Nutritional Support in Stroke Neurorehabilitation

Abstract

Acquired brain injury (ABI) due to stroke or cerebrovascular accident (CVA) is a frequent pathology that leaves sequelae, produces great personal and family suffering and has a great economic impact on health systems. Translational research and clinical evidence have revealed the existence of an intestinal dysbiosis in these patients before and after stroke that, ultimately, through the microbiota-gut-brain axis, is capable of producing neuroinflammation, negatively impacting the evolution of stroke and delaying functional recovery in the neurorehabilitation process. Individualized dietary intervention is proposed in order to reverse intestinal dysbiosis until reaching eubiosis and facilitate recovery. For this it would be necessary to have the figure of the nutritionist-dietician in the multidisciplinary team. The objective of this chapter is to report on the importance of nutritional intervention in stroke to obtain better results. Research in this regard must continue as several questions remain unanswered.

1. Introduction

Stroke or cerebrovascular accident (CVA) is one of the most frequent reasons for urgent neurological care, it is one of the main causes of death and disability in adults and it entails an enormous human and economic cost in developed countries. In recent decades, various advances have been made in the treatment of stroke, such as early medical-surgical care, the creation of stroke units in health centers and rehabilitation treatment. Neurorehabilitation, applied in the different evolutionary stages of stroke, is one of the most decisive interventions when it comes to addressing neurological injuries and their functional repercussions of stroke [1]. Ischemic stroke is responsible for most cerebrovascular accidents, with hemorrhagic stroke being the second most frequent. The annual incidence of stroke in Spain is 156 new cases per 100,000 inhabitants and its prevalence is 500–600 cases per 100,000 inhabitants [2].

Occlusion of the middle cerebral artery produces ischemia in the affected territory, followed by an inflammatory and immune response [3]. Neurological deficits are usually present from the first moment.

In various studies on the gut microbiota (GM) in stroke patients, the presence of dysbiosis, altered intestinal permeability, the passage of bacterial lipopolysaccharides through the intestinal barrier into the bloodstream, the maintenance of a systemic low-grade inflammatory state (SLGIS) and neuroinflammation [4].

Given this state of knowledge, we have to find out what is the degree of contribution of SLGIS and neuroinflammation to the establishment of stroke? Can nutritional intervention to achieve intestinal eubiosis contribute to improving stroke prognosis and/or better functional recovery? Translational research and clinical evidence offer us the opportunity to systematically intervene in the stroke neurorehabilitation process with nutritional support in order to reverse the inflammatory state and facilitate the recovery process. To achieve this goal, it would be necessary to include a nutritionist-dietician in the multidisciplinary team that cares for these patients. We cannot forget the application of a holistic approach to the entire neurorehabilitation process, based on clinical and scientific evidence, all within the context of integrative medicine.

2. Reciprocal influence between microbiota, gut and brain

The intestine and the brain are in constant communication and for this they use different pathways such as endocrine, nervous and immune signaling. The balance between the different symbiotic bacterial species that populate the GM contributes to homeostasis through its participation in various metabolic pathways, the supply of nutrients such as vitamins and short-chain fatty acids (SCFA), stimulating the immune system, facilitating metabolism of substances not digestible by the host, acting on the metabolism of drugs and other xenobiotics, while avoiding colonization by pathogenic species [5].

This exchange of information occurs both via the nerves via neurotransmitters and via the blood (hormones, cytokines, metabolites …). The central nervous system (CNS), the autonomic nervous system (ANS), the enteric nervous system (ENS), the neuroendocrine and neuroimmune systems contribute to this process, forming a fluid exchange network [6, 7].

In murine models, it has been proven that, by stimulating the afferent pathways of the vagus nerve, through the production of metabolites (neurotransmitters, hormones, SCFA) or through interactions with the immune system, GM is capable of modulating brain activity. Similarly, signals are emitted from the CNS that affect the MI [8].

An important pathway by which gut microbes and their metabolites communicate with the CNS involves the cells that make up the gut endocrine system [9]. This communication is mediated by several microbially derived molecules including SCFA, secondary bile acids, and tryptophan metabolites [10]. SCFAs have been implicated as the main signaling molecules that mediate host-microbe communication through enteroendocrine cells (EECs) and enterochromaffin cells (ECCs). SCFAs are generated by the microbial fermentation of resistant starch and non-starch polysaccharides that reach the intestine. These molecules play a role in host energy computation, as well as other functions such as stimulation of local blood flow, fluid and electrolyte absorption, and intestinal mucosal proliferation [11].

SCFAs propagate signals primarily through interaction with EECs, ECCs, and the mucosal immune system. Some cross the intestinal barrier, enter the systemic circulation, and can cross the blood-brain barrier [12]. It has been shown that SCFA production stimulates L cells located in the distal ileum to secrete peptide YY and glucagon-like peptide-1 (GLP-1), which induce satiety and behavioral changes [13]. Among other SCFAs, acetate, butyrate, and propionate modulate GLP-1 expression and secretion via free fatty acid receptor 2 (FFAR2)/G protein-coupled receptor 43 (GPR43) and FFAR3/GPR41 in L cells [13]. Vagal receptors detect gut regulatory peptides, inflammatory molecules, dietary components, and bacterial metabolites and send this information to the CNS [14].

The blood-brain barrier (BBB) regulates the transit of molecules between the circulatory system and the cerebrospinal fluid of the CNS. In murine models, GM can regulate the expression of intestinal cell-to-cell tight junction proteins, including occludin and claudin-5, allowing BBB permeability to be reduced [15]. Systemic immune activation can cause disruptive changes in the BBB and is often modeled using lipopolysaccharides (LPS). Studies evaluating the effects of LPS in vivo on BBB function only showed disruption 60% of the time [16].

3. Relationship between intestinal dysbiosis and neuropsychiatric pathology

The presence of intestinal dysbiosis can affect the proper functioning of the body and is associated with the development of digestive pathologies, as well as other apparatus and systems such as the immune, metabolic, cardiocirculatory or nervous. In recent years, numerous studies have found links between GM alterations and the most frequent neuropsychiatric disorders such as depression, Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, psychosis and demyelinating pathology such as multiple sclerosis [17, 18]. It has been shown that nearly 90% of stroke cases may be related to behavioral factors including poor diet, smoking, and low physical activity, as well as obesity, hypertension, and/or diabetes mellitus. Several studies consider GM as a risk factor for stroke [19].

Under normal conditions, commensal microbes inhabit the outer layer of the colon. The mucus that covers it, rich in glycoproteins, is a source of energy for the microbiota when the amount of fiber in the diet is not sufficient. This circumstance favors the possibility of colonization by pathogenic microorganisms [20]. The inner layer is generally free of bacteria and serves to protect epithelial cells from microbial contact through physical separation and innate immune mechanisms including antimicrobial peptides and adaptive immune mechanisms such as secretory IgA [21].

In murine models it has been shown that stress can cause alterations in the intestinal barrier by directly modulating epithelial permeability and by altering the properties of the intestinal mucosal layer. This fact produces a greater translocation of intestinal microbes or molecules associated with microbes [22]. In these models, it has been shown that the permeability of the jejunum and colon increases in response to either acute or chronic stress [23]. Bacteria, such as Escherichia coli, and their products, as well as bacterial LPS, lead to a pro-inflammatory environment in the gut. Stress-induced changes in the expression of messenger RNA encoding tight junction proteins have also been described in the colon and jejunum [24]. In addition, stress leads to a less protective mucus layer through catecholamine signaling, which alters the composition and size of secreted mucus, as the ANS modulates mucus secretion by intestinal goblet cells, thereby affecting the thickness and quality of the intestinal mucus layer [25].

It is possible that the changes in GM composition observed in murine models of brain injury are the result of altered mucoprotein production and goblet cell population size mediated by increased sympathetic nervous system signaling [26]. Furthermore, epinephrine and norepinephrine have been shown to increase the virulence properties of various enteric pathogens as well as non-pathogenic microbes through stimulation of natural immune sensing mechanisms [27]. Substantial roles for gut microbial regulation of autoimmunity, inflammation, and immune cell trafficking have been identified in mouse models of multiple sclerosis and stroke [28, 29]. Toll-like receptors 3 and 7 recognize viral RNA, and Toll-like receptors 2 and 4 recognize peptidoglycan and LPS. These receptors are expressed in both the murine and human ENS [30].

Under normal conditions, various types of microorganisms and macromolecules manage to cross the intestinal barrier through the M cells, which are part of the lymphoid tissue associated with the intestinal mucosa. This activity allows the constant checking of microorganisms and various molecules [31]. On the other hand, Paneth cells detect bacteria autonomously through the activation of the Toll-like receptor dependent on the MyD88 gene, responsible for the innate immune response to pathogens, which triggers antimicrobial factors and, ultimately, limits the penetration bacteria in host tissue [32]. Microbes and microbial-derived ligands help maintain the tight junctions between cells that are critical for the integrity of the intestinal barrier [33]. All these mechanisms and their alteration for different reasons, make it possible for information to reach the CNS and various types of reactions to occur, such as neuroinflammation and accelerate brain aging, contribute to the genesis of various neuropsychiatric diseases and hinder or delay recovery of ABI.

4. Neuroinflammation in the context of stroke

Increasing evidence suggests that intestinal inflammation together with the immune response plays an essential role in the pathophysiology of stroke and this may become an important therapeutic target for the treatment of ABI [34]. The different communication pathways between the microbiota, intestine and brain, the increase in intestinal permeability and the passage of molecules through the BBB would make it possible to activate the immune cells of the CNS [35].

The BBB is made up of blood vessels that allow substances to pass into the CNS in a very selective manner to maintain correct homeostasis, guaranteeing correct neural function. The properties of this barrier are due to its architecture and the cells that make it up, the most important being the endothelial cells (EC), which have a great capacity to very selectively regulate the movement of ions, molecules and cells between the blood and the brain. Specific transporters are expressed in these cells that allow a selective passage of substances in both directions. To limit passage of immune cells into the CNS, ECs express very few leukocyte adhesion molecules. The set of all these properties allows the maintenance of cerebral homeostasis in a healthy situation [36].

The inflammatory process during cerebral ischemia involves the participation of glia and microglia, mediating the migration, infiltration, and accumulation of leukocytes to the brain parenchyma during ischemia. In ABI, the expression of cytokines (IL-1β, TNFα, IFNγ) and chemokines such as CCL2 (MCP-1), CCL5 (RANTES) and CXCL1 (GRO-α) has been demonstrated, which precedes the infiltration of leukocytes towards ischemic injury, acting through its receptors CCR2, CCR5 and CXCR2, respectively. Inflammation contributes to tissue injury during the early phase of the hypoxic-ischemic response and during the healing process in the late phase of cerebral ischemia. Thus, chemokines exert an inflammatory action against brain damage, although some of them have a neuroprotective effect by inducing the synthesis of growth factors that contribute to brain regeneration based on neuroplasticity, all if the attention process of the patient is carried out in the optimal time and circumstances [37].

The changes in GM in patients who have suffered a stroke have been documented in several studies [38], but it is in murine models that the sequence of events and the repercussions for the evolution and functional recovery of the stroke have been appreciated. In murine models using two types of acute middle cerebral artery occlusion, large stroke lesions were found to cause intestinal dysbiosis, which in turn affected stroke outcome through immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of Bacteroidetes were identified as hallmarks of post-stroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility following injury progression. The impact of the microbiota on immunity and stroke outcome was transmissible by microbiota transplantation [39].

5. Nutritional intervention in stroke

The composition of GM is defined by many factors, including the way of being born, the consumption of antibiotics, infection processes, stress, customs, ethnicity, habitat, hygienic habits, genetics and diet among others. Although used infrequently as an intervention specifically targeting GM, diet can have profound, rapid, and reproducible effects on GM structure in humans and animals [40]. Clinical experience and published studies, both in humans and in murine models, invite us to implement the analysis of GM in patients who have suffered a stroke and, in the case of intestinal dysbiosis, to intervene with the modification of the diet until eubiosis is acquired. At this level, there are still some doubts such as the optimal time to start the dietary intervention to act on dysbiosis, that is, in what phase of the stroke would it start? Table 1 shows the stroke phases, their approximate duration and the units where they are treated according to Murie-Fernández et al. [1].

Phase	Duration	Unit of stay
Acute	2–3 months	Hospitalization
Subacute	6 to 18 months	Rehabilitation, day hospital
Chronic	From 24 months	Residency, physiotherapy

Table 1.

Phases of stroke, duration and where it is treated according to Murie-Fernández et al. [1].

If we are willing to intervene in stroke patients, it would be convenient to add the figure of the nutritionist-dietician in the team that cares for stroke patients. Table 2 shows the members of the multidisciplinary team in stroke rehabilitation according to Murie-Fernández et al. [1], to which we include the figure of the degree in human nutrition and dietetics.

Discipline	Function	Intervenes in phase
Neurology	Diagnostic	Acute
Nursing	Acute hospitalization care	Acute
Neurosurgery	Clot removal (if applicable)	Acute
Nutrition and dietetics	Diet planning according to the patient’s evolution	?
Physical medicine and rehabilitation	Treatment protocol	Acute/subacute
Physiotherapist	Techniques, treatments and strategies to recover damaged functions	Subacute
Neuropsychologist	Action on behavior, emotions, etc	Acute/subacute
Speech therapy	Acting on dysphagia, dysphonia, dysarthria, aphasia, etc	Subacute
Occupational therapy	Stimulation, reeducation,...	Subacute
Orthopedic technician	Adaptations	Subacute/chronic
Social work	Comprehensive management	Subacute

Table 2.

Multidisciplinary team in stroke rehabilitation according to Murie-Fernández et al. [1] and completed by A. Ursa and E. Guzón.

A diet adapted to each patient who has suffered a stroke with intestinal dysbiosis, with adequate dietary fiber, the administration of probiotics, symbiotic, etc., could contribute to a better evolution and functional recovery to the current on neuroinflammation [41, 42]. More studies are still needed to expand knowledge, clear up doubts and design protocols adaptable to different patients and contexts.

6. Conclusions

Acute brain injuries such as stroke induce gut dysbiosis and, in turn, changes in GM influence neuroinflammation and thus function in ABI. GM is a key regulator in preparing the neuroinflammatory response to brain injury. These findings highlight the role that GM plays as a therapeutic target to protect brain function after acute brain injury. Dietary intervention in patients with stroke, either by nasogastric tube in case of unconsciousness or orally if there is no alteration of consciousness, would contribute to a better evolution of the stroke and functional recovery. Much remains to be discovered about the specific mechanisms by which GM is involved in the gut-brain axis and in disease development. Current evidence encourages us to continue researching on this topic.

Funding

This chapter has been funded by the Institute of Integrative Medicine (Valladolid, Spain).

Conflict of interest

There is no conflict of interest.

Abbreviations

CVA	cerebrovascular accident
ABI	acquired brain damage injury
GM	gut microbiota
SLGIS	systemic low-grade inflammatory state
SCFA	short chain fatty acids
CNS	central nervous system
ANS	autonomic nervous system
ENS	enteric nervous system
EEC	enteroendocrine cells
ECC	enterochromaffin cells
GLP-1	glucagon-like peptide 1
FFAR2/3	free fatty acid receptor 2/3
GPR 43/41	G43/41 protein-coupled receptor
BBB	blood-brain barrier
LPS	lipopolysaccharides
EC	endothelial cells