients having shown cognition improvement when receiving a probiotic formulation (Zhu S. et al., 2020; van Olst et al., 2021) which parallels mounting evidence of positive effects of probiotics in animal AD models.
Prebiotics are defined as host non-digestible compounds being used by the GMB to induce host health benefits (Kandpal et al., 2022; van Olst et al., 2021). Some prominent prebiotics considered or tested for use in AD therapy are fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), mannan-oligosaccharide (MOS), yeast β-glucans, oligosaccharides from Morinda officinalis (OMO), and trehalose analogs (Bairamian et al., 2022; Varesi et al., 2022; Zacharias et al., 2022). In the last few years, numerous studies demonstrated positive results in the treatment of AD (Chandra et al., 2023), CNS-conditions like PD (Zhu, X. et al., 2021), and even depression/anxiety disorders (Queiroz et al., 2022) with prebiotics testing in preclinical animal disease models
Combining prebiotics and probiotics results in synbiotics used for combination therapies. Some preliminary results in AD patients demonstrate cognitive benefits as a result of synbiotic therapies (Queiroz et al., 2022). While very promising, all probiotics, prebiotics, and synbiotics studies should be considered preliminary while corroborating evidence is being generated though additional ongoing research activities.
Fecal Microbial Transplantation (FMT)
Fecal microbial transplantation (FMT) is a technique already in medical use to treat certain recurrent Clostridia difficile infections (CDI) (Jungbauer et al., 2022), and has been reported to curtail inflammatory bowel disease (IBD) and inflammatory bowel syndrome (IBS) successfully (Dash et al., 2022). It involves the transfer of the GMB from feces of a healthy donor to an IBD recipient. Today, this procedure is widely used in the research setting to study GMB functions. Just recently, the FDA approved Vowst (fecal microbiota spores, live-brpk), an orally-administered microbiota-based therapeutic that is suggested to prevent recurrence of CDI without inducing trauma to patients. It’s suggested that this type of procedure may also hold promise in AD treatment or prevention. Research findings demonstrated that FMT treatment in AD mouse models has been shown to reverse microbiota alterations, improve cognition and synaptic plasticity, decrease Aβ and tau pathology, and reduce neuroinflammation (van Olst et al., 2021). While it is considered safe and effective for some disease treatment, as demonstrated in a research setting, the current treatment methodology is probably not mature enough and scalable for AD therapeutic interventions.
Antibiotics
Antibiotics, commonly used to treat infections induced by pathological strains of microorganism, can significantly alter the GMB composition (van Olst et al., 2021; Zacharias et al., 2022). Studies in mouse AD models showed antibiotic treatment can ameliorate neuroinflammation and other aspects of AD pathology, including Aβ and tau accumulation and oxidative stress (van Olst et al., 2021). Additionally, animal studies in germ free (GF) mice have shown resistance to development of AD-like pathology (Bairamian et al., 2022). Though GF mice are resistant to AD pathology in model systems it is also noted that GF mice have deficient BBB integrity, (Park and Kim, 2021) altered/immature microglia (Dash et al., 2022, Whitson et al., 2022), underdeveloped immune systems (Chandra et al., 2023), and defects in enteric mucosal development (Kandpal et al., 2022). Because of these changes GF models are good for directing specific features of GMB contributions but not a model for an AD treatment regimen (Chandra et al., 2023). However, it is clear that GMB alterations can result in an AD resistance state and this via the removal of some pathological or undesirable species or groups. To date, clinical AD trials with varying antibiotic treatments have produced mixed results (van Olst et al., 2021). Having said that, the elimination of Helicobacter pylori antibiotic therapy results in improvement of cognition parameters in AD patients (Zhu S. et al., 2020). All of the evidence in this area interestingly ties in with the relatively new hypothesis that Aβ is involved in a brain antimicrobial response pathway, and that over-reaction of this response is part of the AD pathology (Whitson et al., 2022).
A Special Note
Just as we were finalizing the content for this blog a very interesting article pointing at the science tying in behavior, metabolic physiology, and AD risk was published (Min et al., 2023). This paper showed that a practice of home-care biofeedback akin to breathing meditation which seeks to maximize heart rate variability (HRV) lowers blood levels of Aβ and so potentially lowers AD risk. This lowering of risk was associated with noradrenergic signaling and since neurotransmitters are intimately tied in with GMB activity there may be mechanistic overlap with some of the systems we have discussed here.
A Selection Of Companies Involved In AD Research And Therapeutics
Following is a list of companies that are active in the development of AD therapies involving a patient’s GMB as part of the therapeutic approach. Much work and recent drug approvals are in antibody-based biologics. In addition to the truly enormous number of companies working in AD therapeutics, there are some companies focusing on microbiome-based or influenced therapies of which we want to highlight three. While two companies have an active AD pipeline, Axial Therapeutics does not but is working on a related PD drug that has an interesting GMB tie in.
MedBiome aims to develop precision microbiome therapeutics and nutrition. Medbiome is a very small privately funded company that was founded in 2018 and is headquartered in Ottawa, Ontario, Canada. Medbiome develops small molecule drugs and prebiotics by combining the RapidAIM® ex vivo assay with collections of living microbiomes. RapidAIM® enables identification of the most promising compounds for modulating the production of specific gut microbiome metabolites. MedBiome is developing compounds that target the human microbiome in four disease areas; IBD, AD, Chronic Kidney Disease and Colorectal Cancer.
Axial Therapeutics is a clinical stage biopharmaceutical company attempting to harness the gut-brain axis to develop novel Central Nervous System (CNS) therapeutics to improve the quality of life for people with CNS diseases and disorders. Axial Therapeutics is a very small privately funded company headquartered in Woburn, Massachusetts, USA and founded in 2016. Though Axial’s pipeline does not currently target AD it does include AB-5006, a small molecule therapy aimed at Parkinson’s disease (PD). AB-5006 acts by inhibiting aggregation of bacterial amyloid proteins in the gut which Axial has shown to actively contribute to alpha-synuclein pathology and motor dysfunction in PD animal models.
Green Valley Pharmaceuticals is a large, privately held Chinese pharmaceutical company founded in 1997 and headquartered in Shanghai. Green Valley Pharmaceuticals pioneers carbohydrate drug development and new treatment strategies in the areas of chronic and complex diseases. Specifically, the company is focused on advancing research programs in neuropsychiatric diseases, cancer, cardiovascular diseases, metabolic disease, and autoimmune diseases. Approved in China in November 2019, its drug GV-971 became the first Alzheimer’s disease drug marketed in over a decade. GV-971 is a mixture of oligomannate saccharides isolated from the marine algae Ecklonia kurome and may work via modulation of GMB organisms. Unfortunately, the drug is mired in controversy outside of China, and plans to seek U.S. FDA approval are in an uncertain state.
References
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