Bacterial Amyloid Curli Associated Gut Epithelial Neuroendocrine Activation Predominantly Observed in Alzheimer’s Disease Mice with Central Amyloid- Pathology

The gut microbiota is of interest as numerous studies have reported that there are changes in the gut microbiota during obesity, diabetes, liver diseases, cancer, and neurodegenerative diseases. There is compelling evidence linking gastrointestinal dysfunction to the development of neurodegenerative illnesses including Alzheimer’s disease (AD). The prevalence of chronic low grade systemic inflammation is a defining feature of aging. There have been reports of age-related changes in the gut microbiota, including a decline in bacterial diversity and stability. However, little is yet known about vagus communication within the gut-brain axis. It creates one of the main extrinsic connections between the brain and the digestive system and uses afferent fibers to communicate with the brain about the health of the internal organs. All current treatments for AD patients are started after the onset of clinical symptoms, when there is already significant neuronal death. The pathophysiology of the disease is so severe once symptoms appear that any treatment is likely to be ineffective. The lumen and underlying tissue are separated in the gut by a single layer of epithelial cells. Highly specialized enterochromaffin cells, a subtype of enteroendocrine cells, are distributed and electrically excitable inside the epithelial layer. Significant evidence from recent studies points to an important and underestimated factor in the etiology of AD: the pathogenic signals come from outside the brain. Curli proteins form thin amyloid fibers on the surface of enteric bacterial cells. Human amyloids share a strikingly similar quaternary structure with bacterial amyloids, including the pathological and immunomodulatory human amyloids such as amyloid-β (Aβ), which is involved in AD. Through a communication cascade from the gut to the brain, these proteins may expedite the progression of neurological diseases.

In a new study published in the Journal of Alzheimer’s Disease, researchers from the University of Texas Health Science Center, led by Professor Bhanu “Priya” Ganesh and the team Dr. Tushar Das, Maria Blasco-Conesa, Janelle Korf and Pedram Honarpisheh, hypothesized that curli triggers neuroendocrine stimulation in the brain from the gut, which encourages central Aβ disease. Professor Matthew Chapman from the University of Michigan who primarily works on bacterial curli was involved in this study.

The research team using 16S rRNA gene sequencing demonstrated significant bacterial compositional alterations, or dysbiosis in gut microbiota of symptomatic Tg2576 mice compared to WT littermate control. This shift marked a considerable increase in gram positives within the SI lumen. However, because researchers discovered severe dysbiosis in AD mice SI, they were eager to investigate gut-based immune activation. In order to further investigate the integrity of the gut, researchers used FISH to examine the bacterial biofilm and discovered that AD mice have different microorganisms from WT controls. Compared to the cocci-shaped bacteria found in the intestine of WT mice, they were more commonly discovered as rod-shaped and filamentous bacteria in AD animals. Because the SI is specialized in containing ECs, researchers concentrated this investigation mostly there. This is because microbial diversity in the SI is extremely important. Intriguingly, they discovered higher concentrations of bacterial amyloid-curli in the large intestine of Tg AD animal models during the pre-symptomatic timepoint. However, they discovered bacterial-curli in the large intestine of old WT and symptomatic AD animals. Curli proteins were also discovered in SI intestinal tissue from both WT and symptomatic AD animals.

Further research revealed that pre-symptomatic AD mice had a 4- to 5-fold higher ileum TLR2 activation than WT controls. A large increase in TLR2 was also observed in symptomatic elderly AD mice when compared to WT controls, however it was not as great as it was at the pre-symptomatic timepoint. The observation of elevated TLR2 protein levels in the sub-mucosa, led the authors to look closely at the intestinal epithelium. They found that ileal gut ECs significantly expressed TLR2 and that this expression co-localized with the neuronal endocrine marker PGP9.5. In contrast to age-matched WT controls, they observed higher TLR2 levels in the symptomatic AD brain. According to the authors, that bacterial amyloid-curli triggers TLR2 activation primarily in the ileum.

In conclusion, Professor Bhanu Priya Ganesh and her colleagues demonstrated unequivocally that bacterial amyloid load exists in AD mice gut even before the onset of Aβ disease in the brain. It thus offers early proof that the central Aβ pathology of AD may be significantly influenced by TLR2 activation that occurs from the gut to the brain in response to bacterial curli. These results highlight the significance of pathogenic alterations in gut-vagus-brain communication in response to luminal bacterial amyloid, which may be a key factor in the pathogenesis of central Aβ observed in the AD brain.