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Causes of intestinal flora imbalance

The main cause of imbalance in gut microbiota is poor dietary habits high in fat and sugar, abusing antibiotic medications, chronic stress, not exercising enough, and having an irregular routine. Approaches to improvement include having a balanced diet, consuming more fiber and fermented foods, undertaking moderate exercise, using medications judiciously, avoiding stress, and getting enough rest so that restoration of microbial flora is assured.

Flora Basics

Gut microbiota refers to the diversity of microorganisms inhabiting the human gastrointestinal tract, especially the large intestine. These main organisms include bacteria, fungi, viruses, and protozoa; among them, bacteria are the most abundant, with up to trillions of cells, about 10 times the total number of human cells. The most recent metagenomic studies indicated that five major phyla make up the gut microbiota: Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia.

Gut microbiota not only plays a major role in nutrient digestion and absorption but also takes part in metabolic regulation, immune system development and maintenance, neural signal transmission of the host. Undigested carbohydrates fermented by gut microbiota produce SCFAs like acetate, propionate, and butyrate. These metabolites, besides being an energy source for intestinal epithelial cells, have also anti-inflammatory and immune-regulating functions. Besides, gut microbiota can synthesize B vitamins and vitamin K, take part in bile acid metabolism, and regulate the host’s lipid and sugar metabolism.

Types of Flora

Gut flora can be categorized into three main types—probiotics, conditionally pathogenic bacteria, and pathogenic bacteria—by their functions and influence on the health of hosts. Probiotics are useful microorganisms that confer a health benefit on their host, mostly from the genus Lactobacillus and Bifidobacterium, and yeast species including Saccharomyces boulardii. These strains exert gut health promotion via several mechanisms: by checking the growth of pathogens, improving intestinal barrier function, modulating immune responses, and inducing beneficial metabolic products. Lactobacillus probably generates lactic acid; the latter decreases gut pH, while harmful bacteria cannot grow at low pH. Bifidobacterium helps degrade dietary fiber and gives rise to short-chain fatty acids which give energy support to the intestinal epithelial cells.

Conditionally pathogenic bacteria do not harm the host under normal conditions and even perform some physiological roles, but they might become pathogenic under special conditions, causing infection or an inflammatory response. The common conditionally pathogenic bacteria are species such as Escherichia coli, Bacteroides, and Clostridium perfringens. For example, E. coli contributes to intestinal barrier maintenance and metabolic regulation in the intestines, while some strains like EHEC O157 can cause serious foodborne disease.

These pathogenic bacteria are obviously injurious to the host and induce several infections and diseases. Common pathogens include Salmonella, Shigella, and Clostridioides difficile. In any case, these strains cause damage in a variety of ways to the tissues of the host through the production of toxins, invasion into the cells, or induction of an inflammatory response, resulting in acute or chronic diseases. Under normal gut flora conditions, probiotics and conditionally pathogenic bacteria keep a relatively stable ratio, and pathogenic bacteria should be very few in numbers. The microbial balance is important for maintaining not only the physiological environment within the gut but also to protect against invasion from external pathogens due to the “microbial barrier” mechanism. Once the gut microbiota becomes out of balance, several health-related problems can be observed, such as inflammatory bowel disease and irritable bowel syndrome.

Intestinal Flora

Flora and Health

Gut microbiota is an important player in metabolic regulation. It can ferment dietary fiber and undigested carbohydrates to produce short-chain fatty acids, mainly including acetate, propionate, and butyrate. These metabolites not only provide energy to intestinal epithelial cells but also take part in lipid and sugar metabolism. Butyrate has been described as anti-inflammatory, enhancing the integrity of the intestinal barrier and dampening inflammatory responses. Besides, gut microbiota is capable of influencing cholesterol metabolism by regulating cholesterol conversion through dehydrogenase activity, thus influencing blood lipid levels.

Gut microbiota comes into close contact with the host immune system and actively participates in the development and regulation processes of immune cells. Probiotics can induce the capacity of immune cells for the production of anti-inflammatory cytokines, thereby helping the host develop his/her resistance against pathogens. In return, intestinal microbiota proliferates and repairs the intestinal epithelial cells, maintains the intestinal barrier function, and avoids invasion by harmful substances and pathogens. The imbalance of gut microbiota has been closely associated with a number of immune-related diseases including autoimmune diseases, allergic diseases, and inflammatory diseases.

The gut microbiota influences the nervous system through the gut-brain axis: the vagus nerve, immune signaling, and bacterial metabolites, such as short-chain fatty acids and gamma-aminobutyric acid (GABA). The imbalance in gut microbiota has been linked to neurological and psychiatric disorders, which include depression, anxiety, and autism spectrum disorders. Gut microbiota might influence the emotions, cognition, and behavior of the host by the production of neurotransmitters, modulation of the inflammatory response, and affecting neuronal development.

Gut microbiota also promotes the expression of tight junction proteinsOccludin and Claudin—enhancing connections between intestinal epithelial cells and maintaining the integrity of the intestinal barrier. The normal functioning of the intestinal barrier has a direct consequence on the permeability of toxins and pathogens. Compromised intestinal barrier functionleaky gut syndrome—is associated with a range of systemic disorders, including metabolic syndrome and autoimmune disorders.

Diet Role

Prebiotics are mainly obtained from dietary fiber that can be fermented by intestinal microorganisms to promote the proliferation and reproduction of probiotics. High-fiber diets may increase the diversity of Bacteroidetes and Firmicutes, thus producing SCFAs that could help in improving the intestinal environment and enhancing intestinal barrier function. The intake of whole grains, legumes, vegetables, and fruits is important for maintaining gut microbiota balance due to their high dietary fiber content. These foods also contribute to lowering inflammatory responses and decreasing the risk of metabolic diseases.

High-fat and high-sugar diets increase the proportion of pathogenic and conditionally pathogenic bacteria. High-fat diets—especially saturated fatty acid intake—have been shown to significantly alter the structural composition of gut microbiota concerning the increase of pathogenic bacteria. While a high-fat diet decreases the numbers of Bifidobacterium and Lactobacillus, the proportions of Bacteroides and Firmicutes increase. Indeed, an imbalance in such gut microbiota is closely linked with a variety of diseases, including obesity, type 2 diabetes, and metabolic syndrome. Moreover, a high-fat diet could alter gut microenvironment through affecting the bile acid metabolism, thus influencing the structure of gut microbiota.

Excessive consumption of sugar, especially refined sugars, acts as a nutrient source for the overgrowth of pathogenic bacteria, such as E. coli and C. difficile, which then suppress the growth of probiotic bacteria. Such an unfavorable shift in microbiota composition may lead to intestinal inflammation, disrupted gut microbiota composition, and disorders such as IBS. Long-term high sugar intake may affect not only gut microbiota but also induce systemic inflammation through pro-inflammatory processes, increasing the risk for chronic diseases.

The gut microbiota, in particular, relies on protein as a vital nutrient source, especially from animal protein. High consumption of animal protein can lead to an increase in Bacteroides and Prevotella, which are involved in bile acid metabolism and intestinal barrier function, contributing to an increased risk of colon cancer. Plant-based proteins, on the other hand, promote the proliferation of probiotics, which help maintain gut microbiota in a healthy balance.

Fermented foods, such as yogurt, kimchi, miso, and natto, are fermented with active probiotics, including lactic acid bacteria and Bifidobacterium, which can help increase gut beneficial bacteria counts and diversity. They improve the intestinal environment and enhance the immune function, while inhibiting proliferation of pathogenic bacteria and reducing inflammatory responses. For instance, consumption of yogurt can increase the population of Bifidobacterium within the gut, enhance intestinal barrier function, and decrease the incidence of diarrhea and constipation.

Medication Impact

The antibiotics being administered are highly potent to combat bacterial infection, but on the other hand, those broad-spectrum bactericides destroy not only pathogenic organisms but also a large amount of the friendly bacteria. Different classes of antibiotics vary in the degree to which they perturb the gut microbiota. For example, aminoglycosides and tetracyclines are highly perturbing to the gut microbiota, whereas other narrow-spectrum antibiotics may be only minimally perturbing. In any case, antibiotic exposure has been associated with reduced diversity, a lower number of probiotics, and elevated levels of opportunistic pathogens such as C. difficile. This will pave the way for disastrous complications, such as infection with Clostridioides difficile.

Immediately after the use of antibiotics, the diversity and abundance of gut microbiota sharply decrease, especially that of probiotics such as Bifidobacterium and Lactobacillus. Such an imbalance in microbiota may lead to disturbed intestinal barrier function, higher risk of leaky gut syndrome, and even allow the translocation of pathogens and toxins into the bloodstream, leading to systemic inflammation responses and immune dysfunction. Many studies have linked antibiotic use with the rising incidence of chronic diseases such as obesity, diabetes, and autoimmune diseases.

Long-term use of antibiotics leads to changes in the composition of gut microbiota that are permanent and cannot be fully restored to the pre-antibiotic composition. Such long-term disturbance in the gut may enhance the risk of chronic diseases due to disturbances in metabolic and immune function. For example, long-term use of antibiotics is linked with an increased incidence of metabolic syndrome, inflammatory diseases, autoimmune diseases, and neuropsychiatric disorders.

Besides antibiotics, various other drugs, such as NSAIDs, PPIs, anti-depressants, and anti-diabetics, act through different ways and alter the gut microbiota. For example, PPIs inhibit stomach acid secretion, which alters the gastrointestinal pH and promotes the growth of several pathogenic bacteria such as C. difficile and Klebsiella; whereas NSAIDs induce changes in the intestinal mucosal barrier, increasing intestinal permeability and promoting inflammatory responses and microbiota imbalance.

Drugs and gut microbiota interact with each other in a two-way manner, with some drugs being metabolized by gut microbiota and converted to another form. In such cases, each component has the potential to affect drug efficacy and toxicity. The composition and function of gut microbiota could influence the metabolism and effect of medications. For example, active metabolites of certain anticancer drugs were derived from gut microbiota, and disturbance in microbiota may affect its efficacy and adverse effects.

Intestinal Flora

Lifestyle Effects

Chronic psychological stress impinges on gut microbiota via the neuroendocrine pathway. Chronic stress activates the hypothalamic-pituitary-adrenal axis and secretes more stress hormones such as cortisol. Stress hormones directly affect intestinal epithelial cell functions and indirectly interfere with gut environmental factors such as pH and mucus secretion, influencing the structure of the microbiota. Chronic stress reduces the counts of Bifidobacterium and Lactobacillus, while increasing the abundance of some potential pathogenic bacteria, including C. difficile and Clostridium perfringens that are implicated in intestinal inflammation and gut microbiota imbalance.

Adequate sleep and quality are very important in the maintenance of health among gut microbiota. Disturbed sleep disrupts the circadian rhythm and functions to alter the cyclical gut microenvironment. It has indeed been observed that chronic sleep deprivation or poor-quality sleep impairs the diversity of microbiota and is characterized by a higher proportion of Firmicutes, associated with a high risk for obesity, diabetes, and metabolic syndrome. Furthermore, sleep disturbances promote microbiota imbalance in enhancing inflammatory responses and metabolic pathways.

Moderate physical exercises increase microbiota diversity and the number of probiotics. Physical exercises increase blood circulation in the gut, move the intestines, and indirectly change the environment of the gut in a way that favors the proliferation of beneficial bacteria. Some studies have identified that the abundance of Lactobacillus and Bifidobacterium was higher in regular exercisers than in their sedentary peers, while sedentary lifestyle has been associated with reduced microbiota diversity and the increased proliferation of harmful bacteria. Moreover, it is effective in helping to sustain healthy gut microbiota by lessening body weight, improving metabolic functionality, and also lessening the levels of inflammation.

Excessive alcohol consumption and smoking impair gut microbiota. Chronic heavy drinking impairs intestinal barrier function, increased the risk of leaky gut, proliferates harmful bacteria such as C. difficile and Bacteroides, and decreases the amount of beneficial bacteria. Smoking impairs microbiota diversity, enhances pathogenic bacteria like Shigella and E. coli, and induces intestinal inflammation and microbiota imbalance.

Maintaining Balance

For general health, it’s important to keep up the microbial homeostasis, the balance level of gut microbiota. The balance of gut microbiota is important not only in maintaining the normal function of the digestive system but also affects the metabolic, immune, and nervous systems of the host through different mechanisms. Among them, here are the main strategies for maintaining a balance of gut microbiota:

A healthy diet is one of the basic principles of gut microbiota. Consuming whole grains, vegetables, fruits, yogurts, kimchi, miso, and various other ingredients can increase good bacteria and enhance diversity among gut microbiota. Refrain from excessive food high in fat, sugar, and animal protein in order to avoid gut microbiota from being imbalanced and proliferation of harmful bacteria.

While this is important, proper supplementation of probiotics and prebiotics is another very important approach that shall help in maintaining the balance of gut microbiota. Probiotics may involve Lactobacillus and Bifidobacterium, while prebiotics may include inulin and oligofructose as active ingredients that help restore the balance of gut microbiota through oral supplements or food intake. Probiotics directly increase the number of beneficial bacteria and inhibit the growth of harmful bacteria, while prebiotics provide nutritional support for beneficial bacteria and promote their reproduction and functional performance. It is also important to choose scientifically formulated probiotic supplements that match the characteristics of the individual microbiota to enhance effectiveness.

Proper use of medication is also key to gut microbiota protection. Limiting misuse of antibiotics, using them only when necessary, and selecting types of antibiotics only when no alternative exists that have minimal impact on microbiota may reduce killing of beneficial bacteria. As for other medications that have to be used over a long period, such as PPIs or NSAIDs, combining other measures to protect the microbiota under doctor’s guidance can mitigate medications’ adverse effects on the microbiota.

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