In neurological clinical practice, the use of oral nutritional caloric support products, also known as oral nutritional supplements (ONS), is quite common. The use of ONS in acute or chronic neurological disease has the potential to positively affect clinical outcomes [1]. There are no regular studies on the use of ONS in nursing homes, where nutritional problems and neurological diseases are commonly observed. Neurological diseases also increase the risk of malnutrition, especially in patients requiring hospitalization. Malnutrition may have medical, physical and social causes. This risk increases in chronic neurological diseases that lead to immobility, especially in the demential process. There is an increased tendency for neuropsychiatric conditions, especially depression and delirium, in individuals with malnutrition.
Malnutrition can cause geriatric syndromes such as sarcopenia, which can result in decreased skeletal muscle mass or deterioration of its function, resulting in progressive weakness [2].
There is increasing evidence for the relationship between sarcopenia and various physical adverse effects, such as frailty and falls, but its relationship with mental diseases in elderly people is not fully understood [3].
Recent studies have shown that depression in elderly people may be associated with an increase in many health problems with age, and its prevalence has increased to 38% [4].
The pathophysiological components of sarcopenia, such as the presence of chronic neurological diseases, especially neurodegenerative diseases, which increase in frequency with age, limitations in physical activity and malnutrition, may increase the tendency toward depression[5].
Mounting evidence regarding the effects of the gut microbiota on brain development and function has been identified by recent studies in animal models [6].
Microbial molecules produced in the gastrointestinal tract and reaching the blood‒brain barrier via various pathways are thought to be mediators of gut-brain connections [7].
Research in experimental animal models (EAMs) has demonstrated that nutrition can affect neurodevelopmental/neuroplasticity processes such as synaptogenesis, neurogenesis, synaptic maturation and neural activity by altering the levels of various neurotrophic agents, neuropeptides and neurotransmitters, especially brain-derived neurotrophic factor (BDNF) [8, 9].
To understand the gut-brain connection at the molecular level, experimental studies have compared 'conventionally colonized mice', which do not contain specific pathogens, and 'germ-free mice', which lack microbial exposure [10]
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To provide additional information, 'gnotobiotic mice' with controlled introduction of specific microorganisms or treated microbiomes of conventional mice with broad-spectrum antibiotics have also been investigated.
Microbial molecular exposure alters the morphological structure of the brain, especially the amygdala, hippocampus, and thalamus, and affects the hypothalamic‒pituitary‒adrenal axis [11, 12, 13]. The resulting exaggerated glucocorticoid response is associated with various neurobehavioral patterns, such as anxiety [13], depression, and cognitive impairments [14, 15].
The gut-brain axis (GBA) refers to the dynamic and bidirectional communication between the gastrointestinal tract and the central nervous system (CNS)[16]. This bidirectional signaling mechanism enables signals from the brain to change the sensorimotor and secretory functions of the gut via neuroendocrine pathways and visceral afferent signals originating from the gut to modulate brain functions through a number of complex pathways.
An imbalance in the gut microbiota, which consists of symbiotic and pathogenic microorganisms, can be observed in individuals with neurodegenerative diseases, mood disorders and primary gastrointestinal diseases [17, 18]. The GBA has a complex structure that includes the autonomic nervous system and the enteric nervous system and maintains the communication network through the interaction of the immune and neurohumoral systems in signals originating from the microbiota [17].
The presence of neuromodulatory effects has been demonstrated in EAM studies aimed at changing the intestinal microbiome with prebiotic, probiotic and dietary practices [19].
Short-chain fatty acids (SCFAs), one of the main microbial metabolites formed especially by the bacterial fermentation of dietary fibers in the intestine, are important neuroactive mediators of microbiome-gut-brain (MGB) complex interactions with neuroimmune and neuroendocrine effects [20].
SCFAs increase with prebiotics, probiotics and fermentable dietary fiber, fermentation of complex carbohydrates or proliferation of beneficial SCFA-producing bacteria. SCFAs can exert their effects on the GBA directly or indirectly through various pathways [20, 21].
These pathways include immune, neuroendocrine, autonomic nervous system (vagal pathway), and other neurohumoral pathways [20, 22].
The immune pathway is one of the pathways used by SCFAs to modulate brain functions. SCFAs can interact locally with colonocytes (epithelial cells) in this pathway by activating free fatty acid receptors (FFARs) in immune cells (such as neutrophils, monocytes and macrophages) [23]. This interaction is also achieved by inhibiting the activity of histone deacetylases located in colonocyte nuclei or by stimulating acetylation by increasing histone acetyltransferase activity [24]. The interaction in this pathway increases barrier integrity and transepithelial electrical resistance through the expression of tight junction proteins, which are responsible for the tightness of interepithelial connections. In addition to its local effects, it affects systemic inflammation by regulating interleukin secretion and neuroinflammation by modulating microglial functions [25].
The endocrine pathway is another important pathway through which SCFAs modulate the brain. It modulates the secretion of gut hormones by stimulating FFAR receptors on colonocytes and thus affects the GBA. In particular, an increase in fermentable polysaccharide levels stimulates the secretion of intestinal hormones such as peptide YY (PYY) and glucagon-like peptide 1 (GLP1) from enteroendocrine L cells [26]. In addition to these gut hormones, SCFAs may also regulate the activation of other metabolic hormones, such as leptin, ghlerin, and insulin, which influence the regulation of hunger and food intake through systemic circulation and vagal afferents [27].
The clinical implications of these hormones are that they modulate stress, depression and anxiety through the hypothalamic‒pituitary‒adrenal (HPA) axis, serotonergic system and sympathetic nervous system [27].
Afferent fibers that constitute the majority of the vagal nerve innervate almost the entire gastrointestinal tract. Nerve fibers terminating in the lamina propria in the intestinal mucosa are not directly connected to the intraluminal or microbiota. However, it can indirectly sense diffusion-mediated transcellular signals of serotonin (released from enteroendocrine cells, especially enterochromaffin cells) and other intestinal hormones and metabolites. SCFAs can also centrally modulate the levels of neurotrophic factors such as BDNF and GDNF via histone acetylation by affecting intracellular signals in enterochromaffin cells [23].
The blood‒brain barrier (BBB) controls the passage of nutrients and molecules from the systemic circulation to the brain. SCFAs can cross the BBB via enteroendothelial monocarboxylate transporters and inhibit pathways associated with neuroinflammatory responses. An intact BBB ensures the maintenance of homeostatic balance in the CNS [28].
Aging and nutrition can affect each other. With aging, cognitive and physical functions may decline. A vicious cycle develops with depressive symptoms and an impaired balance between nutritional needs and intake [29].
The nutritional behavior of elderly individuals may deteriorate due to factors such as multimorbidity, polypharmacy, decreased sense of taste and smell, social reasons, and impaired purchasing and preparation ability. As a result, all these conditions represent a high risk of malnutrition in elderly individuals [30].
It is known that while there are physical changes in the physiology of aging, such as a decrease in physical activity and a decrease in muscle strength, the frequency of neurodegenerative diseases also increases [29, 30].
Brain atrophy resulting from neurodegeneration can cause hunger, swallowing and eating behavior disorders. This process, resulting in malnutrition, leads to changes in neurotransmitter and neuroendocrine systems at the molecular level and the emergence or overlap of a number of psychiatric problems, including depression [31].
Allostasis is an active process that regulates the body's adaptation to changes in its environment and maintains homeostasis in the case of stress. Disruption of homeostasis and allostatic mechanisms can alter the body's responses to stress, especially molecules that regulate learning and memory signals, such as the HPA axis and BDNF, which regulate glucocorticoid production [32].
Herein, we discuss the effects of signaling pathways from the gut microbiota to the brain and the effects of mediator molecules on brain cells. This discussion aims to provide a clinical and molecular perspective on the relationship between malnutrition, an important public health problem, and the deterioration of the MGB axis, neurodegenerative diseases and depression, especially dementia processes.