Introduction:
The human gastrointestinal (GI) microbiome is a complex source of microorganisms with significant diversity. It is challenging to link specific microbial patterns to age-related neurological diseases due to variability among healthy individuals. While commensal GI microorganisms generally benefit metabolism and immunity, some enterotoxigenic microbes can produce highly neurotoxic and pro-inflammatory compounds. These microbes are symbiotic in producing vitamins and cofactors and processing dietary fiber, supporting human health.
Microbiome-derived substances can negatively affect the GI tract and, blood-brain barrier integrity, nervous system. Notably, toxins like Bacteroides fragilis and fragilysin are barrier-disruptive and proinflammatory neurotoxins. The entry of neurotoxins from the GI tract microbiome into the systemic circulation through the compromised barrier is a precursor that appears to lead to inflammatory neurodegeneration in the brain and central nervous system.
How Are Microbial Neurotoxins Generated?
The abundance of B. fragilis and its neurotoxins in the human GI tract microbiome is largely influenced by dietary fiber intake. Diets low in soluble fiber tend to promote the growth of anaerobic Gram-negative bacteria like Bacteroides, including B. fragilis, and their toxic byproducts. After ingesting dietary fibers, they are quickly broken down into short-chain fatty acids (SCFAs), volatile fatty acids, polysaccharides, and other components by various GI-tract microbial species, including B. fragilis. It's important to note that:
1. Various other types of GI-tract Gram-negative bacteria and microbes also release complex LPS and enterotoxins that can be highly neurotoxic and may act synergistically.
2. These neurotoxins are produced within the host's body.
3. They are consistently present at varying levels throughout the host organism's lifespan.
Anaerobic Gram-negative bacilli, such as Bacteroides fragilis, release a range of neurotoxic, pro-inflammatory, and potentially harmful molecules. These neurotoxins encompass at least six categories, including lipopolysaccharide (LPS), lipooligosaccharide (LOS), endotoxins, exotoxins, bacterial-derived amyloids, and small non-coding RNAs (sncRNA). Different GI-tract resident microbes appear to have their own unique set of neurotoxins. Enterotoxigenic Bacteroides fragilis cultures have extracted specific neurotoxins like BF-LPS and BFT (fragilysin). These substances are highly pro-inflammatory and extremely neurotoxic to human neuronal-glial cells in primary co-culture.
The human GI tract microbiome, consisting of trillions of micro-organisms, relies on an adequate supply of complex dietary fibers (often referred to as "roughage") to maintain its diversity and activity, which in turn supports important functions for both the microbiome and the host. Dietary fibers, specifically the microbiome-accessible carbohydrates they contain, play a crucial role in shaping the microbial community in the GI tract. Notably, Western diets, characterized by high fat and processed carbohydrates but low fiber content, differ significantly from more traditional Paleolithic diets, which have moderate fat and processed carbohydrates but are rich in fiber.
Recent studies have shown that high-fat, high-cholesterol diets lacking sufficient dietary fiber can disrupt the balance of healthy bacteria in the gut, leading to an increase in opportunistic anaerobic bacteria like B. fragilis. This shift in bacterial composition is associated with higher levels of substances like amyloid, LPS, and fragilysin, which can harm overall health. These substances can compromise the integrity of barriers in the body, contributing to inflammation in the peripheral and central nervous systems through various mechanisms.
How Do Microbial Neurotoxins Act in Alzheimer’s Disease?
Over the past few years, research has revealed several significant findings related to LPS (lipopolysaccharide) and BF-LPS:
1. LPS, including BF-LPS, has been found to associate with the periphery of neuronal nuclei in the sporadic Alzheimer's disease (AD) brain.
2. LPS can trigger the production of reactive oxygen species (ROS) and activate the inflammatory transcription factor NF-kB (p50/p65 complex) in human neuronal-glial cells in primary culture.
3. LPS can efficiently enter neurons, especially with the help of Aβ42 peptides, potentially due to Aβ42's ability to form pores in cell membranes.
4. LPS strongly induces the upregulation of the pro-inflammatory transcription factor NF-kB (p50/p65 complex) and the transcription of specific pro-inflammatory NF-kB-sensitive microRNAs (miRNAs), including miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155. These miRNAs subsequently bind to the 3’-untranslated region (3’-UTR) of multiple target messenger RNAs (mRNAs) in brain cells, reducing post-transcription expression.
Downregulated mRNAs include those responsible for encoding complement factor-H (CFH) of the innate immune system, an SH3-proline-rich multi-domain-scaffolding protein called SHANK3, and the triggering receptor expressed in myeloid/microglial cells (TREM2) surface glycoprotein immune receptor. These downregulations and/or loss-of-function mutations in CFH, SHANK3, and/or TREM2 expression are also observed in AD brain and transgenic murine models of AD (TgAD).
One of the primary biomarkers for Alzheimer's disease (AD) is the excessive presence of amyloid beta (Aβ) peptides, which can exist freely or aggregate into senile plaque deposits in the brain tissue of individuals with AD. Nearly three decades ago, it was discovered that Aβ peptides have the ability to form various types of irregular and diverse ionic pores or ion-conducting channels within the lipid bilayer of the cell's plasma membrane. This pore formation is closely linked to the pathogenesis and progression of AD [95,103,104]. Numerous independent studies have since reinforced these findings, particularly regarding Aβ42 peptides, which are two hydrophobic amino acid residues longer at the C-terminal than Aβ40 peptides.
Aβ42 peptides can create pores in the lipid bilayer membranes that are approximately 2.4-3.0 nm in diameter, through which substances like LPS and other neurotoxins can translocate across cellular and nuclear plasma membranes [95,104-108]. It's worth noting that LPS, when in its SDS-dissociated monomer form, has a molecular weight of approximately 10-20 kDa, with a flexible cylindrical shape measuring around 2.4 nm in diameter and 9.6 nm in length. The unique LPS of Bacteroides fragilis (BF-LPS) is notably smaller than the "generic LPS" found in other Gram-negative bacteria like Escherichia coli.
There is evidence suggesting that Aβ42 peptides:
1. May facilitate the entry of LPS through neuronal plasma and nuclear membranes by locally disrupting or reorganizing the lipid bilayer.
2. Enable the transit of LPS into the cytoplasm or nucleoplasm by forming pores.
3. Once inside the cytoplasm or nucleoplasm, both Aβ42 peptides and LPS may interact with nucleosomes, nucleoproteins, nucleic acids, and other intranuclear structures, affecting chromatin organization, disrupting neuron-specific transcription, and potentially modifying genetic or epigenetic gene regulation in the context of the progressive development of neurological diseases.
What Is the Effect of Microbial Neurotoxins on Alzheimer’s Disease?
Several studies have reported an imbalance in microbial populations in the GI tract of Alzheimer's disease (AD) patients, potentially harming human metabolism and neurological health. However, the complexity of microbial composition, even among healthy individuals, has made it challenging to establish specific links between microbial patterns and age-related neurological diseases like AD. Growing evidence suggests that GI tract-resident bacteria can influence neuro-immune functions beyond the gut, communicating with the brain and central nervous system through a network known as the gut-brain axis. This communication involves molecules like SCFAs and microbial components that can cross biophysical barriers and contribute to AD-like changes. Specific GI tract microbiome-derived neurotoxins promote AD-related processes through pathways like the autonomic nervous system, enteric nervous system, neuroendocrine system, immune system, circulation, and vesicular trafficking. Interestingly, neuronal signaling pathways along this bidirectional gut-brain axis remain an understudied area of research despite their crucial roles in coordinating metabolic, nutritive, and neurobiological functions and their involvement in various chronic diseases, including metabolic syndrome, diabetes, obesity, anxiety, autoimmune diseases, stress-induced neuropsychiatric diseases, and neurodegenerative brain conditions like AD.
Conclusion:
The microbiome is a dynamic ecosystem influenced by various factors like age, maternal influences, the presence of antibiotics or drugs, environmental factors, exercise, metabolism, and stress. Some microbial components, such as amyloids, LPSs, and endotoxins produced by bacteria like B. fragilis, notably impact the function of the GI tract and the blood-brain barrier. They can trigger systemic proinflammatory responses and contribute to inflammatory neurodegeneration in the peripheral and central nervous systems.
