Jermane Krishnan
Gut Microbiota
The terms “microbiota” and “microbiome” are frequently used interchangeably. However, microbiota is defined as “a group or populations of microbial organisms,” whereas microbiome is the catalogue of these microbiota and their genes.
The gut microbiota is implicated in the pathophysiology of a wide range of physical and psychological disorders. While research has provided insights into the mechanisms by which the microbiota influences health, much remains unknown or poorly understood.
Once overlooked, this component of the gastrointestinal (GI) tract is now getting a great deal of attention regarding its importance in optimal health. The food and supplements industries have bombarded advertising and sales of food and supplement products promoting “prebiotics,” “probiotics” and “fermented foods.” Yet, at this time science is only scratching the surface in understanding how to best apply knowledge of the microbiota to facilitate better health. This section will review what is currently “known” in an effort to guide patients in this new therapeutic world.
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The widespread influence of the gut microbiome on many physiological and psychological processes is complex. It involves bi-directional communication between the gut and the brain, the hormone, immune and endocannabinoid systems as well as microbial production of neuroactive compounds.
It has been shown that the microbiome of people suffering from various medical conditions differs significantly from that of healthy controls. Research suggests that altering a person’s microbiome through the use of probiotics, prebiotics, or dietary change can alleviate the symptoms and course of many medical conditions including pain.
The Human Microbiome Project (HMP), one of several international efforts, identifies and studies the microbiome in human health. Funded by the National Institute of Health (NIH) in 2008, the HMP has isolated and sequenced over 1,300 reference bacterial strains so far.
The microbiota includes trillions of microorganisms including bacteria, fungus and viruses which are distributed throughout the entire gastrointestinal tract. But different healthy people may have very different microbiomes depending on their diet and their lifestyle. There is considerable intra- and interpersonal variation in the composition of the microbiome because it is influenced by many, many factors including mode of delivery at birth and neonatal feeding, the aging process, dietary factors, geography, medications, and stress.
Changes in the Gut Microbiota with Age
Breast milk is the optimal food for infants as it meets all their nutritional and physiologic requirements. It contains protein, fat and carbohydrate, as well as iantibodies and endocannabinoids. Breast milk is not sterile – it contains more than 600 different species of bacteria including beneficial Bifidobacterium breve, B. adolescentis, B. longum, B. bifidum, and B. dentium
Because an infant’s diet is comprised of breast milk and formula, the microbiome has minimal diversity and with genes that promote metabolism of milk sugar (lactate). With the introduction of solid foods, by 3-years of age the bacterial composition of the gut microbiota is similar to that of an adult and remains stable until old age. In terms of bacterial succession, the Bifidobacterium-dominated microbiota of the infant changes over time into the Bacteroidetes- and Firmicutes-dominated microbiota of the adult. This remains stable throughout adulthood in the absence of disturbances, such as long-term dietary changes or repeated use of antibiotics.
In older age groups, changes in oral and dental health, salivary function, digestive function and intestinal transit time affect the gut microbiota. Notable differences in the microbiota in elderly people compared to young adults include relative proportions of Bacteroidetes predominating in the elderly compared to higher proportions of Firmicutes in young adults. The elderly are also noted to have significant decreases in Bifidobacteria, Bacteriodes, and Clostridium cluster IV. However, there is marked variability among individuals ranging from 3 to 92% for Bacteroidetes and 7 to 94% for Firmicutes.
Decreased microbial diversity has been noted in individuals living in short- or long-term residential care compared to those living in the community, and this difference was associated with increased frailty, decreased diet diversity as well as increased inflammatory markers (serum TNF-α, IL-6, IL-8 and C-reactive protein).
Diet and the Gut Microbiota
Diet is one of the most relevant factors that influences the gut microbiome. Significant changes in the gut microbiota are associated with dietary alterations, especially with consumption of dietary fiber from fruits and vegetables. A varied diet is associated with a more diversified microbiome.
Enrichment of the microbiome is associated with diets high in fruits, vegetables and fiber compared to a western diet rich in fat, sugars and animal protein, one with little fiber. When the microbiota associated with a strict vegetarian diet is compared with that of an omnivorous diet, the vegetarian microbiota has significantly less Bifidobacterium, Bacteroides, E. coli and Enterobacteriaceae species and lower stool pH compared with the omnivore microbiota.
Also, compared to an omnivore diet, a vegetarian diet is associated with a higher carbohydrate and fiber content in which the undigestible polysaccharides can be fermented into short chain fatty acids (SCFA) by the gut microbiota. Production of SCFA is associated with decreased gut pH. The fact that E. coli and Enterobacteriacea do not thrive in lower pH ranges (5.5–6.5) and that they prefer proteins as their energy source, may explain their lower counts in those eating a vegetarian diet.
Depleted microbial biodiversity of the gut microbiota in people consuming a Western diet is associated with increasing incidence of obesity, coronary vascular disease, metabolic syndrome and certain malignancies. The diversity of the gut microbiome may reflect a long-term link to the potential for disease development.
Food Additives and the Gut Microbiota
Emulsifiers are among the most common food additives in butter, milk, mayonnaise, sauces, ice creams, or pastries.They play an important functional role in helping processed food products containing immiscible food ingredients, such as oil and water, to combine. These agents are commonly found in processed foods and are listed on the ingredients label.
The basic structure of an emulsifying agent includes a hydrophobic portion and a hydrophilic portion that provides an interface of water with fat, that avoids the breakdown of food ingredients by preventing separation, melting, or precipitation.
The common emulsifiers include lecithins, mono- and diglycerides, polysorbates, carrageenans, guar gums, and carboxymethylcellulose. Emulsifiers have no calories, proteins or lipids and can seem harmless to consumers as they provide great benefits for stabilizing and texturizing common foods.
Nevertheless, recent research shows that some emulsifiers alter the gut microbiota disrupting the healthy balance of organisms, which are important to maintain good health. Disruption got microbio common biosis common can have a significant impact on the integrity of the gut wall. When the integrity of the gut wall is compromised, contents from the gut, including organisms and inflammatory particles such as lipopolysaccharide (LPS) that can enter into the bloodstream inducing, inflammation locally and systemically. As a result, there are, a multitude of potential problems, including those conditions discussed here, including psychological and physiological impairment. This chronic low-grade systemic inflammation can contribute to metabolic disorders, including hypertension, diabetes, cardiovascular and kidney disease as well as obesity.
Evidence for the role of emulsifiers in contributing to metabolic syndromes through gut microbiota has not been clearly established. Early research suggests that the use of processed foods rich in emulsifiers, characteristic of a modern (Western) diet, may increase the incidence of metabolic syndrome and other chronic inflammatory diseases. Some emulsifiers appear to be safer than others and may even provide beneficial health effects. Unfortunately there has been no quantifying of safe limits. In fact, the quantity of these emulsifiers are not provided in food labeling, only their presence. Currently, all emulsifiers are generally regarded as safe (GRAS) by the FDA.
At this stage, it appears that lecithin, agar agar, and the acacia, guar and xanthan gums are safe whereas carrageenan, carboxymethylcellulose, polysorbate-80, rhamnolipids and sophorolipids may be best avoided in large or frequent amounts. Of course, it is always recommended to avoid eating highly processed foods and emphasize a diet of fresh fruits and vegetables.
Dysregulation of the Gut Microbiota
The study of the gut microbiota is still in its infancy and much remains to be learned. What we do know at this point is that the gut microbiota when this regulated can have a significant impact on any number of health conditions. There are many variables that contribute to the maintenance of a healthy microbiota, especially diet. And there are many variables that contribute to dysregulation of the microbiota resulting in various manifestations of pathology.
Physiological and Psychological Stress and the Gut Microbiota
Stress can be acute or chronic, predictable and controllable or unpredictable and uncontrollable, mild or severe, and and the perception of stress may vary between people, but stress contributes to susceptibility to disease.
Physical and psychological stressors activate the hypothalamic-pituitary-adrenal (HPA) axis between the brain and the adrenal glands. This results in hormonal responses including release of cortisol and the catecholamines, noradrenaline and adrenaline. The GI tract and the gut microbiota are sensitive to stress and some gut bacteria respond to stress by release of neuroactive compounds which can influence the host physiology.
While high intensity exercise can be a physiological stressor that can lead to gastrointestinal distress manifest by nausea, vomiting and diarrhea, regular exercise has an anti-inflammatory effect.
Psychological Stress and the Gut Microbiota
The gut–brain axis is a two-way biochemical signaling process that takes place between the nervous system of the gastrointestinal tract and the central nervous system. The brain and the gut reciprocally influence each other’s expression, providing a conceptual framework in which psychological factors interplay with the gut as exemplified by functional GI disorders such as irritable bowel syndrome. Early life stressors (psychological, sexual and/or physical abuse) have been implicated as important contributors to the development of functional GI disorders and the gut microbiota is particularly vulnerable to these stressors.
Research suggests that stress, whether acute or chronic, creates a dysbiotic gut microbiome which can induce anxiety and depression via metabolites produced by the gut microbiota that can modulate brain biochemistry and behavior. Neurotransmitter metabolism can be altered by the gut microbiota which may then affect depression or anxiety, suggesting the potential for treatment with probiotics, alone or as an adjuvant to traditional therapy.
Pharmaceuticals and the Gut Microbiota
The gut microbiota plays a large role in the metabolism of many common medications, for example by assisting in the conversion of inactive medications (e.g., prodrugs) and nutrients into active medications and nutrients. For example, foods such as fruits, vegetables, cereals and coffee contain conjugated hydroxycinnamates which are antioxidant and anti-inflammatory compounds that require activation by the gut microbiota.
This begs the question as to whether variations in medication responses between people is due to alterations in their gut microbiome. Some drug side effects can be induced via their impact on the gut ecosystem. Most of the studies published on this topic have focused on general population cohorts or single drug–microbe interactions. However, these approaches do not reflect individual clinical situations. Patients with gastrointestinal (GI) diseases like IBD and irritable bowel syndrome (IBS), for example, harbor a different gut microbiota composition than general population controls. This could influence the occurrence of side effects or alter the mechanism of action of certain drugs.
The gut has many mechanisms that protect against ingested pathogens including the gut microbiota as well as an acidic gastric environment, optimal bile flow and propulstion through the gut. The gut microbiota protects against pathogens by competing for binding sites, competing for requirements, and by release of inhibitory molecules. But when these protective mechanisms are disrupted, an imbalance in the gut microbiota can occur.
Medications Impact on the Gut Microbiotia
The gut microbiota has been shown to impact drug responses and effectiveness, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug–microbe interactions are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. a recent study published in 2020 evaluated 41 commonly prescribed medication’s to determine how they impacted the microbiota and found that 19 of the 41 drugs were associated with changes in the microbiota. Of these,, antibiotics, proton-pump inhibitors, metformin, and laxatives show the strongest associations with the microbiome.
Unfortunately, it is still uncertain how to apply this knowledge toward treatment management. At this stage one might argue that the use of these medications should be accompanied by heightened efforts to include probiotic and prebiotic foods in one’s diet that strongly support a healthy microbiota.
Major Brain Diseases
The link between drug-induced imbalance of the microbiota (dysbiosis) and its influence on brain diseases through gut bacteria (the microbiota-gut-brain axis (MGBA)), remains largely unknown. A 2024 review investigated the effects of metformin, statins, proton-pump-inhibitors, NSAIDs and anti-depressants) on the gut microbiota and compared the findings with altered bacterial populations in major brain diseases (depression, multiple sclerosis, Parkinson’s and Alzheimer’s). The report aims to explore whether drugs can influence the development and progression of brain diseases via the MGBA.
The findings indicate that all these drugs induce dysbiosis with patterns associated with brain disorders but their influence on brain diseases varied across different bacteria. Each drug induced both positive and negative changes in the abundance of bacteria, indicating a counterbalancing effect. Moreover, these drugs exhibited similar effects, suggesting that they may counteract or enhance each other’s effects on brain diseases when taken together. The authors concluded that the interplay of bacterial species may have a greater impact on brain diseases than individual drugs or bacterial strains. Future research is needed.
Antibiotics and the Gut Microbiota
Antibiotic therapies not only target specific microorganisms causing an infection, but they also the impact the microbial communities in the gut. Most antibiotics have broad-spectrum activity so they can be used to treat many diseases but the gut microbiota are also affected, with a potentially negative effect that may persist long after the antibiotics have been discontinued. Antibiotics can also trigger the growth of antibiotic-resistant bacteria strains which can act as a reservoir for resistance genes in the gut microenvironment.
Decreased diversity in the microbiome typically follows antibiotic treatment and some healthful bacteria are lost from the community indefinitely. which can leave detrimental effects. The antibiotic spectrum of activity and dose will influence the shift in gut microbiota composition and can lead to increased colonization and infection by opportunistic organisms such as Clostridium difficile and Candida albicans. Antibiotic-induced changes can also include alterations in the metabolites produced by the microbiota such as short-chain fatty acids. Short-chain fatty acids (SCFA) are beneficial for gut health because they serve as a primary food source for the microbiota and they are involved with water and electrolyte absorption and they help to maintain the intestinal barrier (see Leaky Gut).
In summary, a dysregulated, imbalanced gut microbime, whether induced by stress, antibiotics or other conditions can result in disruption of the immune system and lead to increased susceptibility to disease.
Small Intestinal Bacterial Overgrowth (SIBO)
Small intestinal bacterial overgrowth (SIBO) is an example of a pathologic condition associated with dysregulation and impairment of the gut microbiota. SIBO is a condition in which the presence of excessive numbers of bacteria in the small bowel causes gastrointestinal symptoms including abdominal pain, bloating, gas, distention, flatulence, and diarrhea, present in more than two- thirds of SIBO patients. Some patients may also complain of fatigue and poor concentration
In severe cases, nutritional deficiencies including vitamin B12, vitamin D, and iron deficiencies can occur. However, no single symptom can be specifically attributed to SIBO. Symptoms often masquerade as other diagnoses such as IBS, functional diarrhea, functional dyspepsia, or bloating. This is due in part to the varied presentation of patients with SIBO and the number of underlying risk factors that can lead to SIBO. SIBO has been linked to diseases such as irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD) including Crohn’s and ulcerative colitis, cirrhosis, fatty liver, postgastrectomy syndrome, and a variety of other conditions.
For example, in a patient with chronic pancreatitis, it may be difficult to conclude whether diarrhea results from pancreatic enzyme insufficiency or from coexistent SIBO. Similarly, in patients with Crohn’s disease, particularly those having undergone surgery, symptoms of abdominal pain, boating, and diarrhea could result from SIBO vs that of active inflammation, bile acid malabsorption, or postoperative strictures.Several conditions such as intestinal dysmotility, altered GI anatomy, immune deficiencies, and reduced stomach acidity are predisposing factors for the development of SIBO.
While reduced stomach acidity can be a result of Helicobacter pylori colonization and aging, many people also take medications such as proton pump inhibitors (PPIs) to reduce their gastric acidity for stress ulcer prevention or gastric esophageal reflux disease (GERD). PPIs are known to alter the gut microbiota in 50% of patients on long-term treatment withPPIs. Although PPI duration is related to incidence of SIBO, there is a lack of knowledge regarding the appropriate or safe duration for taking PPIs.
Given the protective role gastric acidity has in regards to protecting against ingested pathogens, it is plausible that prolonged use of gastric acid suppressants may contribute to the incidence of SIBO and patients should be judicious in their use.
There are no universally accepted treatment approaches to treatment for SIBO. There are mixed reports of effectiveness for treatment with diet, antibiotics, probiotics and fecal transplantation.
Conclusion
The impact of the gut microbiome on health and disease is currently one of the most stimulating areas of medicine. Learning more about the gut microbiome may provide new treatment options for many conditions and diseases currently resistant to effective management including fibromyalgia, irritable bowel disease, Crohn’s, ulcerative colitis and autism.
The medical world is just beginning to learn about the gut microbiome, its role in dietary intake and disease development, and the effect of probiotic supplementation on various disease states.
References:
Gut Microbiota
Gut Microbiota – Overviews
- The Gut Microbiome- What we do and don’t know – 2015
- The role of the microbiome for human health- from basic science to clinical applications – 2018
- Influence of diet on the gut microbiome and implications for human health – 2017
- Man and the Microbiome- A New Theory of Everything? – PubMed 2019
Gut Microbiota – Medication Overviews
Gut Microbiota – Antibiotics
Gut Microbiota – Opioids
Gut Microbiota – Food & Food Additives
Gut Microbiota – Pain
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- Stress and the Microbiota–Gut–Brain Axis in Visceral Pain – Relevance to Irritable Bowel Syndrome – 2016
- The Role of the Gastrointestinal Microbiota in Visceral Pain – PubMed 2017
- Gut microbiota regulates neuropathic pain – potential mechanisms and therapeutic strategy – 2020
- Pain and Opioid-Induced Gut Microbial Dysbiosis – 2022
Gut Microbiota – Fibromyalgia
Gut Microbiota – Psychiatric Disorders
Gut Microbiota – Small Intestinal Bacterial Overgrowth (SIBO)
Probiotics
Probiotics – Overviews
Probiotics – Foods
Probiotics – IBD (Inflammatory Bowel Diseases)
Probiotics – IBS
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- Stress and the Microbiota–Gut–Brain Axis in Visceral Pain – Relevance to Irritable Bowel Syndrome – 2016
- Adherence to the pro-inflammatory diet in relation to prevalence of irritable bowel syndrome – 2019
- The Evolving Role of Gut Microbiota in the Management of Irritable Bowel Syndrome – An Overview of the Current Knowledge – 2020
Probiotics – Infections
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- Prevention of respiratory syncytial virus infection with probiotic lactic acid bacterium Lactobacillus gasseri SBT2055 – 2019
- Probiotics and Paraprobiotics in Viral Infection – Clinical Application and Effects on the Innate and Acquired Immune Systems – 2018
- Probiotics in respiratory virus infections – 2014
Probiotics – Pain