Dementia and the Gut

Back in Nov 2020, the Journal of Alzheimer’s Disease published a study undertaken in Geneva, that explored the connection between the bacteria and other organisms in the human gut and their possible link to dementia[i].

A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) in Switzerland, together with Italian colleagues from the National Research and Care Centre for Alzheimer's and Psychiatric Diseases Fatebenefratelli in Brescia, University of Naples and the IRCCS SDN Research Centre in Naples, confirmed the correlation, in humans, between an imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are proposed to be at the origin of the neurodegenerative disorders characteristic of Alzheimer's disease.

In simple terms, a loss of bacterial diversity in the gut of people with Alzheimer’s appears to increase systemic inflammation and amyloidosis, related to reduced levels of butyrate and increased levels of LPS.

Loss of barrier integrity

In 2017 the same journal published a paper exploring the loss of barrier integrity in the brain and gut linked to dysbiosis in the gut[ii]. Forward to 2022 and a special issue in the journal Microorganisms explores the intimate role of the microbiota-gut-brain axis covering Alzheimer’s and other disorders – there are hundreds of other papers all demonstrating a strong association between a loss of diversity, alteration of barriers, increased inflammation and neurological challenges[iii].

This implies that there may be a therapeutic strategy to both prevent and reverse said problems utilising the microbiome and its by-products to act as a therapeutic medium in some of the most challenging of symptom presentations. The International Journal of Molecular Science took a detailed look at some of the strategies to explore in Jan 2022[iv]. Its focus was on the dynamic interaction between our lifestyle, diet and the microbiota – the relationship being one that can generate excess and abnormal inflammation, or resolution and management of risk.

Probiotics

Exploring specific bacterial risk or benefit is a complex process but a group from China examined the role of Akkermansia Muciniphilia in reducing neurological risk in a mouse model. They report that Akkermansia Muciniphilia effectively improved glucose tolerance, intestine barrier dysfunction and dyslipidaemia in an AD model, suggesting it may be a clinically useful approach in the prevention and treatment of Alzheimer’s and other neurodevelopmental disorders[v].

Dysbiosis

When the microbiome becomes unbalanced, the first sign is usually digestive problems, known as gut dysbiosis[vi]. Symptoms can include, intestinal inflammation, leaky gut (where the gut wall begins to weaken), constipation, diarrhoea, nausea, bloating and other gut-based metabolic changes. Immune responses and normal bodily functions such as liver, heart and kidney function may also be negatively affected by dysbiosis. Dysbiosis can be reversed depending upon cause[vii].

The gut microbiome can also be modified. A diet rich in fibre, limiting stress, alcohol use and smoking, exercising daily, and using a probiotic can all bolster the gut microbiome’s health [viii],[ix],[x].

Hope for safe interventions

These approaches and their outcomes indicate that there is a modifiable risk factor for dementia, that is not reliant on pharmaceutical involvement alone. Around 40% of worldwide dementia can be prevented or delayed by modifying 12 risk factors: low educational attainment in early life, mid-life hypertension, mid-life obesity, hearing loss, traumatic brain injury, excessive alcohol consumption, smoking, depression, physical inactivity, social isolation, diabetes mellitus, and air pollution[xi]. Plus achieving and maintaining eubiosis and eating a healthy, fibre-rich diet, especially where additional butyrate a short chain fatty acid (SCFA) created by bacteria fermenting fibre in the colon is essential[xii].

Summary

So, what have we learned over the last 25 years of discovery? Dysbiosis in gut microbiota correlates with many diseases such as cancer, autoimmunity, neurological disorders, and other diseases. Bacteria manage the host immune reactions, in part, by generating metabolites. A growing body of documents shows that various bacteria metabolites, such as SCFAs, deeply modulate host receptors and target molecules' immune responses. Our gut bacteria also play a crucial activity in intestinal mucosa's structural integrity by producing SCFAs, such as butyrate, propionate, and acetate. SCFAs and their receptors make various signals to respond to alterations in health, nutrition, and immunological conditions[xiii].

Given the flexibility in bacterial structure and function, bacteria-based or focussed therapeutic interventions, such as dietary modulation, bacterial metabolites, in particular SCFAs, probiotics, prebiotics, and faecal microbial transplants, potentially demonstrate supportive approaches for neurological disorders and other diseases associated with gut bacterial dysbiosis.

Strategy

Avoid high sugar, high fat, low fibre diets which reduce the number of fibre-digesting bacteria in favour of less-beneficial bacteria. The production of essential metabolites, such as butyrate, also drops in the typical modern western diet[xiv]. The Alzheimer’s Society already recommends that a Mediterranean style diet low in red meat and sugar could help reduce dementia risks. The addition of specific nutrients, prebiotics, probiotics and essential fatty acids should further enhance possible prevention and or resolution – a process that the pharmaceutical research community has spent decades and billions of pounds searching for a magic bullet – unfortunately, without real success to date.

References

[i] Moira Marizzoni, Annamaria Cattaneo, Peppino Mirabelli, Cristina Festari, Nicola Lopizzo, Valentina Nicolosi, Elisa Mombelli, Monica Mazzelli, Delia Luongo, Daniele Naviglio, Luigi Coppola, Marco Salvatore, Giovanni B. Frisoni. Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease. Journal of Alzheimer's Disease, 2020; 78 (2): 683

[ii] Jiang C, Li G, Huang P, Liu Z, Zhao B. The Gut Microbiota and Alzheimer's Disease. J Alzheimers Dis. 2017;58(1):1-15.

[iii] Obrenovich M, Reddy VP. Special Issue: Microbiota-Gut-Brain Axis. Microorganisms. 2022;10(2):309. Published 2022 Jan 28.

[iv] Toledo ARL, Monroy GR, Salazar FE, et al. Gut-Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders. Int J Mol Sci. 2022;23(3):1184. Published 2022 Jan 21. doi:10.3390/ijms23031184

[v] Ou Z, Deng L, Lu Z, et al. Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer's disease. Nutr Diabetes. 2020;10(1):12. Published 2020 Apr 22.

[vi] Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis. 2015;26:26191. Published 2015 Feb 2.

[vii] Belizário JE, Faintuch J. Microbiome and Gut Dysbiosis. Exp Suppl. 2018;109:459-476.

[viii] Megan W. Bourassa, Ishraq Alim, Scott J. Bultman, Rajiv R. Ratan,Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health?, Neuroscience Letters, Volume 625, 2016,Pages 56-63

[ix] Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G and Hyland NP (2015) Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front. Cell. Neurosci. 9:392.

[x] Gaisford S. The gut microbiome and the potentials of probiotics: an interview with Simon Gaisford. Future Microbiol. 2019 Mar;14:263-265.

[xi] Cabrera C, Vicens P, Torrente M. Modifiable Risk Factors for Dementia: The Role of Gut Microbiota. Curr Alzheimer Res. 2021;18(13):993-1009

[xii] Stadlbauer V, Engertsberger L, Komarova I, Feldbacher N, Leber B, Pichler G, Fink N, Scarpatetti M, Schippinger W, Schmidt R, Horvath A. Dysbiosis, gut barrier dysfunction and inflammation in dementia: a pilot study. BMC Geriatr. 2020 Jul 20;20(1):248.

[xiii] Jalalifar S, Karimitabar Z, Teimoori A, Keyvani H, Zamani F, Yousefimashouf R, Karampoor S. Role of microbiota-derived short-chain fatty acids in nervous system disorders. Biomed Pharmacother. 2021 Jul;139:111661.

[xiv] Jordan E. Bisanz, Vaibhav Upadhyay, Jessie A. Turnbaugh, Kimberly Ly, Peter J. Turnbaugh,Meta-Analysis Reveals Reproducible Gut Microbiome Alterations in Response to a High-Fat Diet,Cell Host & Microbe, Volume 26, Issue 2, 2019, Pages 265-272.e4