**6. Neuro-nutraceuticals/gut-brain axis targeting in clinical trials**

The direct modulation of gut microbiome by targeted dietary and probiotic uptake seem to have a positive impact in treating particular age-related disorders and represent a promising therapeutic option for the aging process itself [28]. Well supported evidence came from findings from ELDERMET, a research consortium (http://eldermet.ucc.ie) which studied and characterized the gut microbiota in an Irish elderly population anti its relationship to mental health in aging [92]. As a consequence of a growing body of evidence regarding a positive correlation between the health of gut microbiota and brain health, funding for clinical research is also spent for study of modulation of gut-brain axis with impact on healthy aging and mental health.


Since short-chain fatty acids (SCFA) seem to play an important role in shaping the gut microbiota metabolism, it was necessary to study the effect of omega-3 polyunsaturated acids (n-3 PUFA) on cognitive decline in aging. Animal studies have shed light on their neuroprotective roles through pathways of synaptic plasticity, neuroinflammation and oxidative stress, evidencing also positive correlations between peripheral n-3 PUFA levels and regional gray matter [86]. Supplementation of n-3 PUFA increased hippocampal neurogenesis and the fatty acid docosahexaenoic acid (DHA—an intermediate molecule in the metabolism of eicosapentaenoic acid) was able to down regulate microglial activation [87]. Furthermore, age-related decline in c-Fos expression, that reflects neuronal response to extracellular signals such as growth factors and is triggered during action potentials, is attenuated by n-3 PUFA diet [88]. The protective role of n-3 PUFA supplementation in counteracting cognitive decline, emotional dysfunctions and brain atrophy is governed by antioxidant and anti-inflammatory mechanisms [86, 89]. Some evidence in animal models suggested that long-term consumption of fish oil (rich in n-3 PUFA) may predispose the brain to lipid oxidation. The enrichment of fish oil with quercetin significantly attenuated behavioral impairments, restored the ROTinduced oxidative markers, depleted dopamine levels in striatum and reduced mitochondrial

*Phytosterols*, a class of nutraceuticals derivated from plant foods, have been demonstrated to possess cholesterol-lowering, antioxidant effects and recently neuroprotective role on cognitive deficit induced by a cholesterol-enriched diet in aged rats. The phytosterol ester (PSE) treatment maintained the body weight balance, reduced serum lipid levels and improved the cognitive performance of aged rats in the Morris water maze test. Importantly, histological and immunohistochemical results in the brain showed that PSE supplementation alleviates neuroinflammation by significantly increasing the number of pyramidal cells and decreasing the number of astrocytes. Furthermore, PSE improved cholinergic activities by restoring the acetylcholine (ACh) content and decreasing acetylcholinesterase (AChE) activity in the cerebral cortex, as well as by elevating choline acetyl transferase (ChAT) activity in the hip-

In conclusion, preclinical studies support the rationale of further clinical testing of nutritional strategies to improve aged brain function, including the use of bioactive compounds with antioxidant, anti-inflammatory or neuroprotective properties in the diet of the elderly.

The direct modulation of gut microbiome by targeted dietary and probiotic uptake seem to have a positive impact in treating particular age-related disorders and represent a promising therapeutic option for the aging process itself [28]. Well supported evidence came from findings from ELDERMET, a research consortium (http://eldermet.ucc.ie) which studied and characterized the gut microbiota in an Irish elderly population anti its relationship to mental health in aging [92]. As a consequence of a growing body of evidence regarding a positive correlation between the health of gut microbiota and brain health, funding for clinical research is also spent for study of modulation of gut-brain axis with impact on healthy aging and mental health.

**6. Neuro-nutraceuticals/gut-brain axis targeting in clinical trials**

dysfunction, offering a higher neuroprotection in animal model [90].

pocampus and the cerebral cortex [91].

254 Gerontology


inputs. A third player with a determinant role in the health of both systems is the gut microbiota. Aging affects all players of the microbiota-gut-brain axis, leading to modified composition of bacterial taxa, chronic low-grade inflammation, modified intestinal metabolism, resulting in diminished availability of neurotransmitters or neurotransmitter precursors and short-chain fatty acids. Along with synaptic impairment, oxidative stress and neuroinflammation, aging leads to behavior alterations, anxiety and cognitive impairment. Interventions on gut-brain axis with nutraceuticals (food or food-derived products that have putative beneficial effects) alleviate some age-associated behavioral and cognitive alterations, as repeatedly demonstrated in animal models. Recently, clinical trials have begun to explore the beneficial effect of gut-brain axis modulation, in mood or cognition-associated disorders. Upon reports of positive results, gut-brain axis emerges as an important, easy to access target for promoting

Role of Nutraceuticals in Modulation of Gut-Brain Axis in Elderly Persons

http://dx.doi.org/10.5772/intechopen.73005

257

This work has been supported by National Authority for Scientific Research and Innovation (ANCSI), Program POC Axis 1 Action 1.2.3. Grant ID P\_40\_197, Contract No. 52/05.09.2016.

, Simona Mihai1

[1] Gershon MD, editor. The Second Brain: The Scientific Basis of Gut Instinct and a Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestines.

, Cristina Mariana Niculite1,2, Laura Necula3

, Emilia Manole1

, Sevinci Pop1

, Isabela Tarcomnicu4

,

,

a healthy brain aging.

**Acknowledgements**

**Author details**

Eleonora Codorean1

Elvira Gille5

**References**

Ana-Maria Enciu1,2\*, Elena Codrici1

 and Cristiana Pistol Tanase1,6 \*Address all correspondence to: ana.enciu@umfcd.ro

1 Victor Babes National Institute of Pathology, Bucharest, Romania

3 Stefan S Nicolau Institute of Virology, Bucharest, Romania

4 SC Cromatec Plus SRL Bucharest, Romania

6 Titu Maiorescu University, Bucharest, Romania

New York, NY: HarperCollins Publ; 1998

5 CCB "Stejarul", Piatra Neamt, Romania

2 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

**Table 1.** Clinical trials related to investigation of gut-brain axis in relationship with mental health.

Clinical trials targeting not only the cross-talk between the gut microbiota and the central nervous system focus on its association with various neuropsychiatric and neurodegenerative disorders (anxiety, depression, dementia, etc.), but also on its involvement in the regulation of hunger/satiety and in pathologies affecting the digestive tract (**Table 1**). The therapeutic solutions investigated these clinical trials involve the use of prebiotics and probiotics, dietary changes and fecal microbiota transplant.

Reports of already completed trials support the findings of preclinical trials, demonstrating that modulation of gut microbiota results in anxiolytic effect without a direct intervention on neurotransmitter circuitries. For example, the reported results of Schmidt et al. [93], after completion of trial, supported previous evidence that fructooligosaccharides, or Bimuno® galactooligosaccharides supplementation lowered neuroendocrine stress response, measured by cortisol awakening response. Rao et al. [94] reported that supplementation with specific lactic acid probiotic bacteria for 8 weeks improved the anxiety scores of patients with chronic fatigue syndrome. A complex report by Messaoudi et al. [95], involving both laboratory rats as well as healthy human volunteers showed that supplementation with a combination of *Lactobacillus helveticus* and *Bifidobacterium longum* displayed beneficial psychological effect. Finally, a recent publication regarding the effect of "4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood", [96]. These results open a promising avenue not only for age-related mental disorders, but also for selected cases of psychiatric pathologies.
