**5. Modulation of gut-brain axis with nutraceuticals in the elderly: evidence-based benefits in animal models**

Diet and altered gut physiology, together with age-related changes in intestinal microbiome and a weakened immune system [74, 75] result in low-grade inflammation in the gut, that is associated with systemic release of pro-inflammatory metabolites. Finally, the inflammatory process is related to glial cells activation, neuroinflammation and to cognitive decline in the elderly [37, 41].

A useful model for the study of gut-brain axis is the germ-free (GF) mouse. GF mice have socially impaired behavior [12] and present an exaggerated stress response [76] that can be directly correlated with changes occurring in different regions of the brain [13], depressed neurogenesis [77] and prefrontal cortical hypermyelination [78]. However, preclinical studies reveal that oral administration of probiotics and/or nutraceuticals is sufficient to reduce anxiety-like and depressive-like behaviors and to induce changes in brain chemistry [10, 79]. For example, the impaired microglial function in GF animals was rescued by the oral treatment with short-chain fatty acids [80]. Also, Distrutti et al. [81], showed that a *probiotic* mixture (VSL#3) induced a significant change in the composition of gut microbiota of aged rats and increased brain tissue expression of genes associated with inflammation and neural plasticity such as BDNF and synapsin.

The gut microbiome is also essential to the bioavailability of *polyphenols*, *unsaturated fats* and *antioxidants,* all of which may help protect against neuronal and cell aging under normal circumstances [82]. For example, the diet supplemented with blueberries (rich in anthocyanin and flavanols) improved spatial working memory in aged animals [83]. This process is accompanied by increases in neural stem cells proliferation, extracellular receptor kinase activation and increase of insulin-like growth factor-1 (IGF-1) level, the key modulator of hippocampal neurogenesis [84]. Also, aged rats consuming berry diets exhibited enhanced motor performance and improved cognition, correlated with increased hippocampal neurogenesis and expression of IGF-1 [85].

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

**No. Clinical trial Main objective Status Reference**

and mental health

dementia

between digestive tract microbes

microbiome composition and gut permeability in the progression of

tolerability of oral fecal transplant in patients with cirrhosis and hepatic encephalopathy

To investigate the changes in activity in areas of the brain that

To observe the clinical efficiency of fecal microbiota transplant and the role of the gut microbiome in treating patients with constipation, depression and/or anxiety

To investigate the effects of two prebiotics on the secretion of cortisol and emotional response in

To study how the administration of *Lactobacillus casei* strain Shirota affects the mood of patients with chronic fatigue syndrome

To study the effects of probiotic formulations on stress, anxiety, depression and coping strategies

To evaluate whether a multispecies probiotic formulation can reduce cognitive reactivity in nondepressed individuals

To measure the effectiveness of coffee melanoidins, bread melanoidins, beta-glucans and a *Gentiana lutea L*. extract in decreasing energy intake and modifying the physiological markers of satiety in the short term

To examine how dietary manipulation influences the relationship between hunger/ satiety/food preference and gut hormones, neural activation and

energy metabolism

control food intake

healthy individuals

in healthy volunteers

Completed https://clinicaltrials.gov/

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

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

Recruiting https://clinicaltrials.gov/

Completed https://clinicaltrials.gov/

Recruiting https://clinicaltrials.gov/

Recruiting https://clinicaltrials.gov/

Recruiting https://clinicaltrials.gov/

Completed [93]

Completed [94]

Completed [95]

Completed [96]

Recruiting https://clinicaltrialbase.

com/study/NCT01851304/

ct2/show/NCT02693327

255

ct2/show/NCT03167983

ct2/show/NCT01597024

ct2/show/NCT03152188

ct2/show/NCT02772458

ct2/show/NCT03233100

1 Microbiome and the gut-brain axis To examine the relationship

2 Microbiome and dementia To study the role of gut

4 Oral fecal transplant in cirrhosis To evaluate the safety and

3 Full4Health: understanding

5 Reduced appetite in Crohn's

control of food intake

potential mechanisms

7 Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers

8 A randomized, double-blind,

9 Assessment of psychotropiclike properties of a probiotic formulation (*Lactobacillus helveticus* R0052 and *Bifidobacterium longum* R0175) in rats and human subjects

10 A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity

11 Metabolic effect of new foods through gut-brain axis

to sad mood

placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome

disease: the role of the brain in the

6 FMT treating constipation patients with depression and/or anxiety symptoms - clinical efficacy and

course

food-gut-brain axis across the life

*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 hippocampus and the cerebral cortex [91].

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.
