Probiotic Research in Therapeutics

The role of gut bacteria in neurodegenerative disease has long been speculated; however, the extent of influence and the exact composition of microflora that mechanistically alter outcomes are less understood.

While aging was thought to be a major contributor to neurodegenerative disease, the role of the immune system started to become more appreciated bringing the hypothesis of “inflammaging” to the forefront. Gut bacteria serve to prime our immune system and therefore play a role in shaping our immune response to infection and disease. The differences in gut flora between healthy individuals and ones suffering from Alzheimer’s or Parkinson’s disease have been widely documented; however, it is not understood if they are the cause or the effect of the disease. The second hypothesis in the field is the antimicrobial response hypothesis or infection hypothesis, which proposes that the neurodegenerative disease is an undesired outcome of the brain’s immune response against pathogens. In this context, it is important to understand whether it is the presence of microbes themselves in the brain or just the microbes in the gut that prime the immune system and cause an amplified immune response in the brain cumulatively leading to neurodegenerative disease. It is also important to understand the concept of pathogen-associated molecular patterns (PAMPs) that serve to trigger innate immunity by engaging toll-like receptors (TLRs) and that these PAMPs or molecular patterns may be present and trigger inflammation without the presence of actual pathogen.

The ultimate goal of delineating these mechanisms is to then use this knowledge to develop treatments. Some approaches that have been tested in preclinical and clinical studies including fecal transplants have been summarized here as well.

Homeostasis is the dynamic process of maintaining self-balance or to put alternatively the body’s natural tendency to poise equilibrium in response to external stimuli and reorient itself toward undulating environmental circumstances. Various physiochemical and biological processes work in tandem to maintain homeostasis. The microbiota allied to host is an important biological intermediary that plays a pivotal role in maintaining this homeostasis. It consists of a myriad of commensal and symbiotic microbes which are an important dynamic determinant of human health. The host-health promoting microbes, known as probiotics, are the center of intense research which has been extensively reviewed in the previous chapters. It has become patently evident in the recent years that the gut microbiome and the brain communicate in a bidirectional fashion with a great possibility of mutual implication pertaining to each other’s functions. Modulation of intestinal microbiota with probiotics is used as a therapeutic modality in prevention and treatment of a multitude of ailments. Emerging evidence from interdisciplinary research corroborates the incident of communication axis between various organs, for instance, the brain–gut or brain–skin axis. In this chapter with reliance placed on prior published compelling evidence from extant literature, we aim to endeavor and comprehensively comprehend the underlying mechanism which further helps to unravel the interrelationship between gut–brain–skin axis and the modulation of their microbiota by deployment of designer probiotics. The chapter also presents fresh impetus on the evidence demonstrating how the gut microbiome may possibly affect brain function in adults, thereby having an extensive impact on neurological disorders.

Probiotics are live microorganisms which work for the human benefit by improving their intestinal microbial balance. Originally they were used to enhance both animals and humans health by modulating intestinal microbiota. There is a biological connection between probiotics and brain as they can communicate via neurotransmitters system, anti-oxidative defence mechanism and neuroinflammatory pathways. Probiotic bacteria are also involved in the production of neuroactive molecules that act on the brain–gut axis. Probiotic treatments that help to improve mood, anxiety and strengthen memory using them in the form of food or supplements to alter the gut microbiota and treat psychiatric conditions are considered as psychobiotics. Dietary ingestion such as prebiotics, probiotics and polyphenol can influence gut microbiota composition. Dysbiosis of the gut microbiota is associated with brain dysfunctions. Regulation of microbiota by probiotics and prebiotics may help to restore gut equilibrium. The impact of nutrients on microbiota composition strengthens the reports that regulating a therapeutic microbiota is essential for a healthy brain. They could be useful as novel therapeutics to protect the brain from neurodegeneration. But research is still needed, mainly clinical and translational studies to determine pharmacokinetics and pharmacodynamics of probiotics.

The human gut harbors up to 100 trillion of microorganisms out of which only a few microorganisms could be considered as probiotics. The alteration in the gut microbial composition can cause a considerable effect on central physiology as well as act on behavioral or the physiological phenotype of an individual. Presently, various studies on probiotics have increased our interest in the role played by the brain–gut–microbiota axis in diverse neurodevelopmental disorders such as obesity, depression, and autism. Although the exact etiology and pathology of autism spectrum disorder (ASD) are not understood well; several studies indicate the link between gut microbiota and neurodevelopmental disorders in offspring, including ASD. Certain intestinal bacteria such as Clostridium and Sutterella genera have been reported in abundance in ASD condition, suggesting their crucial role in manifestation of ASD. Similarly, there are also preclinical evidences which mark that the supplementation of probiotics and/or prebiotics results in an improvement in behavior of the children with ASD. The chapter will discuss different mechanisms involved in manifestation and amelioration of ASD by gut microbiota and probiotics–prebiotics, respectively. Therefore the chapter will provide all the available preclinical and animal studies for depicting the current clinical picture of autism by representing the relationship between gut microbiota, probiotics, prebiotics, and their role in ASD.

Autism spectrum disorder (ASD) involves deficient ability to socially interact and communicate, pervasive, and stereotypic behavior. It also involves co-morbidities such as anxious and aggressive nature and epilepsy. Apart from above, this disorder also involves physiological symptoms which co-exist with behavioral symptoms, such as dysfunction of immune system and mitochondria as well as gastrointestinal complications, which lead to oxidative stress and neuroinflammation, further worsening the behavioral complications. Twenty-three percent to 70% of patients suffering from ASD account for gastrointestinal complications and these correlate with behaviors which are relevant to autistic endophenotype. A strong gut–brain dysbiosis occurs in ASD patients in consequence to the enormous production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora which worsens the behavioral, neurochemical, and mitochondrial dysfunction. This further leads to the generation of free radical species responsible for the synthesis of pro-inflammatory cytokines, which cause microglia activation. The Nrf2-Keap1 signaling pathway in the brain might be a plausible therapeutic target in autism for targeting gut–brain dysbiosis responsible for worsening behavioral and biochemical alterations. Its activation can serve as a putative link in targeting oxidative stress as the delicate balance of the Nrf2-NFkB pathway is responsible for either protection by antioxidant genes and phase II enzymes or generation of pro-inflammatory cytokines. Probiotics are potential neurotherapeutics which can target the Nrf2-Keap1/ARE pathway and mitigate the neuroinflammatory cascade. Hence, it can prove to be utilized as an adjunct therapy for targeting the gut–brain dysbiosis generated inflammatory cascade.

Alzheimer’s disease (AD) is a major form of dementia characterized by the appearance of amyloid beta aggregation (amyloid plaque—outside the nerve terminals), formation of neurofibrillary tangles (within the neuron) hyperphosphorylated tau aggregation, reduced synaptic function, and marked neuronal death. These changes occur around and within the neurons due to the different biochemical changes in AD brain and these changes provided us the underlying cause of AD. However, a full understanding of the exact underlying mechanism involved in AD pathology remains elusive. Psychobiotics are probiotics or prebiotics or combination of these two, when ingested generate a beneficial effect on the nervous system mediated by gut–brain axis (GBA) through several ways (neuroendocrine, neuroimmune, and enteroendocrine) resulted in improved function in both gastrointestinal and CNS. We mainly focus on how gut microbiota alteration involved in AD pathogenesis and how a leading class of probiotics, i.e. psychobiotics, manipulate the gut–brain axis (bidirectional communication) and prove to be beneficial or alternative therapeutic strategy in treatment of AD. Moreover, we also summarize the current scientific findings from different researchers about the psychobiotics and their role in treatment of AD.

Depressive disorders are repetitive, enervative, degenerating with ever lasting impact on socio-economic and prompt with life-threatening illness. Recent development in the area of probiotics states that in the state of chronic illness and stress there is marked decrease in levels of potentially beneficial bacteria. Bacterial presence in an intestinal tract are involved in various processes such as synthesis of vitamins, triggering of immune response, protection of defence barrier system with production of certain bioprotective molecules and neutralization of various toxins. Adaptation of western culture and modernization of lifestyle encounters with certain stressful events in daily life which leads to slow prognosis of depression and serious episodes of many disorders. Research on certain animals and humans states that stress has negative impact on an intestinal microflora, as well as affects gastrointestinal motility, imbalance in certain chemicals which will directly affect the local flora. Gastrointestinal tract is a house of around 100 million neurons, immune responsive cells and certain microorganism. Many researchers have linked certain inflammatory responses which affects the mood of humans due to intestinal disturbances. Probiotics can be explored as an adjuvant therapy along with management therapy. Some attention must be drawn towards potential benefits of already marketed probiotics in market. In this comprehensive literature review on certain factors associated with depressive disorders and probiotics as supplements for countering depressive disorders is done.

Prolonged insomnia may shorten the life expectancy in humans, as this sleeping disorder has already been associated with miscellaneous detrimental health effects on humans such as risk of elevated blood pressure, type 2 diabetes, hyperlipidemia, obesity, coronary heart disease (CHD), and stroke. Numerous studies manifested that onset of sleeplessness and insomnia is linked to disruption of circadian and microbiome rhythms, immune response, and nutrient metabolism, however, precise mechanism is yet to be elucidated. Moreover, it is now understood that gut dysbiosis and circadian rhythm disruption can affect the quality of sleep, and are associated with other metabolic disorders. Considerable evidences have shown that gut microbiome regulates sleep and psychological states of its host through microbiome–gut–brain (MGB) axis. Research findings have indicated that diurnal variations, emotional state, and physiological stress can disrupt the composition and function of gut microbiota which in turn destabilizes host’s circadian gene expression and functions. Consequently, disruptions of gut microbiome-mediated functions such as diminished bile acids conjugation or enhanced generation of H₂S, and the reduced butyrate production, in turn affect substrate oxidation and metabolic homeostasis of the host. Furthermore, gut dysbiosis and altered circadian gene expression may cause onset of insomnia, circadian misalignment, and metabolic disorders. Nevertheless, insomnia condition can be reversed by: (1) achieving daily rhythmicity of gut bacteria by prebiotics enriched dietary interventions; (2) adopting healthy lifestyle especially meal timing, selective eating patterns and sleep timing; and (3) oral administration of probiotics in order to restore the gut microbial balance. Thus, manipulation of gut microbiome structure through synbiotic diet and chrononutrition-based approaches may therefore hold promise to consolidate host circadian rhythms.

Chronic fatigue syndrome (CFS) is a combination of complex illness characterized by tiredness or intense fatigue that may worsen with too much exertion. Among the wide range of neuropsychological symptoms, 97% CFS patients have been reported with neuronal disorders such as headaches and symptoms in the emotional realm. Patients with CFS also show noticeable alterations in microflora, lowering level of Lactobacilli and Bifidobacterium. Recent researches explain that probiotics in the gastrointestinal tract (GIT) can greatly influence the neuronal pathways and central nervous system (CNS) to modulate behavior. Various studies expressed the benefit of probiotic therapy in normalizing fatigue patients and also restored mitochondrial electron transport function in patients with CFS. In this chapter, we provided a historical skeleton, bidirectional communication pathophysiology, selection criteria of probiotics, CFS treatment, and clinical implications of gut–brain connections. In summary, various aspects concerning the potential and safety of probiotics in the management of chronic fatigue syndrome are discussed in this chapter.

Neurodegenerative sicknesses, viz., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and the spinocerebellar ataxias pose a significant risk to human well-being. These disorders are known to progress inexorably to severe inability and death. Presently, about 30 million people in India are known to suffer from one or the other forms of neurodegenerative disorders with an average prevalence rate of 2394 patients per 1,00,000 of the population. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” A novel class of probiotics called “Psychobiotics,” a group of probiotics that has ability to affect the central nervous system (CNS) and its related functions and behaviors are currently reviewed by scientific community for its potential application in the treatment of mental illness. An abundance of information has demonstrated that psychobiotics residing in gut play crucial roles in the prevention and treatment of various neurodegenerative disorders. Emerging evidences demonstrate that these psychobiotics protect CNS by positively modulating gut–brain axis (GBA) via immune, humoral, neural, and metabolic pathways. Furthermore, preclinical trials involving animal models have claimed the therapeutic benefit of several psychobiotics. However, recognizing appropriate animal model is vital for evaluating the therapeutic efficiency of psychobiotics. Thus, this chapter outlines the advantages and challenges of current animal models and discusses future research directions of neurodegenerative disorders.