Michael Gershon: The Gut-​​Brain connection

Gut Anatomy and Blood Supply

• The gut is divided into three parts: foregut, midgut, and hindgut 
  • Foregut: first part of the small intestine, lungs, pharynx, pancreas, gallbladder
  • Midgut: majority of the small intestine, first part of the large intestine
  • Hindgut: end of the large intestine
• Blood supply to the gut comes from three vessels off the aorta: celiac artery, superior mesenteric artery, and inferior mesenteric artery 
  • Celiac artery supplies the foregut
  • Superior mesenteric artery supplies the midgut
  • Inferior mesenteric artery supplies the hindgut
• The liver receives blood from the gut through a portal system, allowing it to process nutrients absorbed by the gut

Gut Nervous System

• The gut has its own intrinsic nervous system, called the enteric nervous system or “second brain” 
  • Can function independently of the central nervous system (CNS)
  • Present in all vertebrates, with complexity increasing as vertebrates become more complex
• Two major parts of the enteric nervous system: submucosal plexus and myenteric plexus 
  • Submucosal plexus: located in the dense layer of connective tissue beneath the mucosa
  • Myenteric plexus: located between the two layers of smooth muscle (circular and longitudinal) on the outside of the gut
• The enteric nervous system communicates with the CNS, with the brain acting like a CEO giving general commands while the gut controls the details of its behavior

Gut Layers and Epithelial Turnover

• From the inside out, the layers of the gut are: 
  • Mucosa: lining of the gut, including the epithelium and a loose nervous system called the lamina propria
  • Submucosa: dense layer of connective tissue
  • Circular layer of smooth muscle
  • Longitudinal layer of smooth muscle
  • Thin epithelial layer if in the peritoneal cavity

• Epithelial cells in the gut have a turnover rate of about once a week, with variation depending on the type of cell
  Gut Innervation and Pain

• Gut experiences pain primarily in response to dilation or pressure 
  • Cutting inside the gut does not cause pain
  • Pain fibers located in dorsal root ganglia, relay signal to the brain via spinal cord
  • Vagus nerve carries some pain information, but mostly homeostasis signals
• CNS can affect gut function, e.g., anxiety-​​induced diarrhea or travel-​​induced constipation 
  • Sympathetic nerves can slow gut function in response to fright

CNS Communication with the Gut

• CNS communicates with the gut via sympathetic and parasympathetic nerves 
  • Acetylcholine involved in communication
• Gut receives message from CNS and responds accordingly, e.g., rapid peristalsis and less absorption in anxiety-​​induced diarrhea 
  • Enteric nervous system functions in response to CNS input
  • Command neurons in the gut receive input from CNS and start reflexes
  • Intrinsic nerve cells in the gut outnumber extrinsic nerve cells by three orders of magnitude
  • Gut has various behaviors, not just constant propulsion
    Gut Function and Appetite Regulation
• Gut has various behaviors: propelling, mixing, and cleaning 
• Mixing allows enzymes to digest food effectively
• Cleaning process occurs during sleep, clearing out larger particles

Appetite Regulation

• Mechanical and chemical factors affect appetite
• Distension of the stomach and rise of blood glucose levels contribute to satiety
• Gut hormones like cholesystechinan and leptin signal to the brain to regulate appetite
• Ghrelin is a gut hormone that promotes appetite, secreted at a constant rate and can be upregulated or downregulated

Gastric Bypass Surgery

• Reroutes the upper GI tract, triggering satiety signals sooner
• Can be effective for treating obesity and type 2 diabetes
• High-​​calorie liquids can still be consumed, bypassing the surgery’s effects

Neurodegenerative Diseases and the Gut

• Connection between CNS diseases and the gut has been studied for around 30 years
• Varicella Zoster virus (chickenpox and shingles) can infect the gut, causing serious complications
• The virus remains latent in the body after chickenpox and can reactivate as shingles later in life
  Chickenpox and Varicella Zoster Virus
• Chickenpox virus remains latent in nerve cells for life 
• Reactivation causes shingles, a painful rash 
  • 15% of people develop postherpetic neuralgia (PHN), persistent pain for years
• Immune system can’t eradicate the virus when it’s in nerve cells 
  • Virus is sequestered and not expressed on the surface of nerve cells

Autism and Gastrointestinal Issues

• Autism severity correlates with increased prevalence of gastrointestinal issues 
  • Constipation, diarrhea, food sensitivities, and allergies
• Autism likely involves synaptic transmission in the central nervous system (CNS) and enteric nervous system
• No regularity to symptoms, difficult to document rigorously
• Andrew Wakefield’s discredited theory: 
  • Measles, mumps, and rubella vaccine caused gut defects
  • Gluten consumption led to absorption of opiate-​​like substances, causing autism
  • This theory has been debunked and discredited
    Serotonin and Autism
• Serotonin levels are higher in a subset of kids with Autism Spectrum Disorder (ASD)
• Serotonin is a neurotransmitter and endocrine substance in the gut
• 95% of the body’s serotonin is made in the gut, while the brain produces about 2–3%
• Serotonin is important in feeling pain in the gut, triggering nausea, and as a growth factor during development

SSRIs and the Gut

• SSRIs (Selective Serotonin Reuptake Inhibitors) are used to treat depression and anxiety
• SSRIs can cause nausea and change gut motility
• SSRIs given during pregnancy can lead to an abnormal nervous system in the offspring
• There is evidence that conditions like irritable bowel syndrome are increased in offspring of mothers treated with SSRIs during pregnancy

Leaky Gut

• Tight junctions are connections between epithelial cells that prevent material from passing through the channel between two cells
• Leaky gut occurs when tight junctions are compromised, allowing material from the lumen to enter the body and vice versa
• The most common cause of leaky gut is allergy, where the immune system reacts and causes tight junctions to open
• If the gut lining is wounded, adjacent cells can crawl over the space and cut it off

Gut Health Assessment

• If someone has a substantially leaky gut, it can be detected by determining the serum protein albumin; if the gut is leaking, albumin will be low
  Leaky Gut and Autism Spectrum Disorder

• Leaky gut is a controversial topic 
  • Some believe it allows toxins and microorganisms to enter the body
  • No clear evidence that leaky gut is related to autism spectrum disorder (ASD)
• ASD is a disorder of the nervous system 
  • Gut problems in ASD are related to serotonin and the ability of serotonin to act as a growth factor
  • Deficiency in numbers of neuro cells in the bowel

Bacteria in the Gut

• Bacteria in the gut are mostly anaerobes (live in the absence of oxygen) 
  • Hard to culture, making them difficult to study
• Bacteria in the colon: 
  • Produce short-​​chain fatty acids, which are absorbed by the lining of the colon
  • Make certain vitamins, like vitamin K
  • Regulate mood and obesity
• Bacteria in the gut can interact with the nervous system 
  • Activate lining epithelial cells to release serotonin or other chemicals
  • Signal through the vagus nerves to the brain
  • Chemical products from bacteria can trigger nerve signals or affect the brain through the blood-​​brain barrier

Germ-​​Free Mice

• Germ-​​free (notobiotic) mice are bred without any contact with organisms 
  • Allows for studying the effects of bacteria on the gut and nervous system
    Germ-​​Free Animals and Gut Microbiome
• Germ-​​free animals are born via Caesarean section, fed sterile food, and live in incubators 
• After one year, germ-​​free animals have more primitive gut systems, fewer nerve cells, and almost no immune system
• Bacteria in the gut can determine obesity or lack thereof in mice
• Fecal transplants from lean to obese individuals have been done, but not under controlled settings
• Antibiotics can have a major effect on the human microbiome, altering gut bacteria

Fecal Transplants and Risks

• Fecal transplants are used to treat C. difficile infections
• Procedure involves transferring fecal matter from a healthy donor to the patient’s gut
• Risks include potential transfer of harmful bacteria or organisms
• Synthetic biology could potentially create microorganisms for controlled transplants, but currently limited by the inability to grow and maintain these organisms in vitro

Commercial Home Kits for Gut Microbiome Analysis

• Home kits provide information on the classes of organisms and their proportions in the gut
• Current resolution is too low to provide actionable information
• Cologuard is a more accurate test that looks for genetic signatures of GI cancers in stool samples
  Probiotics and the Gastrointestinal System
• Probiotics are live bacteria that provide health benefits when consumed 
• The FTC regulates claims made for probiotic products 
  • Companies must demonstrate evidence that their product does what they claim
• Probiotics can help restore the GI system after antibiotics 
  • Lactobacillus and Saccharomyces are examples of probiotics that colonize the GI tract
• Probiotics do not necessarily need to be refrigerated 
  • Depends on the specific probiotic and its formulation
• Bioengineering could potentially improve the growth and effectiveness of probiotics in the future

The Human Gastrointestinal System

• Unique embryology and innervation
• Cohabitation with bacteria that outnumber human cells
• Still considered a “black box” in terms of understanding and research
• Ongoing research and advancements in understanding the GI system and its interactions with bacteria and probiotics