**3.** *Candida* **hypersensitivity syndrome**

*Candida* hypersensitivity syndrome was first described 20 years ago. For many years, *C. albicans* has been mentioned as the cause of *Candida* hypersensitivity syndrome. This chronic syndrome is also known as chronic candidiasis, *Candida*related complex, and "the yeast connection" [14].

A *Candida* "infection" or colonization—not proven—is associated with a variety of diseases, e.g., cancer, permanent fatigue and exhaustion, depression, and headache. In addition, there is always speculation that the irritable bowel may have to do with an overgrowth of fungi in the intestine. Still enough scientific evidence is lacking [15–17].

*Candida* is often held responsible for unspecific physical complaints or symptoms. As explained above, the simple detection of fungi in the intestinal flora in small numbers does not justify the start of a corresponding therapy [18]. Extensive and often costly treatment methods such as stool enema, colonic hydrotherapy, detoxification, and antifungal diets are particularly special or rejecting self-urine therapy as unscientific and unsuccessful [19].

Symptoms such as fatigue general malaise and genitourinary and neuropsychiatric complaints and nonspecific gastrointestinal symptoms are reported.

The syndrome is considered to be caused by vaginal and intestinal fungal overgrowth, production of fungal toxins, inflammation, and invasion of mucous membranes. In such conditions, the usual therapy will consist of a rigorous longterm antifungal treatment and "yeast elimination" diet [20–22].

A nutritional imbalance demonstrated by diet analysis could lead to the development of further nutritional deficiencies for a prolonged period of time diet [19, 23].

### **4. An overview of** *Candida***-related conditions in athletes' case: impact on athlete physiological performance capacity**

Exercise has a strong impact in an athlete's body. In fact, intense exercise, and particularly endurance exercise, requires an adaptive regulation of athletes' body in order to fulfill the new physiological and biochemical demands. Under these stimuli, the muscle adapts by improving its metabolic, mechanical, contractile, and neuromuscular functions [24]. Glycogen storage decreases, mitochondrial biogenesis increases, and the balance of electrolytes varies [25]. Moreover, in response to the higher demand of oxygen and nutrients by the muscle, cardiac output, ventilation, and gas exchange increase, which finally results in an increased vascular dilatation. Exercise increases the risk of dehydration as a result of the increment of body temperature. In order to compensate for and reestablish the homeostatic equilibrium, the amount of glucocorticoids and adrenaline release should be higher [26, 27]. Furthermore, blood flow decreases in the liver, pancreas, and kidneys where metabolism activity increases.

Exercise also damages the muscle and highly influences systemic inflammation, intestinal permeability, and an increase in oxidative stress as well as immune response, all of them being related with delayed onset muscle soreness (DOMS) [28].

DOMS is a muscle pain or discomfort that begins after unaccustomed or highintensity exercise [29]. Usually the peak of the pain appears 1–3 days after exercise and can last for 5–7 days postexercise [30]. DOMS is recognized as one of the most frequent and recurrent forms of sport injury affecting both athletic (including elite athletes) and nonathletic population. Its prevalence is higher when exercise activity increases (e.g., beginning of sporting season) or when a new type of activity is introduced. Duration and intensity of exercise also influence DOMS. Thereby, intense exercise is related to higher degrees of DOMS, immune system suppression, inflammation, and oxidative stress, while low-to-moderate exercise is related with enhancing the immune system and healthy lifestyle. Despite its high incidence, the mechanisms of DOMS remain uncertain, and there are no specific treatment strategies. DOMS can negatively affect several factors of athletic performance such as muscular pain, reduced joint range of motion, power reduction, altered muscle sequencing and recruitment patterns, and muscular strength [29]. Additionally, DOMS affects athletic performance by increasing the risk of other muscle injuries but also by making athletes more prone to suffer from opportunistic infections such as candidiasis. This may be mainly because of the underlying state of chronic inflammation due to exercise, altered immune system, and oxidative stress. Actually, infectious diseases and particularly fungal infections [31] have been identified as the most common and important health problems in athletes [32], especially in contact sports. Some studies found that among wrestlers, skin infections are a common cause of training and match disruption, thus directly affecting athletic performance [31]. Also it has been determined that *C. albicans*, one of the most important causative agents of opportunistic infections, was responsible of those infections in 5% of the analyzed athletic population [9]. Therefore, it can be assumed that the alterations due to the impact of exercise (mainly increase of inflammation, affected immune system, and oxidative stress) may alter gut microbiota, increasing the risk of opportunistic infections such as *Candida* infections. Other studies found that in comparison with controls, athletes used twice as frequently oral antibiotics [33]. This supports the hypothesis that specific variations in gut microbiota may even be the starting point of different diseases development [34].

Diet and nutritional or dietary supplements have been identified as the main factor affecting gut microbiota (**Table 1**). In fact, it has been proven that dietetic changes can induce up to 57% of gut microbiota [35] variations in terms of composition and functioning in 24 hours [36, 37]. On the other hand, several studies have demonstrated the influence that gut microbiota have on essential processes affecting the individual's health and performance (e.g., immune response and metabolism of nutrients) [34, 38]. Therefore, it could be assumed that diet and food supplements (also called nutritional or dietary supplements) may be a critical factor through which gut microbiota can be modulated in order to benefit athletes in their performance. Actually a recent study has identified several dietetic patterns which address this idea [39]*.*

Most studies analyzing the impact of probiotics in athletic performance highlight their positive impact on the immune function, gut mucosa permeability, and oxidative stress resulting from intense exercise but also they increase the risk of respiratory diseases that are very common in athletes [40]. Thus, probiotics have been proven to improve athletes' performance.

Up to now, there is no specific information on how diet and food supplements directly affect *Candida* and how *Candida* further impact athletic performance. However, interesting data shown may give a hint regarding *Candida* behavior with respect to probiotic consumption [41]. A study [41] evaluated healthy young individuals and analyzed the impact that probiotics consumption has on the presence of *Candida* in oral cavity. Results show 46% reduction in *Candida* prevalence after probiotics consumption in oral cavity. *C. albicans* was the main *Candida* spp. identified followed by *C. tropicalis* [42].

Finally, evidence supports that also antibiotics influence gut microbiota composition. The use of antibiotics increases the risk of opportunistic candidiasis


*The Influence of* Candida *spp. in Intestinal Microbiota; Diet Therapy, the Emerging Conditions… DOI: http://dx.doi.org/10.5772/intechopen.92791*

#### **Table 1.**

*Dietary modifications for the improvement of gut microbiota [39].*

infections. Additionally, it has been also reported that antibiotics may cause fatigue and therefore negatively influence athletic performance [41]. Research done to analyze the relation between the total use of antibiotics (duration of antibiotic courses) and the degree of fatigue has shown that the longer the antibiotic courses, the higher the fatigue scores obtained [43, 44]*.*

Lately studies evaluated the ergogenic effect of probiotic supplementation and their effect on physical exercises, trying to identify their mechanisms of action and on how could they influence the improvement of performance. Due to the fact that only few studies were performed and demonstrated the ergogenic effect of probiotics, further studies should investigate the subject for better understanding [45–52].

## **5. An overview of** *Candida***-related conditions in elderly case: physiological alterations**

The term "elderly" comprises those individuals aged 60 and older, and they represent the fastest growing population group. In fact, in 2017 the global population of 60 years old and over totaled 962 million, and it is foreseen to reach 2.1 billion by 2050 [53]. Already by 2030 it is anticipated that nearly 35% of the European population will be over 60 and 11% over 80 years [53]. With age progression, deficiencies of physiological functions occur, making elderly more vulnerable to diseases and infections, particularly from fungal species [54]. Genus *Candida* is considered the most important cause of opportunistic infections affecting

especially immunocompromised patients and elderly people and the major causative agent of nosocomial infections [55]. The step from *Candida* colonization to subsequent infection is not yet clear. However it has been proven that the natural flora which develops within the gastrointestinal tract can represent the main source in the development of severe infections.

*Candida* infections are very difficult to diagnose in the elderly and have a complicated therapeutic management [56]. Signs and symptoms are often nonspecific and can vary depending on the area affected. Thus, diagnosis depends on the clinical evaluation supported by biochemical and microbiological analysis. Given the difficulty of diagnosing *Candida* infection, efforts have been focused on the development of new strategies and diagnosis methods such as new culture methods with increased sensitivity. Also novel antigen-based tests are available for the detection of mannan levels which is the main component of *Candida* cell wall and 1,3-β-D-glucan which is mainly used in critically ill patients as it has high sensitivity [54, 57]. Finally, real-time polymerase chain reaction technique is also applied for the detection of five different *Candida* spp. [54].

Regarding the epidemiology, 90% of all *Candida* infections are caused by *C. krusei*, *C. glabrata*, *C. albicans*, *C. tropicalis*, and *C. parapsilosis* [58].

Aging-related physiological changes and other factors frequently affecting the elderly such as comorbidities, polypharmacy, and high colonization rate result in an extremely high mortality rate (from 36 to 63%) [59].

The oral cavity is considered a major physiological importance and experiences numerous alterations with aging process. The impaired functioning of the salivary gland alters the quality and quantity of saliva (hyposalivation). This impacts the equilibrium of the resident oral microbiota and also results in the decrease of defensive proteins (such as salivary peroxidases or myeloperoxidase) as well as other substances with antimicrobial activity (e.g., lysozymes), facilitating the development of oral candidiasis. Using removable dental prostheses and their deficient hygienization also contribute to oral candidiasis. *C. albicans* followed by *C. glabrata* and *C. tropicalis* have been identified as the most prevalent *Candida* spp. found in dental prostheses [60]. The use of drugs that irritate or damage the oral mucosa, such as long-term antibiotic intake, as well as the presence of chronic and/or concurrent diseases may also lead to candidiasis. As already mentioned, *Candida* colonization can lead to severe infections. Thus, from oral cavity colonization, *Candida* may increase the colonization index and reach easier other areas such as the respiratory system [61].

Further, oral candidiasis may lead to appetite decline, and this can limit the nutrient intake which can directly influence gut microbiota growth. Appetite decline can also be a consequence of other age-related physiological alterations (**Table 2**) [62]. The impaired masticatory efficiency produced by poor dental health and related pain, loss of teeth and muscle bulk, and lower sensitivity (including taste, smell, and sight) have a negative influence on appetite as food remains uninteresting [62, 63]. Oropharyngeal and esophageal motility diminished the risk of swallowing impairments (e.g., dysphagia) and prevalence of gastroesophageal reflux. Additionally, alterations in the secretion and peripheral action of the hormones that regulate the wish to eat, hunger, and satiation can also reduce appetite. Besides the reduction of appetite, the nutritional status of the elderly can be influenced by the changes in gastrointestinal motility which can lead to reduced digestion and absorption, among others. All those result in the changes in the availability of nutrients in the gut which influence the abundance of *Candida* and may lead to dysbiosis. For example, it has been proven that a high-fat diet stimulated the increase in Firmicutes and Proteobacteria and a decrease in Bacteroidetes [64]. Poor nutrition has been also proven to be associated with the development of inflammatory pathologies (e.g. Crohn's disease) and chronic disease associated with


#### **Table 2.**

*Natural aging physiological alterations.*

nutritional status (e.g., diabetes mellitus and cardiovascular diseases). Finally, poor nutrition can also derive in malnutrition which is one of the key factors influencing the growth of gut microbiota and, thus, may also lead to the dysregulation of the immune system and posterior infection.

The immune system is also affected with aging (a process known as immunosenescence) [65]. Hence, there have been identified several altered immune parameters as well as adaptive and innate immunity influencing the development of chronic inflammatory status. Also the composition of gut microbiota varies with aging [66]. It decreases the number and variety of many protective commensal anaerobes such as lactobacilli and bifidobacteria. Beside this, phagocytosis is altered as a consequence of the functional insufficiency of monocytes and macrophages. On the other hand, "altersinvolution" (referring to age-related involution of the thymus) leads in a decline in circulating antigen-presenting cells (e.g., dendritic and T cells) [67]; T cells show altered cytokine production and lose their memory capacity as well as decrease the number of circulating B cells. Consequently, the immune system is compromised, and thus, there is a higher risk for the elderly to develop serious fungal infections, especially disseminated candidiasis. The source of this infection is often the gastrointestinal tract. The administration of broad-spectrum antimicrobial agents to these patients increases their risk of *Candida* infections by increasing the frequency and magnitude of gastrointestinal tract colonization by *Candida* spp.

Physiological changes associated with aging also affect the metabolism of many drugs [68]. As time passes, the hepatic capacity diminishes, affecting drug clearance. Specifically, the microsomal cytochrome P450-dependent monooxygenase system is altered, and therefore, the drugs that undergo this pathway cannot be cleaned properly. Liver volume and blood flow also decline, impacting drug clearance. In addition renal size and volume are reduced. There are less glomeruli and juxtamedullary nephrons, resulting in a decrease in filtration area of the glomerular basement membrane and decreased permeability. Thus, the glomerular filtration rate (GFR) is decreased [69]. Both liver and renal modifications impact the elderly's pharmacokinetics and pharmacodynamics variables, thus making them at higher risk of adverse drug reactions and harmful drug interactions. Together with the above information, other common factors such as serious underlying diseases and comorbidities, the use of antibiotics and immunosuppressive drugs, living in care facilities, or being hospitalized increase the risk of the elderly suffering from *Candida*-induced infections (particularly *Candida* oral infections) and make them more vulnerable.

For frail elderly, severe surgeries, the use of central venous catheter, and parenteral nutrition are associated with candidemia related to biofilm formation and hence persistent colonization and infections [70]. Biofilm formation by an irreversible adhesion of a community of microorganisms which attached to each other on a surface, inert material, or living tissue, produce extracellular polymers that provide a structural matrix. The microorganism in this community behaves differently, showing more resistance to antibiotics and lower growth rates. Different *Candida* spp. have been identified to be implicated in biofilm formation. Each of them exhibits particularities in terms of biofilm formations (morphology, extracellular matrix, antifungal resistance, etc.) and thus complicating treatment. *C. parapsilosis* has been characterized as the most frequently causative agent of catheter-related infections through biofilm formation [71]. It is an exogenous pathogen found mostly on the skin of healthy hosts which easily spread through hand contamination in hospitals and care facilities. *C. tropicalis* is particularly relevant in urinary tract infections [72, 73].
