Alzheimer’s disease and depression in the elderly: A trajectory linking gut microbiota and serotonin signaling

Abstract

The occurrence of neuropsychiatric symptoms in the elderly is viewed as an early sign of subsequent cognitive deterioration and conversion from mild cognitive impairment to Alzheimer’s disease. The prognosis in terms of both the severity and progression of clinical dementia is generally aggravated by the comorbidity of neuropsychiatric symptoms and decline in cognitive function. Undeniably, aging and in particular unhealthy aging, is a silent “engine of neuropathology” over which multiple changes take place, including drastic alterations of the gut microbial ecosystem. This narrative review evaluates the role of gut microbiota changes as a possible unifying concept through which the comorbidity of neuropsychiatric symptoms and Alzheimer’s disease can be considered. However, since the heterogeneity of neuropsychiatric symptoms, it is improbable to describe the same type of alterations in the bacteria population observed in patients with Alzheimer’s disease, as well as it is improbable that the variety of drugs used to treat neuropsychiatric symptoms might produce changes in gut bacterial diversity similar to that observed in the pathophysiology of Alzheimer’s disease. Depression seems to be another very intriguing exception, as it is one of the most frequent neuropsychiatric symptoms in dementia and a mood disorder frequently associated with brain aging. Antidepressants (i.e., serotonin reuptake inhibitors) or tryptophan dietary supplementation have been shown to reduce Amyloid β-loading, reinstate microbial diversity and reduce the abundance of bacterial taxa dominant in depression and Alzheimer’s disease. This review briefly examines this trajectory by discussing the dysfunction of gut microbiota composition, selected bacterial taxa, and alteration of tryptophan and serotonin metabolism/neurotransmission as overlapping in-common mechanisms involved with depression, Alzheimer’s disease, and unhealthy aging.

Physical Exercise as Disease-Modifying Alternative against Alzheimer’s Disease: A Gut–Muscle–Brain Partnership

“…In recent years, a great deal of interest has been focused on the deleterious impact produced by GM dysbiosis, the growth of pro-inflammatory bacteria, increased permeability of the intestinal barrier, and systemic inflammation in AD pathogenesis [72,73], including the comorbidity of NPSs and AD [74].…”

“…In fact, some bacterial genera such as Escherichia coli, Bacteroides, Eubacterium, and Bifidobacterium are involved in the production of neurotransmitters such as acetylcholine, GABA, and glutamate, and alterations in these were found in AD patients [105,106]. Moreover, metabolomic analysis on amnestic MCI and AD patients showed the dysregulation of tryptophan metabolism with a reduction in 5-HTP [74,107]. Interestingly, by using the pharmacological AD-like mouse model of Aβ 1-42 peptide delivery into the lateral ventricle, both an alteration in GM and the inhibition of cholinergic anti-inflammatory patterns by the reduction in choline acetyltransferase (CHAT) expression in the colon, and a parallel decrease in the expression of M1 acetylcholine receptor in hippocampus and forebrain [108], have been shown.…”

“…There is increasing evidence that depression could be linked to GM alterations, strengthening the involvement of the gut-brain axis in this mood disorder [74,[122][123][124]. Cross-sectional studies reported an increasing abundance of Actinobacteria and decreased levels of Bacteroidetes, and mixed results on Firmicutes and Proteobacteria in subjects with major depressive disorder [125,126].…”

“…Despite the level of knowledge gathered about the changes occurring in the gut microbial population and risk of AD or neurodevelopmental disorders [72][73][74]124], as well as about the tight relationship between PE and the colonization of health-promoting bacterial taxa [131], there is only sporadic information concerning the beneficial effects exerted by PE on the gut-brain axis and AD progression [131,132]. Since many detailed descriptions either of the gut microbial ecosystem or of the entire genome of gut microorganisms (i.e., the microbiome) have already been provided [74,124,133], no further explanation of GM and its communication pathways, main composition, and characteristics will be considered in this context. Thus, according to the present scenario, the functional contribution of skeletal muscle (SM) to the equation linking the gut-brain axis, PE, dementia, and NPSs in AD has been frequently undervalued or neglected.…”

Gut Microbial Metabolome and Dysbiosis in Neurodegenerative Diseases: Psychobiotics and Fecal Microbiota Transplantation as a Therapeutic Approach—A Comprehensive Narrative Review

“…This neurotransmitter can be directly synthesized by different bacteria, such as Corynebacterium spp., Streptococcus spp., and E. coli (at least in cultures) [136]. Serotonin is synthesized from tryptophan, and GM is essential for the production of different tryptophan metabolites [137]. After tryptophan is produced by GM, about 90% of serotonin synthesis occurs within the enterochromaffin cells (by TPH enzymes) in the gut [138].…”