The gut being central to health and disease is a concept that needs revisiting from time to time. Despite the tsunami of studies corroborating this simple point (good enough to win the Nobel Prize in Medicine in 1908,) I still run into people who find it hard to believe that the answer to their health problems lies in their diet, how food is processed in their gut, the detoxification-immune function therein, and the brain-gut connection. This issue revisits some of the references that prove those points, while the attached blog comments on the fact that good ideas are always simple, while complicated ones often reflect a poor understanding of the whole. H. Rodier, MD.
Gut cell metabolism shapes the microbiome[1]
The food we eat determines the health of our gut bacteria, which in turn helps us with the food we eat. If these functions are optimized our immune/detoxification system works best.
“Gut microbes are key partners in host defense against potential pathogens. This might be achieved through cross-talk between gut bacteria, epithelial cells lining the gut (colonocytes), and immune cells. Part of this cross-talk involves metabolites derived from the bacteria, such as the short-chain fatty acid butyrate… [which]instructs colonocytes to consume oxygen through the β-oxidation metabolic pathway and consequently protects the host against the expansion of potentially pathogenic bacteria that can lead to inflammatory bowel diseases.”
Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion[2]
Our gut bacteria controls how we metabolize in the gut. This is why people process calories differently, depending on what kind of gut flora they have. Good bacteria enhance optimal use of caloric intake, and keep bad bacteria from overgrowing. It’s all about how we fuel each cell of our body. Whether we are talking about brain cells, heart cells, or bone cells they all need Energy & Information to work, just like our engines. Hence, how important it is that we eat good food to keep our good bacteria happy; then, they will work for you. Antibiotics inhibit all the above, and cause key nutrients, like fatty acids to go missing. Without them we are more likely to grow inflamed and oxidized.
“Normally, the lumen of the colon lacks oxygen. Fastidiously anaerobic butyrate-producing bacteria thrive in the colon; by ablating these organisms, antibiotic treatment removes butyrate… the loss of [which] deranges metabolic signaling in gut. This induces nitric oxidase to generate nitrate in the lumen and disables β-oxidation in epithelial cells that would otherwise mop up stray oxygen before it enters the colon. Simultaneously, regulatory T cells retreat, and inflammation is unchecked, which contributes yet more oxygen species to the colon. Then, facultative aerobic pathogens, such as Escherichia coli and Salmonella enterica, can take advantage of the altered environment and outgrow any antibiotic-crippled and benign anaerobes.”
The microbiota maintains oxygen balance in the gut[3]
Our gut flora keeps all gases in the intestines within proper levels, including oxygen. When we have an overgrowth of bad bacteria we end up with an imbalance of gases (think of bloating) that can be very uncomfortable. Trapped gases cause the small intestine to stretch excessively, causing significant pain. This is often the case when imaging of the gut yields no reason for a patient’s abdominal discomfort.
Organoids reveal clues to Gut-Brain communication[4]
What we feel and think have a significant effect on all the above functions, and vice versa. The serotonin drugs we use to treat patients with depression have most if their effect in the gut.
“Enterochromaffin cells in gut send neurotransmitters signals to brain (90% of serotonin in the body comes from them) about metabolic, inflammatory, and environmental problems.”
Seasonal change in the gut[5]
Patients often ask me why their symptoms come and go for no rhyme or reason. The answer lies in the vast universe of thousands of species that come and go within our gut. Think of an ocean calm as a teapot. Suddenly, a storm comes around generating huge waves. Such are the violent fluctuations of quadrillions of organisms in the gut. As they wax and wane they produce “metabolites,” which can leak into our circulation, especially in people with “leaky gut.” These metabolites may cause inflammatory, and toxic symptoms all over our body.
“We live in a dynamic environment where diet, weather, social interactions, lifestyles, and a host of other factors change on a regular basis. Consequently, the microbial composition of even a healthy person’s gut is subject to natural variations; however, not much is known about these variations… Seasonal changes in the gut microbiome of the Hadza population, a hunter-gatherer community residing near Lake Eyasi in Tanzania, [are due to] seasonal changes in diet, activity, and the external environment, thereby maintaining a healthy gut.”
Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells[6]
Another important micronutrient is tryptophan, the amino acid needed to synthesize serotonin. Like all foods, it cannot help us unless we have the right kind of bacteria in the gut. A corollary of this is that any food sensitivity, or allergy, is due to a deficiency of the gut bacteria that governs the processing of said food. Thus, the “proof of the pudding is in the eating.” Never accept the results of food allergy testing UNLESS you have addressed the quality and quantity of your good bacteria in the gut.
“A particular species of probiotic bacteria, Lactobacillus reuteri, induces [our immune system.] This does not occur by stimulating the immune system directly. Instead, L. reuteri generates a specific derivative of dietary tryptophan that promotes differentiation of DP IEL precursors. These findings underscore the delicate interplay between benign bacteria, diet, and gut health.”
Rosacea linked with GI problems[7]
The above problems tend to show up first on our skin. Topical treatment only addresses symptoms. Practically all patients with skin problems have gastrointestinal issues.
Chronic gum inflammation may be associated with higher risk of Alzheimer’s disease[8]
The gums are also a reflection of what is going on at the cellular level, even in our brain neurons.
“Chronic gum inflammation may be linked to ‘an increased risk of developing Alzheimer’s disease.’ Investigators ‘found no overall link between periodontitis and Alzheimer’s, but people who had’ periodontitis ‘for 10 or more years were 70 percent more likely than people without periodontitis to develop Alzheimer’s disease’.”
More on the brain-gut connection
Microbiota-Gut-Brain Axis: Modulator of Host Metabolism and Appetite[9]
This article puts together the concepts mentioned above. After all, Integrative Health tries to put Humpty-Dumpty back together again, especially after you have been to many specialists who act as if your symptoms are totally unrelated.
“The gut harbors an enormous diversity of microbes that are essential for the maintenance of homeostasis in health and disease. A growing body of evidence supports the role of this microbiota in influencing host appetite and food intake. Individual species within the gut microbiota are under selective pressure arising from nutrients available and other bacterial species present. Each bacterial species within the gut aims to increase its own fitness, habitat, and survival via specific fermentation of dietary nutrients and secretion of metabolites, many of which can influence host appetite and eating behavior by directly affecting nutrient sensing and appetite and satiety-regulating systems. These include microbiota-produced neuroactives and short-chain fatty acids. In addition, the gut microbiota is able to manipulate intestinal barrier function, interact with bile acid metabolism, modulate the immune system, and influence host antigen production, thus indirectly affecting eating behavior. A growing body of evidence indicates that there is a crucial role for the microbiota in regulating different aspects of eating-related behavior, as well as behavioral comorbidities of eating and metabolic disorders. The importance of intestinal microbiota composition has now been shown in obesity, anorexia nervosa, and forms of severe acute malnutrition. Understanding the mechanisms in which the gut microbiota can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic strategies.”
Check out the articles below; they highlight a very important reason why a lot of patients are depressed, and slowly plant the seeds that lead Disease.
The Inflammatory Potential of the Diet Is Associated with Depressive Symptoms in Different Subgroups of the General Population[10]
Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis[11]
Inflammatory Dietary Pattern Linked to Brain Aging[12]
“Researchers believe they have uncovered a key piece of the puzzle in the connection between diet and dementia. They linked a specific dietary pattern to blood markers of inflammation. In addition, they showed that in elderly adults who followed such a dietary pattern, brain gray matter volume was less, and they had worse visuospatial cognitive function. We found that people who consume less omega 3, less calcium, vitamin E, vitamin D, and vitamin B5 and B2 have more inflammatory biomarkers,” study investigator Yian Gu, PhD, Columbia University and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York City, told Medscape Medical News. An inflammatory dietary pattern, said Dr. Gu, ‘is bad for both the brain and cognition.’
“Evidence cited by Dr. Gu suggests that dietary factors such as fish, nuts, omega-3 polyunsaturated fatty acids, and folate, as well Mediterranean-type diets, are associated with lower risk for Alzheimer’s disease (AD) and better brain health in the elderly. Other evidence, she said, shows that many foods and nutrients modulate inflammatory processes. Other studies have linked chronic inflammation to an increased risk for AD. Dr. Gu’s group previously showed an association between increased C-reactive protein (CRP) and interleukin-6 (IL6) levels and worse cognition and smaller brain volumes. But none of this research addressed whether diet affects brain and cognitive health by modulating inflammation. ‘No study has formally tested whether the relationship of diet with cognition, or with the brain, is actually because of inflammation,’ said Dr. Gu.
“The new cross-sectional study included 330 elderly adults from the Washington Heights–Inwood Community Aging Project imaging study. In these participants, researchers carried out structural MRI scans and measured levels of the inflammatory biomarkers CRP and IL6. Study participants completed a 61-item food frequency questionnaire that asked about nutrient intake during the past year. From this information, the researchers used a statistical model to create the inflammation-related nutrient pattern (INP). ‘The INP is basically a linear combination of 24 nutrients, each with a different weight on the INP,’ said Dr. Gu. ‘For example, omega-3 is negatively ‘loaded’ – which is similar to ‘correlated’ – on this pattern. Lower consumption of omega-3 will contribute to a higher INP score’.”
“Study participants also underwent neuropsychological testing that assessed memory, language, executive speed, and visuospatial function. From these test scores, the researchers calculated a composite mean cognition score for each participant. The study showed that the INP was positively correlated with CRP level (P = .009) and IL6 level (P < .0001). Those with fewer years of education had a relatively high INP. The INP was higher for African Americans (P < .0001) and Hispanics (P = .003) compared to whites. The analysis uncovered a significant association between INP and visuospatial function (P = .015) and total gray matter volume (P = .002) after adjusting for age, sex, race/ethnicity, APOE4 status, calorie intake, body mass index, and vascular comorbidity. The researchers determined that having a smaller brain gray matter volume might help explain why those who consume more inflammatory nutrients have worse visuospatial cognition.”
“This study is important because ‘now you have a linkage to measurable biological differences,’ said Keith Fargo, PhD, director of scientific programs at the Alzheimer’s Association. ‘If your cognition is poor, we know something has to be going on. But it’s sort of a black box; it’s not clear what’s going on. Now, though, you can measure the level of these proteins in the body’. These new findings suggest that interventions that decrease inflammatory markers may be helpful. ‘It gives us some ideas of what pathways might be involved,” said Dr. Fargo. Once that is known, it may be possible to intervene, not just through a healthier diet but perhaps also with medications. ‘At least, there may be some targets to work with,’ said Dr. Fargo. ‘It is possible the study’s observations are not directly linked to diet,’ said Dr. Knopman. ‘They could be due to the socioeconomic context of those diets that reflect a lifelong exposure to either poor or better health, which could in turn affect brain volume and cognition’.”
Sure, they cover their derriere with a disclaimer at the end, but, we have had hundreds of studies associating brain inflammation to diet, especially when the Microbiome is unbalanced.
Are Some Psychiatric Disorders a pH Problem?[13]
Many of my patients worry their pH is critical to their health. It is true, but some take it a bit far, eschewing some acidic foods like rice. Remember that the proof of the pudding is in the eating—our gut flora is the ultimate arbiter of how food affects us. And, don’t forget your kidneys—they take care of pH fluctuations. Consequently, pH issues are rare if you eat a plant-based diet, and minimize processed foods. Then, you may METABOLIZE well, which is what your pH really reflects—Energy and Information, or the electrical potential of your cells. Having cleared that issue, read below how an acidic pH can mess with your brain.
“Sometimes our brains are on acid—literally. A main source of these temporary surges is the carbon dioxide that is constantly released as the brain breaks down sugar to generate energy, which subsequently turns into acid. Yet the chemistry in a healthy human brain tends to be relatively neutral, because standard processes including respiration—which expels carbon dioxide—help maintain the status quo. Any fleeting acidity spikes usually go unnoticed. But a growing body of work has suggested that for some people, even slight changes in this balance may be linked with certain psychiatric conditions including panic disorders. New findings this month provide additional evidence that such links are real—and suggest they may extend to schizophrenia and bipolar disorder.
There were earlier hints that this was the case: Post-mortem studies of dozens of human brains revealed lower pH (higher acidity levels) in patients with schizophrenia and bipolar disorder. Multiple studies in the past few decades have found that when people with panic disorders are exposed to air with a higher-than-normal concentration of carbon dioxide—which can combine with water in the body to form carbonic acid—they are more likely to experience panic attacks than healthy individuals are. Other research has revealed that the brains of people with panic disorders produce elevated levels of lactate—an acidic source of fuel that is constantly produced and consumed in the energy-hungry brain. Yet despite those initial clues, researchers continued to puzzle over if the increased acidity seen in schizophrenia and bipolar patients was truly disorder-related—or the result of other factors, such as a person’s history of antipsychotic drug use or condition just before death. For example, ‘If you’re dying slowly, there would be a longer period where there’s a greater chance that you would have low oxygen levels and that’s going to change your metabolism,’ explains William Regenold, a psychiatrist and professor at the University of Maryland. During a prolonged death, he explains, the body and brain begin to rely more heavily on an oxygen-independent pathway to produce energy. This can lead to higher-than normal lactate levels that subsequently decrease pH.
“Such questions are why Tsuyoshi Miyakawa, a neuroscientist at Fujita Health University in Japan and his colleagues recently decided to scour the 10 existing datasets from post-mortem brains of over 400 patients with either schizophrenia or bipolar disorder. Some prior studies did not bother to focus on acidity because researchers assumed the lower pH was the result of extraneous factors, Miyakawa says. In their new analysis, however, he and his team tried to test each of the leading theories around the disorder-acidity connection. First, they controlled for potential confounding factors such as a history of antipsychotic medication use and age at death. As they had suspected, brain pH levels in individuals with schizophrenia and bipolar disorder were significantly lower than in healthy controls. The team also examined five mouse models—rodents with mutations in genes associated with these conditions—and found similar results: The pH levels in the brains of these mice (which were free of antipsychotic drugs) were consistently lower, and their lactate levels higher, than those in comparable healthy animals. What’s more, the researchers had euthanized all the mice in the same way—which suggests the pH differences cannot be explained away by how long it takes to die.
“These findings collectively provide the most convincing evidence to date that the link between brain acidity and psychiatric disorders is real, Miyakawa says. Regenold, who was not involved in the new work, agrees. ‘When you combine all these [datasets] and you find strong statistical significance, that’s when it becomes more convincing that [lower pH] would be inherent to the disorders,’ he says. ‘I think what’s novel about this paper is that they are singling out lower pH and saying that this is something that—in and of itself—could well be part of the pathophysiology of these disorder, irrespective of what’s causing it’.”
“But John Wemmie, a neuroscientist at the University of Iowa, says that while the findings of Miyakawa’s group are intriguing, ‘it’s tissue after the animals or the humans have died, so it’s hard to know if that’s related to the pH changes [in the living brain].’ Live imaging studies conducted on people with bipolar disorder, schizophrenia and panic disorder provide much more direct evidence for the hypothesis that acidity may underlie these various psychiatric conditions, he says. By using magnetic resonance spectroscopy, a method that can detect biochemical changes in tissue, scientists have consistently found elevated levels of lactate in these individuals’ brains. Even as it becomes clearer that brain acidity may be a key characteristic of schizophrenia and bipolar disorder, whether it is a cause or an effect remains an open question. According to Miyakawa, one possibility is that the increased acidity results from higher-than-normal neuronal activity in the brains of people with these disorders. ‘The neurons are more activated, more energy is needed, and that energy is provided by lactate,’ he explains. Another popular theory is that the greater brain acidity among people with these psychiatric disorders could be due to impairments in mitochondria, the powerhouses of cells, Regenold says. Richard Maddock, a psychiatry professor at the University of California, Davis, who did not take part in the new study, also believes that this could be the case. However, he adds, these two hypotheses are ‘not mutually exclusive’.”
“Going forward, the big question will be whether low brain pH can lead to the cognitive or behavioral changes associated with these disorders, Miyakawa says. There are hints that this is the case—a study published last year in Translational Psychiatry, for example, found that elevated lactate levels in the brains of living patients with schizophrenia were associated with poorer cognitive function. There is also some evidence from rodent studies that acid buildup in the brain can influence behavior. ‘We know that receptors [that are activated by acid] have prominent effects on behavior in animals,’ Wemmie says. ‘That implies that there may be changes in brain pH in the awake and functioning brain that people haven’t appreciated all that well’.”
“Work by Wemmie’s group has revealed that lowering brain pH by modifying carbon dioxide inhalation can evoke fear-associated behavior in mice. They have also found that the activity of acid-sensing ion channels—receptors located at synapses, the junctions between neurons—can contribute to synaptic transmission and plasticity in some areas of brain such as the amygdala, which is involved in processing emotions. How relevant these findings are to people with schizophrenia or bipolar disorder remains unclear. But answering these questions could change how people with some psychiatric disorders are treated and diagnosed, Wemmie says. Right now, he adds, ‘it’s a potentially untapped avenue for therapeutics’.”
Great article, but, too bad they don’t mention that our Ph is determined by what we eat and our gut flora.
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