Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs)

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Communication between the gut travels in both directions.

Health of the gut (intestines) plays an important role in the health of the brain. The gut contains 500 million neurons and holds trillions of microbes which in turn make other chemicals that affect how the brain works. But inflammatory lifestyle and dietary habits that effect the gut can give rise to a sequence of events which trigger neuroinflammation and neurodegenerative diseases.

Communication between the gut and the brain is called the gut-brain axis. The connection is both physical and biochemical. The physical connection is through the vagus nerve. The vagus nerve is one of the longest nerves in the body extending from the brain to the gut and signals are sent through it in both directions.

Biochemical communication comes from neurotransmitters. Neurotransmitters are chemical messengers that transmit signals from nerve cells to target cells.

The gut contains a microbiome. The microbiome refers to the microbes and their genetic material. Gut microbiota, sometimes called gut flora or gut bugs refers to the microorganisms themselves and include: bacteria, fungi, viruses, protozoa, and archaea. The microbiome is not static, it varies by individual and is influenced by many factors such that its composition changes continuously. The microbiome can contain both beneficial microbes as well as undesirable pathogens. Ideally these gut bugs are in balance. But when the overall diversity is diminished and there’s an overgrowth of bad microbiota (bad bugs) the result is gut dysbiosis. The gut can be likened to a garden, when nurtured, it flourishes with healthful flora or if neglected it becomes overcome by noxious weeds.

Gut issues are a major source of inflammation, and inflammation is the root of many health issues, including neurodegenerative conditions. Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity

The digestive tract contains the largest component of the body’s immune system so the gut-brain axis is also connected through the body’s immune system. If your immune system is switched on for too long, it can lead to chronic inflammation, which is associated with a number of brain disorders, including Alzheimer’s Disease. [Source: The role of inflammation in CNS injury and disease (Sian-Marie Lucas et al, 9 Jan 2006)]

In the "gut-brain axis" the gut and its microbial inhabitants send signals to the brain, and vice versa. For further reading: Gut communicates with the entire brain through cross-talking neurons

Some Introductory videos on this subject

Gut concerns and strategies for improvement

Research shows that there is a difference in microbiota diversity and abundance between ApoE genotypes. The deficiencies ApoE4s hold could be a driver in our greater association with Alzheimer’s. [Source: APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer’s disease pathophysiology(Tam T. T. Tran et al, 8 Apr 2019)] Gut dysbiosis can lead to leaky gut and leaky gut can lead to “leaky brain.” Leaky brain produces neuroinflammation in the brain which can result in Alzheimer’s Disease and certainly ApoE4s are more susceptible to inflammation. Inflammation disrupts the blood brain barrier, so potentially ApoE4s are more susceptible to “leaky brain.”

For further reading on differences the gut microbiome among APOE alleles, see Murine Gut Microbiome Association With APOE Alleles(Ishita J. Parikh et al, 14 Feb 2020).


A healthy gut has a tight barrier, a leaky gut lets undesirable particles into the bloodstream inciting inflammation. Source: Leaky Gut, what is it?

Although some medical professional refuse to admit that leaky gut is even a real condition, the published papers presenting evidence of its existence and the subsequent negative effects are numerous, have been growing impressively in recent years, and continue to grow.

Leaky gut, or increased permeability of the intestinal mucosa, is a very common ailment largely attributed to the Western Diet. Leaky gut is the most common cause of chronic inflammation, which in turn can compromise the Blood Brain Barrier (BBB) setting up neuroinflammation. But the inflammation from leaky gut, while chronic, can be low grade, therefore subtle and sometimes overlooked.

In a healthy gut, the epithelial cells (the cells that cover a surface) in the lining of intestinal walls are aligned very close to each other, called tight junctions. These tight junctions allow water and nutrients to pass through to the bloodstream but prohibit harmful substances of the intestines from passing through. In a leaky gut, these tight junctions are degraded allowing harmful food particles, bacteria, and toxins to enter directly into the bloodstream. The immune system responds to these leaked materials resulting in inflammation. This is how the process is supposed to work, the immune system tamps down inflammation to return to homeostasis (stable equilibrium). Issues develop when the immune system has to respond to continuous (chronic) inflammation and becomes overworked. Leaky gut is the most common cause of chronic inflammation and inflammation is associated with a number of brain disorders including Alzheimer’s Disease.

Of particular interest when it comes to leaky gut are lipopolysaccharides (LPS). LPS are a significant cause of inflammation and the researchers of this paper, Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease found that high blood levels of lipopolysaccharides (LPS) were associated with large amyloid deposits in the brain, a condition associated with Alzheimer’s Disease.

A leaky gut is one of the three ways LPS enter the bloodstream with toxic results. Lipopolysaccharides are bacterial toxins in the body (an endotoxin) but they are usually contained safely within the gut. But if (1) the gut becomes leaky, or (2) if there is an infection or (3) a person’s diet contains too many fatty foods, lipopolysaccharides enter the bloodstream and become toxic.

LPS are found on the outer membrane of Gram-negative bacteria. The largest concentration of Gram-negative bacteria, such as E. coli and Salmonella, are found in the gut. If LPS remain in the gut, they don’t activate the immune system or cause harm. But if LPS enters the bloodstream, it promotes inflammation in the body. (Source: Lipopolysaccharide: Basic Biochemistry, Intracellular Signaling, and Physiological Impacts in the Gut(Sang Hoon Rhee, 29 Apr 2014). Besides infection and leaky gut, LPS can enter the blood from the gut through fat-containing chylomicrons. Chylomicrons are fat transporters responsible for the absorption and transfer of dietary fat and cholesterol from the gut to the blood. This binding process is necessary to transport them to the liver for detoxification. However, not all get detoxified quickly leaving some unbound in the blood (Source: Chylomicrons promote intestinal absorption of lipopolysaccharides(Sarbani Ghoshal et al, Jan 2009). That stimulates production of inflammatory cytokines: TNF-α, IL-1β, IL-6 and CRP. It appears higher-fat meals may increase LPS and inflammation, particularly in obese people.

From leaky gut to leaky brain

A leaky gut promotes inflammation which in turn loosen the junctions of the blood brain barrier. Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity

The leaky gut can in turn lead to a leaky brain, that is to say permeability of the blood-brain barrier (BBB). The blood-brain barrier is how the brain protects itself from damaging, inflammatory influences. The endothelial cells of the BBB’s blood vessels fit together tightly (tight junctions) so substances such as disease-causing pathogens and toxins cannot pass out of the bloodstream into the brain.

When the BBB is compromised, neuroinflammation results. BBB crossover by the foreign molecules and cells leads to the activation of microglia. Microglia are the immune cells in the brain. Microglia regulate the pro-inflammatory activity of astrocytes, which are the most numerous cell type of the central nervous system (CNS) that perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow. In response to the foreign invasion, the microglia activated astrocytes destroy neurons and nerve processes and initiate scar formation.

The whole process from gut inflammation to neuroinflammation is schematically represented in the adjacent figure.

For further reading, see Leaky Gut, Leaky Brain?(Mark E. M. Obrenovich, 18 Oct 2018)

Some Causes of Leaky Gut

Common dietary practices and stress erode the intestinal barrier, but many factors can help rebuild or keep it intact.

Leaky gut has long been associated with celiac disease, an autoimmune disease where the ingestion of gluten leads to damage in the small intestine. Gluten is a protein found in most grains such as wheat, barley, and rye. But there are many other causes beyond celiac disease and gluten sensitivity.

As shown in the adjacent figure, factors that loosen the tight junctions and increase gut permeability: Western diets, saturated fatty acids, gluten, salt, alcohol and chemical additives present in processed food. Non-steroidal, anti-inflammatory drugs and stress may also damage the gastro-intestinal tract. Stress causes deterioration of the barrier by activation of the corticotropic-releasing factor (CRF) mast cell axis. [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)] With so many contributors, is it no wonder leaky gut is so common and inflammatory health issues are rampant. Some, not necessarily all, of the causes of leaky gut are discussed below.


Even without celiac disease, “It is known that gluten has a direct action on the mucosal barrier of the intestine [36]” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]

Gluten activates the protein zonulin. Zonulin is a protein that modulates the permeability of tight junctions between cells of the wall of the digestive tract. Thus zonulin loosens the tight junctions and makes the intestinal barrier more permeable. “The increased permeability of the intestinal barrier caused by gluten is particularly evident in individuals with non-celiac gluten sensitivity [36].” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]

“Gluten is resistant to digestion. Fragments of not completely digested gluten may be mistaken for a microbial molecule [36]” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)] “For this reason gluten fragments cause the release of zonulin and the opening of the tight junctions. In a similar way, when in the blood stream, gluten opens another barrier equipped with tight junctions: the blood-brain barrier (BBB). As gluten fragments pass through the intestinal wall, they are recognized as a foreign molecule, similar to a viral protein. Following the opening of the barrier, other undigested dietary molecules and microbes also pass through the barrier. All the invaders trigger an immune response. Antibodies against gluten and gliadin can cross react with some brain proteins and can promote neurodegenerative diseases [39,40]." [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]

Gut Dysbiosis

“What can damage the integrity of the intestinal barrier is first of all gut dysbiosis, often associated with the increase in the Firmicutes/Bacteroidetes ratio and the decrease in overall microbial diversity [19,20]. Firmicutes and Bacteroidetes are the most represented bacterial phyla in the intestine. Persistent dysbiosis leads to an increase in the Th17/Treg ratio and of the lipopolysaccharide LPS, and triggers intestinal inflammation. As a consequence, the tight junctions loosen and the barrier opens. What is in the lumen comes out and enters the blood stream: namely fragments of undigested food; microbes, pro-inflammatory cytokines such as interleukin 6; and endotoxins such as LPS, an endotoxin that is a marker of the translocation of gram-negative bacteria [47,48]. As a result, systemic endotoxemia, chronic systemic inflammation and chronic inflammatory diseases develop. Since intestinal dysbiosis depends primarily on our dietary habits and our life-style, we are the ones who cause intestinal inflammation, the opening of the intestinal barrier, and the metabolic and chronic diseases of our time. Among them it is possible to associate to gut dysbiosis the development of neurodegenerative diseases, which have an inflammatory basis.” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)] Beyond causing leaky gut, gut dysbiosis is further discussed below in the Gut Microbiome section.


“Chronic alcohol intake promotes bacterial overgrowth and gut dysbiosis [41]. It also alters the integrity of the intestinal barrier by decreasing the levels of the anti-microbial molecule REG3, thus favoring microbial access to the gut mucosa [42]…Moreover, alcohol interferes with the metabolism of fatty acids, proteins and carbohydrates, as it converts NAD+ into NADH, and is a pro-inflammatory molecule.” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019]

Glyphosate may have an impact on half of the species in the core human gut microbiome Source: Classification of the glyphosate target enzyme (5-enolpyruvylshikimate-3-phosphate synthase) for assessing sensitivity of organisms to the herbicide

Herbicides, insecticides, and pesticides introduce poisons into our bodies from the plants we eat, the animals we eat, the produce we touch, even the water we drink. While all those are problematic, glyphosate (brand name Roundup) is the most commonly used broad spectrum herbicide.

Numerous households use Roundup on their lawns. But the most common exposure comes from farmers who often spray crops with it for two reasons: (1) to control weeds, and (2) as a desiccant to aid with harvesting various crops. Glyphosate can also be found in the animals and the milk of animals who are fed the grains and beans which have been sprayed with it. Glyphosate has also been found to leach into drinking water sources.

Glyphosate kills off good gut bugs potentially resulting in dysbiosis. Glyphosate also enhances gluten sensitivity, which additionally breaks down the intestinal barrier, thus increasing leaky gut. {Source: Classification of the glyphosate target enzyme (5-enolpyruvylshikimate-3-phosphate synthase) for assessing sensitivity of organisms to the herbicide ](Lyydia Leinoa et al, 14 Nov 2020)

Additional reading on glyphosate and the gut microbiome:

Chemicals in Processed Foods

“Processed food may contain diverse chemicals added to food in order to improve its stability over time and its appeal to the consumer. The additives may be preservatives, artificial flavorings, colorants, emulsifiers, artificial sweeteners and/or antibiotics. All are deleterious for the human gut microbiota [35,43–46]. For example, dietary emulsifiers decrease the gut microbiota diversity, favor inflammation and reduce the thickness of the mucus layer. Non-nutrient sweeteners (stevia, aspartame and saccharin) have a bacteriostatic effect on gut microbiota. The intake of antibiotics, which may be present in processed food, decreases microbial diversity too, but in addition may cause resistance to antibiotics. An important problem is the addition to processed foods of components from other foods, such as lactose, sugar, whey proteins, gluten, lactose and casein. These added ingredients can represent an overload of particular foods and can create intolerances." [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]

Signs and Symptoms of Leaky Gut

Problems and imbalances in our gut can cause far more than just a stomach ache, they can be the root cause of many chronic health problems. Since the causes and symptoms are so diverse, pinpointing an issue as leaky gut is admittedly challenging.

Symptoms of leaky gut include:

  • Bloating and fluid retention
  • Diarrhea and constipation
  • Fatigue and chronic fatigue
  • Headaches, brain fog, memory loss, difficulty concentrating
  • Cravings for sugar or carbs
  • Poor immune system, Autoimmune diseases
  • Mood imbalances such as depression and anxiety
  • Skin issues – rashes, acne, eczema, rosacea
  • Arthritis, Joint pain and fibromyalgia
  • Thyroid conditions
  • Arthritis or joint pain
  • Cholesterol markers

Regarding that last bullet, cholesterol markers

The significant association between increased gut permeability and elevated serum HDL-cholesterol is consistent with the role of HDL as an acute phase reactant, and in this situation, potentially dysfunctional lipoprotein. This finding may have negative implications for the putative role of HDL as a cardio-protective lipoprotein. [Source: Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men(M D Robertson et al, Dec 2018)]


The connection between gastrointestinal inflammation or microbiome imbalances and cholesterol levels in the blood is a bit more complex, but it has been established that when gram negative bacteria from the gut produce an abundance of lipopolysaccharide (LPS), and this LPS slips through the gut barrier, being picked up in the blood stream, LDL cholesterol levels may rise in response to this increased toxic load coming from the gut [5, 6].
When this happens, seeing LDL cholesterol levels rise is actually a good sign that the body’s built-in defenses are responding to this inflammatory threat coming from the gut.
It is still a sign that an inflammatory imbalance of bacteria exists in the gut, however, and you may need to do further testing to assess how best to intervene when this has happened.

[Source: The Link Between Your Gut Health and Cholesterol(by VibrantWellness)]

Addressing a Leaky Gut

Eliminate damaging foods Gluten (even if tested negative for celiac disease), non-organic foods (pesticide treated, aka GMO), processed foods, alcohol, and whatever other foods you are individually sensitive to. Cut them out for at least three months and avoid in excess thereafter.

Reduce stress Stress hormones break down the tight junctions of the digestive tract. Take time to relax, stretch, do breathing exercises, meditate, practice mindfulness. Stress has numerous negative effects in the body beyond the gut. To read more, see Stress

Fast/Dietary restriction Food availability 24/7 is a recent phenomenon. For much of human history there were times of food paucity. As the ancestral gene, ApoE4s are especially well suited to food deprivation. The microbiota of the large intestine is especially dependent on fasting.

“Fasting for several days, fasting mimicking diet (FMD) [59], intermittent fasting, short term fasting, caloric restriction and time restricted feeding [60] are different fasting or food restriction plans that have been recently proposed to improve health. All improve the integrity of the intestinal barrier, induce a higher microbial diversity, and counteract intestinal inflammation [61–63]. [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity (Paolo Riccio and Rocco Rossano, 9 Nov 2019)]

Generate butyrate The short-chain fatty acid (SCFA) butyrate is a metabolite produced by intestinal bacteria through the fermentation of nondigestible polysaccharides (dietary fiber).

Butyrate holds numerous health benefits, one of which is keeping the gut lining healthy and functioning properly. "At the intestinal level, butyrate plays a regulatory role on the transepithelial fluid transport, ameliorates mucosal inflammation and oxidative status, reinforces the epithelial defense barrier, and modulates visceral sensitivity and intestinal motility." [Source: Potential beneficial effects of butyrate in intestinal and extraintestinal diseases(Roberto Berni Canani et al, 28 Mar 2011)] There is more discussion on butyrate beyond leaky gut below under the Gut Microbiome section.

Add collagen Such foods as bone broth, gelatin, and collagen powders can help mend a leaky gut. Also the body can produce its own collagen through such foods as eggs, citrus fruits, broccoli, sunflower seeds, and mushrooms. Collagen contains the amino acids glycine, proline, and hydroxyproline that are needed to repair and rebuild your gut lining. Supplemental collagen peptides can help to strengthen the gut barrier, making it less permeable. [Source: Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions(Qianru Chen et al, 22 Mar 2017)] Adding bone broth during a fast could doubly help repair a leaky gut, plus bone broth can help satisfy feelings of hunger during a fast.

Exercise Exercise benefits more than just muscles, it improves circulation, transport of oxygen, and helps promote diversity of gut microbes. [Source: Gut microbiota diversity is associated with cardiorespiratory fitness in post‐primary treatment breast cancer survivors(Stephen J. Carter et al, 14 Feb 2019)] For more info on the benefits of exercise see Exercise - Types, Lengths, and Benefits

Sleep Sleep is regenerative, it is a time of fasting, (discussed above as improving the integrity of the intestinal barrier) detoxification and repair. Ideally one’s bedtime should be 3-4 hours after the last meal, with no late night snacks. This gives the body a chance to direct its energy while sleeping to detoxification and autophagy (cellular housecleaning) not digestion. When the body is faced with having to choose between digestion and cellular cleansing, it will prioritize digestion thus neglecting the very important cleansing processes. For additional reading on sleep, see Sleep

Vitamin A+D

It has been recently shown that vitamin A improves the integrity of the intestinal barrier, even in the presence of intestinal inflammation and higher LPS level. It seems to counteract the action of LPS and to enhance the expression of tight junction proteins [78].
However, vitamin A is not sufficient. As reported in our previous review [25], vitamin A and vitamin D have synergistic anti-inflammatory effects and should be administered together. This is not surprising as they are both liposoluble and often present together in the same food. Their nuclear receptors cooperate if both vitamins are bound to them. Shared functions of vitamin A and vitamin D include the enhancement of tight junction proteins, the suppression of IFN-γ and IL-17, and the induction of regulatory T cells (Treg) [79]. Finally, vitamins A and D are effective against chronic inflammation and favor the stability of the intestinal barrier. Their action on microbiota is not direct as their nuclear receptors are expressed only by the host, not by the microbiota. Deficiency in vitamin D leads to disruption of the intestinal barrier, gut dysbiosis and intestinal inflammation [80].”

[Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019]


Many factors influence an individual’s microbiome Source: Chapter 4 - Gut Microbiome

The human body is host to a number of microbiomes: oral (ear, nose and throat), skin, lung, urinary tract, vagina, and the largest by far with 100 trillion microorganisms, the gut (the gastrointestinal tract, with the majority, approximately 70% , housed in the colon). Our bodies host far more microorganisms than cells. The gut microbiota, sometimes called gut flora, consist of such microorganisms as bacteria, fungi, viruses, protozoa, and archaea.

The “seeds” of our gut microbiome comes from the mother’s own intestinal microbiota. We get our first dose of microbes at birth while traveling through the birth canal. The rest come through bacteria from breastfeeding, At least that’s how humans did it for most of our history, until recent times with cesarian section births and canned baby formula. Evidence suggests that births by cesarean section impact a baby’s immune system. If facing a cesarean section birth, insist on a vaginal swab, also known as vaginal seeding, to transfer the vaginal flora to the newborn infant.

Microorganisms of the gut. Source: Chapter 4 - Gut Microbiome

For the vast majority of human history all humans were ApoEε4/4s. Also for most of human history, man ate what he could find. Man roamed from place to place in search of food influenced by the seasons, migration patterns, and growth cycles of plants. It was only in the last 100,000 years (recent in human evolutionary terms) that man jumped to the top of the food chain, before that time the human diet consisted of hunted small creatures, insects, and whatever plant based food that they could forage.

From the book, Sapiens: A Brief History of Humankind by Yuval Noah Harari, PhD, "The foragers’ secret of success, which protected them from starvation and malnutrition, was their varied diet. … Furthermore, by not being dependent on any single kind of food, they were less liable to suffer when one particular food source failed. … Ancient foragers also suffered less from infectious diseases." (pages 58-59, Kindle location 843- 853).

Through human history a mutualistic (beneficial to both parties) albeit complicated relationship evolved between man and his microbes. But our precious gut microbiome, the basis for healthy function of our nutritional, immune, hormonal, and neurological systems has been devastated with our modern sedentary, stressful, over-sanitized lives eating a limited, unvaried diet overrun with sugar and simple carbohydrates, devoid of fiber, and exposed to antibiotics, herbicides, pesticides, plastic wrapping, preservatives, additives and other unnatural exposures.

While mostly established by age 3, the microbiome is not static, there are many factors which impact its diversity and composition, such as age, diet, stress, and drugs.

Gut Eubiosis

When the intestinal microbial ecosystem is in balance, this is called eubiosis. “A healthy intestinal microbial ecosystem is balanced but flexible enough to tolerate the intrusion of potential pathogens … A healthy intestinal flora is essential to promote the health of the host, but the excessive growth of the bacterial population leads to a variety of harmful conditions.” (Source: Eubiosis and dysbiosis: the two sides of the microbiota(Valerio Iebba et al, 2016).

Gut Dybiosis

Consequences of intestinal dysbiosis. Dysbacteriosis of the colon. Image Credit: Timonina / Shutterstock Source:

Dysbiosis is when the “good” gut bugs no longer control the “bad" gut bugs and the bad bugs take over. Dysbiosis is associated with a number of negative health consequences.

Causes of gut dybiosis.

When there is an interruption in the balance of microbiota, it can lead to dysbiosis. There are many possible causes of this condition. A dietary change wherein there is an increased intake of sugar, protein, and food additives may lead to dysbiosis. The other causes include frequent antibiotic use, excessive alcohol consumption, frequent antacid use, accidental ingestion of pesticides or exposure to chemicals, chronic physical or psychological stress, previous parasitic or bacterial infection of the gastrointestinal tract, and a diet that is low in fiber.
Other causes include consuming new medications that can affect the gut flora, poor dental hygiene, anxiety, and unprotected sex that can expose the person to bacteria. Some studies have linked being formula fed and born via C-section, as some factors can change the type of strains of beneficial bacteria present in newborns. These factors can increase the risk of developing gut dysbiosis in later life. (Source: Preventing Dysbiosis(Angela Betsaida B. Laguipo, BSN, 8 Oct 2018)
Foods of the western diet feed bad bugs which can overtake the good bugs, but probiotic microorganisms and high fiber prebiotic foods that feed them make for happy good gut bugs.

Reestablishing Eubiosis Many therapeutic strategies have been developed to reestablish intestinal eubosis and new strategies are constantly being investigated, but the best known and most adopted therapeutic strategies are probiotics and prebiotics.

Probiotics are live microorganisms (good gut bugs) that are found in fermented products like yogurt, kimchi and sauerkraut. Not all fermented foods qualify as probiotic, there must be sufficient beneficial living bacteria that survive such that they’re found in the final food or beverage. Probiotics are also found in dietary supplements. The gut microbiome is dominated by two main groups of bacteria: Bacteroidetes and Firmicutes. The two bacteria commonly labeled as probiotics are Lactobacillus, which is in the Firmicutes group, and Bifidobacterium, a type of Actinobacteria. An important consideration when choosing to consume probiotics is to select a probiotic that will actually be helpful which means the microorganisms need to be able to survive stomach acid. For example, using a product that contains BC30. BC30 is a patented strain of probiotic bacteria designed for resilience. Studies have shown it can survive 100 times better than those found in yogurt and other probiotics.

Potential beneficial effects of butyrate in intestinal and extraintestinal diseases Source: The short chain fatty acid (SCFA) butyrate has many health benefits.

Prebiotics are food for the good gut bugs. Prebiotics are found in high-fiber foods. The fiber isn’t broken down by the digestive enzymes so it passes to the large intestine undigested where it is fermented by the gut bacteria. Inulin and oligosaccharides are also classified as prebiotics. The Western Diet, followed by so many, is low on fiber consumption. The average American eats about 16 grams of fiber per day, while the recommendation is 25 to 38 grams of fiber a day. (Source: Nutrition 101: Prebiotics, Probiotics and the Gut Microbiome(Allison Webster, PhD, RD, 17 Apr 2019)

When the gut metabolizes prebiotics, short chain fatty acids (SCFAs) like butyrate, acetate, and propionate are produced. As shown in the adjacent figure Butyrate has many health benefits, including: intestinal barrier fortification, ameliorating inflammation and oxidation, cell growth and differentiation, intestinal motility and visceral perception, immune regulation, and ion absorption.

Of particular interest to ApoE4s, researchers of this paper Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease( Marizzoni, Moira et al, 10 Nov 2020) found that high levels of butyrate was associated with less amyloid pathology in the brain.

Conversely to butyrate, the short chain fatty acid propionate in high levels may play a role in Alzheimer’s disease. This paper Propionate and Alzheimer’s Disease discusses propionate and the different mechanisms by which excess levels of propionate may lead to AD, such as hyperammonemia. Potential points for intervention are also discussed including this observation, “"Diet may be a target for intervention, as diet could directly impact one’s intake of propionate. Furthermore, diet can impact the levels of the Bacteroidetes phylum. In comparison to non-Western diets, a Western diet, which consists of high protein and fat, was found to increase the levels of Bacteroidetes or Bacteroides in several studies (Filippo et al., 2010; Wu et al., 2011; David et al., 2013; Yeagle, 2015; Heinritz et al., 2016). Furthermore, keeping in mind that propionate is used as a food preservative, a diet that features low consumption of foods with propionate may be another viable intervention."

Another subject of interest when discussing the gut microbiome is trimethylamine N-oxide abbreviated TMAO. TMAO is a metabolite produced when gut bacteria digest choline, lecithin and carnitine, nutrients that are abundant in animal products. The saturated fat in animal products used to be singled out as raising the risk of heart disease, but these recent findings on the effects of TMAO have clouded the situation. Studies have found high blood levels of TMAO to be associated with a higher risk for both cardiovascular disease and all cause mortality (early death from any cause).

Some research papers/articles of interest related to the microbiome

The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology(Andrina Rutsch et al, 10 Dec 2020)

Gut Microbiota Resilience: Definition, Link to Health and Strategies for Intervention(Shaillay Kumar Dogra et al, 15 Sep 2020)

Microbiota modulate sympathetic neurons via a gut–brain circuit(Paul A. Muller et al, 8 Jul 2020)

Gut Microbiota during Dietary Restrictions: New Insights in Non-Communicable Diseases(Emanuele Rinninella et al,28 Jul 2020)

Rapid improvement in Alzheimer’s disease symptoms following fecal microbiota transplantation: a case report(Sabine Hazan, 30 Jun 2020)

The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders(Madushani Herath et al, 28 May 2020)

Crosstalk Between the Gut Microbiome and Bioactive Lipids: Therapeutic Targets in Cognitive Frailty(Liliana C. Baptista et al, 11 Mar 2020)

The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication(Ygor Parladore Silva et al, 31 Jan 2020)

Dynamics of Human Gut Microbiota and Short-Chain Fatty Acids in Response to Dietary Interventions with Three Fermentable Fibers(Nielson T. Baxter et al, 1 Mar 2019)

Gut microbiota in neurodegenerative disorders(Suparna Roy Sarkar and Sugato Banerjee, Mar 2019)

Do gut bacteria make a second home in our brains?(Kelly Servick 9 Nov 2018)

Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice(Stephanie M. Matt et al, 14 Aug 2018)

Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases(Lindsay Joy Spielman et al, 14 Aug 2018)

The Human Microbiota in Health and Disease(Baohong Wang et al, Feb 2017)

Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health?(Megan W.Bourassa et al, Jun 2016)

The vagus nerve extends from the brain to the gut. Source: Vagus Nerve

Minireview: Gut Microbiota: The Neglected Endocrine Organ(Gerard Clarke et al, 3 Jun 2014)

Impacts of Plant-Based Foods in Ancestral Hominin Diets on the Metabolism and Function of Gut Microbiota In Vitro(Gary S. Frost et al, May 2014)

Resistant Starch: Promise for Improving Human Health(Diane F. Birt et al Nov 2013)


The Vagus Nerve is what connects the gut to the brain. The vagus nerve is one of the longest nerves in the body extending from the brain to the gut. Signals are sent through the nerve in both directions: from the gut to the brain and from the brain to the gut.

For information on the Vagus Nerve, including how to tap into the Vagus Nerve for healing purposes, see Vagus Nerve

A Deeper Dive into the science

While gut issues promote a long list of health concerns, the three primary health conditions that effect ApoE4s are: Alzheimer’s Disease, Cardiovascular Disease, and shortened longevity. The following are some research findings of how gut health affects those conditions.

Alzheimer’s Disease and gut health

Holding one or two ApoEε4 alleles places that individual at higher risk for Alzheimer's Disease. Some of the research supporting the importance of gut health with respect to Alzheimer's Disease:

The Microbiome and Alzheimer’s Disease: Potential and Limitations of Prebiotic, Synbiotic, and Probiotic Formulations (Karan Arora et al, 14 Dec 2020)

"The findings in this review suggest that probiotics, prebiotics or synbiotics have potential as novel biological prophylactics in treatment of AD, due to their anti-inflammatory and antioxidant properties, their ability to improve cognition and metabolic activity, as well as their capacity of producing essential metabolites for gut and brain barrier permeability."

Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease (M Marizzoni et al, 10 Nov 20) Link goes to the abstract only, the full paper is behind a paywall, however this article addresses this research: Link between Alzheimer's disease and gut microbiota is confirmed’ by University of Geneva(MedicalXpress, 13 Nov 2020) And from this article in quoting the primary researcher

"Our results are indisputable: certain bacterial products of the intestinal microbiota are correlated with the quantity of amyloid plaques in the brain," explains Moira Marizzoni. "Indeed, high blood levels of lipopolysaccharides and certain short-chain fatty acids (acetate and valerate) were associated with both large amyloid deposits in the brain. Conversely, high levels of another short-chain fatty acid, butyrate, were associated with less amyloid pathology." (larger, bold font added to draw attention to strong wording of the correlation.)

Target Dysbiosis of Gut Microbes as a Future Therapeutic Manipulation in Alzheimer’s Disease(Feiqi Zhu, et al, 6 Oct 2020) Highlights from this paper:

  • The gut microbes communicate with the brain by several regulating pathways via the gut–brain axis involved in the physiological activities to maintain homeostasis of the human body. The imbalance of gut microbiota is associated with AD
  • The gut dysbiosis caused by several factors may aggravate neuroinflammation and other pathologies promoting the development and progression of AD.
  • Targeting the gut dysbiosis or remodeling the gut microbiota might be a novel strategy for AD therapy.

Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia(Zhenhuang Zhuang, et al, 2 Oct 2020) From conclusions section:

These data for the first time provide evidence of potential causal links between gut microbiome and AD [Alzheimer’s Disease], MDD [Major Depressive Disorder], and SCZ [schizophrenia]. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.

Gut mycobiome and its interaction with diet, gut bacteria and alzheimer's disease markers in subjects with mild cognitive impairment: A pilot study(Ravinder Nagpal et al, 27 Aug 2020)

Specific fungi in the gut associated with a higher risk of Alzheimer's disease and found in people with mild cognitive impairment (MCI) can be altered in a beneficial manner by eating a modified Mediterranean diet, researchers have found.

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice(Malena dos Santos Guilherme et al, 31 Aug 2020)

We demonstrate that ATIs, [wheat amylase trypsin inhibitors] with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress(Manoj Govindarajulu et al, 12 Aug 2020)

Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer’s model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. …Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease(Tiantian Guo et al, 16 Jul 2020)

Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota.

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease(Hussein N. Yassine and Caleb E. Finch, 10 Jun 2020)

The APOE gene alleles modify human aging and the response to the diet at many levels with diverse pleotropic effects from gut to brain. To understand the interactions of APOE isoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction

The Links Between the Gut Microbiome, Aging, Modern Lifestyle and Alzheimer's Disease(Sholpan Askarova et al, 18 Mar 2020)

Gut microbiome is a community of microorganisms in the gastrointestinal tract. These bacteria have a tremendous impact on the human physiology in healthy individuals and during an illness. Intestinal microbiome can influence one's health either directly by secreting biologically active substances such as vitamins, essential amino acids, lipids et cetera or indirectly by modulating metabolic processes and the immune system. In recent years considerable information has been accumulated on the relationship between gut microbiome and brain functions. Moreover, significant quantitative and qualitative changes of gut microbiome have been reported in patients with Alzheimer's disease. On the other hand, gut microbiome is highly sensitive to negative external lifestyle aspects, such as diet, sleep deprivation, circadian rhythm disturbance, chronic noise, and sedentary behavior, which are also considered as important risk factors for the development of sporadic Alzheimer's disease. In this regard, this review is focused on analyzing the links between gut microbiome, modern lifestyle, aging, and Alzheimer's disease.

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication(Heather Hulme et al, 11 Mar 2020)

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen–free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.

Brain-Gut-Microbiota Axis in Alzheimer’s Disease(Karol Kowalski and Agata Mulak, Jan 2019)

A growing body of experimental and clinical data confirms a key role of gut dysbiosis and gut microbiota-host interactions in neurodegeneration. The convergence of gut-derived inflammatory response together with aging and poor diet in the elderly contribute to the pathogenesis of AD. Modification of the gut microbiota composition by food-based therapy or by probiotic supplementation may create new preventive and therapeutic options in AD.

This paper includes a two tables citing (1) Current Data From Animal Studies on the Role of Microbiota in the Pathogenesis of Alzheimer’s Disease, and (2) Recent Clinical Data on the Role of Microbiota in the Pathogenesis of Alzheimer’s Disease

China Approves New Alzheimer’s Disease Drug: Here’s What to Know(by Gigen Mammoser, healthline, 10 Nov 2019)

  • China has approved a new drug for Alzheimer’s disease.
  • But many experts remain skeptical without more evidence and phase 3 trials are ongoing.
  • The drug works to alter bacteria in the gut microbiome to affect changes in the brain.

The drug, Oligomannate, is derived from marine brown algae, a type of seaweed

Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)

Gut dysbiosis, as a consequence of Western diets, leads to intestinal inflammation and a leaky intestinal barrier. The efflux of undigested food, microbes, endotoxins, as well as immune-competent cells and molecules, causes chronic systemic inflammation. Opening of the blood-brain barrier may trigger microglia and astrocytes and set up neuroinflammation. We suggest that what determines the organ specificity of the autoimmune-inflammatory process may depend on food antigens resembling proteins of the organ being attacked. This applies to the brain and neuroinflammatory diseases, as to other organs and other diseases, including cancer. Understanding the cooperation between microbiota and undigested food in inflammatory diseases may clarify organ specificity, allow the setting up of adequate experimental models of disease and develop targeted dietary interventions.

Neuroinflammation and the Gut Microbiota: Possible Alternative Therapeutic Targets to Counteract Alzheimer’s Disease?(Milica Cerovic et al, 18 Oct 2019)

Neuroinflammation is re-emerging as determinant in the neuropathological process of AD. A new theory, still in its infancy, highlights the role of gut microbiota (GM) in the control of brain development, but also in the onset and progression of neurodegenerative diseases.

APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer’s disease pathophysiology(Tam T. T. Tran et al, 8 Apr 2019)

Together, these findings indicate that APOE genotype is associated with specific gut microbiome profiles in both humans and APOE‐TR mice. This suggests that the gut microbiome is worth further investigation as a potential target to mitigate the deleterious impact of the APOE4 allele on cognitive decline and the prevention of AD.

The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer’s Disease—a Critical Review(Marta Sochocka et al, 23 June 2018)

One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the “second brain” and be responsible for neurodegenerative disorders like Alzheimer’s disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD.

Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota(T. Harach et al, 8 Feb 2017)

Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease(Francesca Pistollato et al, Oct 2016)

It has been hypothesized that alterations in the composition of the gut microbiota might be associated with the onset of certain human pathologies, such as Alzheimer disease, a neurodegenerative syndrome associated with cerebral accumulation of amyloid-β fibrils. It has been shown that bacteria populating the gut microbiota can release significant amounts of amyloids and lipopolysaccharides, which might play a role in the modulation of signaling pathways and the production of proinflammatory cytokines related to the pathogenesis of Alzheimer disease. Additionally, nutrients have been shown to affect the composition of the gut microbiota as well as the formation and aggregation of cerebral amyloid-β. This suggests that modulating the gut microbiome and amyloidogenesis through specific nutritional interventions might prove to be an effective strategy to prevent or reduce the risk of Alzheimer disease. This review examines the possible role of the gut in the dissemination of amyloids, the role of the gut microbiota in the regulation of the gut–brain axis, the potential amyloidogenic properties of gut bacteria, and the possible impact of nutrients on modulation of microbiota composition and amyloid formation in relation to the pathogenesis of Alzheimer disease.

Cardiovascular implications

Low microbiome diversity correlates with higher arterial stiffness Source: Eur Heart J, Volume 39, Issue 25, 01 July 2018, Pages 2390–2397,

Role of Gut Microbiota and Their Metabolites on Atherosclerosis, Hypertension and Human Blood Platelet Function: A Review(Asim K. Duttaroy, 3 Jan 2021)

Abstract: Emerging data have demonstrated a strong association between the gut microbiota and the development of cardiovascular disease (CVD) risk factors such as atherosclerosis, inflammation, obesity, insulin resistance, platelet hyperactivity, and plasma lipid abnormalities. Several studies in humans and animal models have demonstrated an association between gut microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids, and bile acid metabolites (amino acid breakdown products) with CVD. Human blood platelets are a critical contributor to the hemostatic process. Besides, these blood cells play a crucial role in developing atherosclerosis and, finally, contribute to cardiac events. Since the TMAO, and other metabolites of the gut microbiota, are asociated with platelet hyperactivity, lipid disorders, and oxidative stress, the diet-gut microbiota interactions have become an important research area in the cardiovascular field. The gut microbiota and their metabolites may be targeted for the therapeutic benefit of CVD from a clinical perspective. This review’s main aim is to highlight the complex interactions between microbiota, their metabolites, and several CVD risk factors.

Gut microbiota‐derived trimethylamine N‐oxide is associated with poor prognosis in patients with heart failure(Wensheng Li et al, 19 Oct 2020)

Conclusions: Elevated plasma TMAO level in patients with heart failure is associated with poorer prognoses. This association is only partially mediated by renal dysfunction.

Machine Learning Strategy for Gut Microbiome-Based Diagnostic Screening of Cardiovascular Disease(Sachin Aryal et al, 10 Sep 2020) Paper behind paywall but from abstract:

Overall, our study is the first to identify dysbiosis of gut microbiota in CVD patients as a group and apply this knowledge to develop a gut microbiome–based ML approach for diagnostic screening of CVD.

Also, in reporting on this paper, from this article Gut microbiome data may be helpful in routine screening of cardiovascular disease(by American Heart Association" ScienceDaily. 10 Sep 2020):

Previous studies have found the human gut microbiome, bacteria in the gastrointestinal tract, is associated with cardiovascular disease (CVD). This study used machine learning to analyze data from nearly 1,000 stool samples from people with and without CVD. Results show potential for developing a convenient, new diagnostic approach for CVD.

Sleep fragmentation increases blood pressure and is associated with alterations in the gut microbiome and fecal metabolome in rats(Katherine A. Maki et al, 13 Jul 2020)

The gut microbiota, via the production of metabolites entering the circulation, plays a role in blood pressure regulation. Blood pressure is also affected by the characteristics of sleep. To date, no studies have examined relationships among the gut microbiota/metabolites, blood pressure, and sleep….These data reveal associations between sleep fragmentation, mean arterial pressure, and the gut microbiome/fecal metabolome and provide insight to links between disrupted sleep and cardiovascular pathology.

MtcB, a member of the MttB superfamily from the human gut acetogen Eubacterium limosum, is a cobalamin-dependent carnitine demethylase(Duncan J. Kountz et al, 22 Jun 2020)

The conversion of L-carnitine and its derivative g-butyrobetaine to trimethylamine by the gut microbiome has been linked to cardiovascular disease. The activities of MtcB and related proteins in E. limosum might demethylate proatherogenic quaternary amines and contribute to the perceived health benefits of this human gut symbiont.

From the abstract (full paper behind paywall) Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. … Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.

Since that paper is behind a paywall, this article Why do arteries age? Study explores link to gut bacteria, diet(by University of Colorado at Boulder, ScienceDaily, 1 July 2020) addresses the research:

Eat a slab of steak and your resident gut bacteria get to work immediately to break it down. But new research shows that a metabolic byproduct, called TMAO, produced in the process can be harmful to the lining of arteries, making them age faster.

Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis(Poshen B. Chen et al, 15 Jun 2020)

The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth.

Since that paper is behind a paywall, from this article Molecules that reduce 'bad' gut bacteria reverse narrowing of arteries in animal study(by Scripps Research Institute, ScienceDaily 15 Jun 2020):

Scientists at Scripps Research have developed molecules that can remodel the bacterial population of intestines to a healthier state and they have shown -- through experiments in mice -- that this reduces cholesterol levels and strongly inhibits the thickened-artery condition known as atherosclerosis.

Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?(Christopher Papandreou et al, 7 May 2020)

Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO. Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous studies questioned the role of TMAO in these diseases. Several animal studies reported neutral or even beneficial effects of TMAO or its precursors in cardiovascular disease model systems, supporting the clinically proven beneficial effects of its precursor, L-carnitine, or a sea-food rich diet (naturally containing TMAO) on cardiometabolic health. In this review, we summarize recent preclinical and epidemiological evidence on the effects of TMAO, in order to shed some light on the role of TMAO in cardiometabolic diseases, particularly as related to the microbiome.

The Microbiota–Gut–Brain Axis–Heart Shunt Part II: Prosaic Foods and the Brain–Heart Connection in Alzheimer Disease(Mark Obrenovich et al, 31 Mar 2020) This paper explores how the French with their well-known consumption of largely fatty, saturated, rich, and unhealthy foods have less heart disease and less Alzheimer’s Disease. These researchers suggest that bugs could act as drugs or psychobiotics.

There is a strong cerebrovascular component to brain aging, Alzheimer disease, and vascular dementia. Foods, common drugs, and the polyphenolic compounds contained in wine modulate health both directly and through the gut microbiota. This observation and novel findings centered on nutrition, biochemistry, and metabolism, as well as the newer insights we gain into the microbiota-gut-brain axis, now lead us to propose a shunt to this classic triad, which involves the heart and cerebrovascular systems. The French paradox and prosaic foods, as they relate to the microbiota-gut-brain axis and neurodegenerative diseases, are discussed in this manuscript, which is the second part of a two-part series of concept papers addressing the notion that the microbiota and host liver metabolism all play roles in brain and heart health.

Long-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk(Yoriko Heianza RD, PhDa et al, 25 Feb 2020)

Long-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.

The full paper is behind a paywall, however, from this article Plant-based diets improve heart health via the gut microbiome(by Dr. Liji Thomas, MD, Medical News 17 Feb 2020):

A new study published in February 2020 in the Journal of the American College of Cardiology reports that a reduced intake of animal-based foods and a diet based on plants can result in a lower risk of coronary heart disease (CHD) by influencing the gut microbiome pattern to favor beneficial species.

Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice(Vienna E. Brunt et al, 4 Feb 2019) Key points

  • Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases.
  • To investigate whether age‐related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad‐spectrum, poorly‐absorbed antibiotics in drinking water for 3–4 weeks.
  • In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation.
  • To provide insight into age‐related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine N‐oxide.
  • The results of the present study provide the first proof‐of‐concept evidence that the gut microbiome is an important mediator of age‐related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases.

Gut microbial diversity is associated with lower arterial stiffness in women(Cristina Menni et al, 1 Jul 2018)

Gut microbiome diversity is inversely associated with arterial stiffness in women. The effect of gut microbiome composition on PWV is only minimally mediated by MetS. This first human observation linking the gut microbiome to arterial stiffness suggests that targeting the microbiome may be a way to treat arterial ageing.


Relationship between Diet, Microbiota, and Healthy Aging(Elisa Sanchez-Morate, et al 14 Aug 2020)

Due to medical advances and lifestyle changes, population life expectancy has increased. For this reason, it is important to achieve healthy aging by reducing the risk factors causing damage and pathologies associated with age. Through nutrition, one of the pillars of health, we are able to modify these factors through modulation of the intestinal microbiota. The Mediterranean and Oriental diets are proof of this, as well as the components present in them, such as fiber and polyphenols. These generate beneficial effects on the body thanks, in part, to their interaction with intestinal bacteria. Likewise, the low consumption of products with high fat content favors the state of the microbiota, contributing to the maintenance of good health.

The predictive power of the microbiome exceeds that of genome-wide association studies in the discrimination of complex human disease(Braden T Tierney et al, 2 Jan 2020)

Over the past decade, studies of the human genome and microbiome have deepened our understanding of the connections between human genes, environments, microbes, and disease. For example, the sheer number of indicators of the microbiome and human genetic common variants associated with disease has been immense, but clinical utility has been elusive. Here, we compared the predictive capabilities of the human microbiome versus human genomic common variants across 13 common diseases. We concluded that microbiomic indicators outperform human genetics in predicting host phenotype (overall Microbiome-Association-Study [MAS] area under the curve [AUC] = 0.79 [SE = 0.03], overall Genome-Wide-Association-Study [GWAS] AUC = 0.67 [SE = 0.02]). Our results, while preliminary and focused on a subset of the totality of disease, demonstrate the relative predictive ability of the microbiome, indicating that it may outperform human genetics in discriminating human disease cases and controls. They additionally motivate the need for population-level microbiome sequencing resources, akin to the UK Biobank, to further improve and reproduce metagenomic models of disease.

The Gut Microbiota of Healthy Aged Chinese Is Similar to That of the Healthy Young(Gaorui Bian et al, 27 Sept 2017)

Taken together, the present findings suggest that the microbiota of the healthy aged in this cross-sectional study differ little from that of the healthy young in the same population, although the minor variations that do exist depend upon the comparison cohort.