Dalal Akoury

Dalal A. Akoury, MD

AWAREmed Health & Wellness Resource Center

Talks
Great Talk 202 - 4/12/2016 4:00pm
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title

Stress Wreaks Havoc on Brain Gut Connection Creating Cancer


chartThe complex System Biology: Limbic, HPA, HPT, HPG, Serotonergic, Dopaminergic system & Gut-Brain-Skin-Micobiata Axis conduct the Symphony of Survivorship vs environment. The gut is one of the major organs in humans that interacts with the environment, and is involved in adaptations and stress responses. The intestinal microbiota and gut immune system constantly communicate to maintain a balance between tolerance and activation. The immune system protects us from pathogenic microbes while collaborating harmoniously with millions of symbiotic and innocuous beneficial microbiota. A bidirectional-signaling pathway between the gastrointestinal tract and the brain regulated at neural, hormonal, and immunological levels is a pivotal player. The brain–gut axis is vital for maintaining homeostasis. Bacterial colonization of the intestine plays a major role in the post-natal development and maturation of the immune and endocrine systems. Human microbiota is a diverse and dynamic ecosystem, which has evolved in a mutualistic relationship with its host. It is a super-complex ecosystem containing trillions of bacteria and other microorganisms that inhabit all our surfaces; skin, mouth, sexual organs, and specially intestines. Furthermore multiple direct and indirect pathways maintain extensive bidirectional interactions between the gut microbiota and the CNS; involving endocrine, immune and neural pathways and form the basis of the so-called MGB axis (brain–gut–enteric microbiota axis). Microbiota and host form a complex ‘super-organism’ in which symbiotic relationships confer benefits to the host in many key aspects of life



While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1α, IL-1β, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-κB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic, pathological microbiata, viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV). These observations imply that anti-inflammatory states such as intact Gut-Brain-Skin-Micobiata Axis that suppresses NF-κB or NF-κB-regulated products should have a potential in both the prevention and treatment of cancer.


The microbiome: stress, health and disease model is rapidly gaining national and international scientific support. The correlations between changes in composition and activity of the gut microbiota and common disorders, such as cancer, inflammatory bowel diseases, obesity, diabetes, and atopic diseases is gaining increasing interest in the scientific community. Under stress, the brain may influence the composition of the gut microbiota via the hypothalamus–pituitary–adrenal (HPA) axis, which regulates cortisol secretion, affecting immune cells activity; both locally in the gut and systemically. The necessary communication processes are based on neurotransmitters, neuropeptides, cytokines, hormones, growth factors (among others), which mediate the relationship between the immune system and the CNS. A feedback process leading to homeostasis yet, disorders like stress can impact such equilibrium, leading to disease, allergic reactions, inflammatory disease and predisposition to infection. Additionally, cortisol alters gut permeability and barrier function, thus contribute to variations in gut microbiota composition. Vice versa, experimental evidence indicates that the gut microbiota, and pre- and probiotic agents can alter the levels of circulating cytokines, which in turn can have a marked effect on several brain functions.

Healthy immunophysiologic regulation in the gut has been hypothesized to depend on the establishment of indigenous microflora that create specific immune responses at the gut and system levels. Alterations in the microbiome composition have been reported in cancer, inflammatory bowel disease, inflammatory conditions, ulcerative colitis and more.


Stress modifies the Metagenomics: key to human gut microbiota The comprehensive genome of these microbial populations (intestinal microbiome) is estimated to have a far greater genetic potential than the human genome itself in health and in disease. Exposure to various stressors changes the stability of the microflora and leads to bacterial translocation. Stress induced by microgravity alters Bacterial Virulence. Studies have also shown an increase in the virulence, changes in growth modulation and alterations in response to antibiotics in certain bacteria both in space and simulated microgravity; Circulating levels of IL-6 and MCP-1 increased with stressor exposure and these increases were significantly and positively correlated to changes in bacterial species. The increase in circulating cytokines indirectly suggests that microbiome contribute to stressor-induced immune imbalances.


Furthermore scientific research indicates that Stress induced oxidative stress modifies microbiota biofilm structure and formation. Bacterial biofilm creates superior resistance to oxidative, osmolarity, pH and antibiotic stresses. Bacterial biofilm production, which enhances bacterial survival by resistance to the immune system and antimicrobial agents, may increase the risk and/or severity of infection. Biofilm formation is linked to chronic diseases that are difficult to treat such as endocarditis, cystitis and bacterial otitis media.

Stress that results in over stimulation of the HPAA Axis Creates a Chaos that affects the integrity of this vital circuitry. CRF the major stress induced switch disrupts the host microbes’ axis, which control bacterial sensing, and homeostasis, altering the microbiome, through stress induced micro-environmental changes (infection, diet or lifestyle), that may disturb this symbiotic relationship and promote disease.

Another fascinating line of research emphasizes The Gut-Brain-Skin Axis, which plays an important role in our overall health. Stress-induced alterations to microbial flora could increase the likelihood of intestinal permeability, which in turn sets the stage for systemic and local skin inflammation. When gut integrity is compromised, an increase in circulating endotoxins derived from gut microbes can manifest as skin eruptions such as rosacea and acne underscoring the role of stress in Gut-Brain-Skin Axis disturbances.

The Gut–brain–liver axis plays a dominant role in blood glucose homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of glycogenesis and gluconeogenesis. Stress causes disruption of glucocorticoid and catecholamine hormones via activation of the hypothalamic-pituitary–adrenal axis.

This presentation will also underscore: the role neuroenteric–pulmonary axis and the role of the vagus nerve participates in tumorigenesis. Cancer is promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment.

Many epidemiological studies underscore the clinical importance between dysbiosis and intestinal carcinogenesis. Dysbiosis causes carcinogenesis by: 1/ altering the composition of the microbiota, 2/ producing substances that directly target intestinal epithelial cells and mediate oncogenic effects (hydrogen sulfide and the bacteroid fragilis toxins). Experimental alteration of microbiata suggests a link between dysbiosis and breast cancer. In addition to breast and colon cancer, chronic Salmonella enterica infection has been associated with gallbladder cancer; & Chlamydia pneumonia, Haemophilus influenza, and Candida albicans have been linked with lung cancer. Moreover Helicobacter pylori can result in stomach cancer. The increase in free radicals and subsequent inflammation and DNA damage is implicated in influencing the incidence and progression of extra-intestinal cancers. Since the inflammatory microenvironment plays a pivotal part in tumor-genesis it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue (MALT) lymphoma have been caused by the presence of certain pathological bacteria.

Cancer prevention and cure cannot be attained unless stress, and Gut-Brain-Skin-Micobiata Axis are properly addressed. Cancer is a complex collection of distinct stress induced epigenetic dis-eases united by common hallmarks.

This presentation describes a conceptual framework of how Gut-Brain-Skin-Micobiata Axis contribute to the hallmarks of cancer and how it can be exploited through stress reduction and microbiata reprogramming to restore allostatic balance and energy metabolism evading immune destruction and subsequently selectively kill cancer cells. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved.

Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining right-angled cancer therapies by addressing stresses and Gut health

Goals:

  1. Emphasize a wholistic approach to understanding the Biologic stress and Gut-Brain-Skin-Micobiata Axis networks and sub-networks including the Limbic, HPA, HPT, HPG, Serotonergic and Dopaminergic system.
  2. Focus on the non-linear interactions between the various components and pathways of stress and Gut-Brain-Skin-Micobiata Axis to determine the major players in the pathophysiology of cancer and suggested targets of therapy.
  3. A “paradigm shift” of molecular biology from a reductionist approach to a more wholistic approach will be highlighted.
  4. We will allude to the complex genomics, transcriptomics, epigenomics, and proteomics involved in the neuroendocrine system creating an exceptional self-healing brain circuitry including sub-networks.
  5. We will discuss the effect of hypothalamic pituitary adrenal (HPA) axis is deregulation in Gut-Brain-Skin-Micobiata Axis. Reflecting on the effect of these HPA imbalances on all the Limbic and HPT circuits and emphasizing the restoration of these circuits as a first step in Gut-Brain-Skin-Micobiata Axis recovery and cancer treatment.