By Jack Osborn, Fall 2019.

The effects of intestinal hyperpermeability on Alzheimer’s Disease pathogenesis are not clearly understood. In previous studies that investigated the pathophysiology of leaky gut, the syndrome has been associated with endotoxemia, whereby increased permeability allows for entry of toxins into the intestinal wall. Additionally, a variety of diseases seem to be comorbid, or linked, including IBD, liver disease, pancreatitis, liver cirrhosis, and IBS. Hyperpermeability assays display changes in endotoxin levels and alterations in tight junction proteins, transmembrane structures that line the intestinal wall, including claudins, occludin, and ZO-1. Thus, by directly harming the proteins that regulate the entry and removal of bacteria in the gut, hyperpermeability seems to be related to gut microbiota regulation. Additionally, it has been found that the products of intestinal microbiota may activate microglia, thereby prompting an inflammatory response within the CNS, precluding the clearance of Aβ plaque, the infamous plaque associated with Alzheimer’s Disease pathology.

In one study [1] that analyzes the effect of dextran sodium sulfate (DSS), a chemical associated with increased intestinal permeability that is widely utilized by gastroenterologists to impair the epithelium, DSS-treated male mice displayed reduced cortical amyloidosis compared to vehicle (control) male mice. In contrast to the hypothesis, which proposes that DSS-induced leaky gut exacerbates AD pathology, the results obtained were statistically significant. Alternatively, female mice displayed no changes (no statistical difference) in amyloidosis with DSS treatment. Treatment resulted in no changes in plaque-localized cell numbers but significantly reduced microglial cell body size in male mice. This suggests that intestinal hyperpermeability does not directly affect microglial cell count, but instead affects their size; it is theorized that microglia act as macrophages toward Aβ plaque. Thus, fluctuations in cell body size may be influenced by Aβ counts. Further studies are warranted to explore this concept. DSS-treated female mice displayed no significant difference in microglial cell counts and microglial cell body size than control mice. By virtue of these results, there seems to be a sex-specific role of leaky gut syndrome in Alzheimer’s Disease pathology.

         Additional studies are warranted in order to investigate the pathomechanisms by which DSS could be displaying the observed effects in a sex-specific manner. Further studies will investigate the interaction of the chemical with the microbiome. The changes observed in gut flora might confer anti-inflammatory properties, which might explain reduced cortical Aβ burden and altered microglia phenotypes in DSS-treated male mice. More significantly, sex-specific effects, such as those observed in female Alzheimer’s Tg (genotype) mice, require further analysis in order to investigate the microbiome-brain axis in a sex-specific manner. In future studies, the employment of stress-induced leaky gut will preclude the effect of DSS, which potentially interacts with anaerobic and/or aerobic microbiota and thereby hinders endotoxin in the bloodstream and lowers plaque levels observed in male mice. As a result, the utilization of stress induction to induce leaky gut will substantiate the above-mentioned results, confirming that leaky gut exacerbates AD pathology, independent of the method of induction. The success of stress-induced intestinal hyperpermeability would suggest that leaky gut, comorbid with inflammatory diseases, confers the Alzheimer’s Disease phenotype, whereby plaque levels are exacerbated. In that case, understanding this dichotomy in induction methods could shed light on utilizing chemical induction as treatment to reduce cortical Aβ burden in Alzheimer’s Disease patients.

1. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Gut microbiome alterations in Alzheimer’s disease. Scientific  Reports. 2017 Oct 19;7(1):13537.
2. Eichele DD, Kharbanda KK (2017) Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis. World Journal of Gastroenterology 23(33): 6016-6029.
3. Kowalski K, Mulak A (2019) Brain-Gut-Microbiota Axis in Alzheimer’s Disease. Journal of Neurogastroenterology and Motility 25(1):48-60.
4. “Leaky Gut” with Age Improved through Dietary Restriction. GEN. https://www.genengnews.com/news/leaky-gut-with-age-improved-through-dietary-restriction/. Published November 9, 2018.
5. Leblhuber F, Geisler S, Steiner K, Fuchs D, Schütz B. Elevated fecal calprotectin in patients with Alzheimer’s dementia indicates leaky gut. J Neural Transm (Vienna). 2015 Sep;122(9):1319-22
6. Osborn J, et al. (2019) Low-dose DSS treatment affects Alzheimer’s pathogenesis in a sex-specific manner. Poster presented at: Katen Scholars Program Symposium; 2019 Aug 16; Chicago, IL.