A diet rich in fermented foods improve gut microbiome diversity and reduce symptoms of chronic inflammation


A diet rich in fermented foods enhances the diversity of gut microbes and decreases molecular signs of inflammation, according to researchers at the Stanford School of Medicine.

In a clinical trial, 36 healthy adults were randomly assigned to a 10-week diet that included either fermented or high-fiber foods. The two diets resulted in different effects on the gut microbiome and the immune system.

Eating foods such as yogurt, kefir, fermented cottage cheese, kimchi and other fermented vegetables, vegetable brine drinks, and kombucha tea led to an increase in overall microbial diversity, with stronger effects from larger servings.

“This is a stunning finding,” said Justin Sonnenburg, PhD, an associate professor of microbiology and immunology. “It provides one of the first examples of how a simple change in diet can reproducibly remodel the microbiota across a cohort of healthy adults.”

In addition, four types of immune cells showed less activation in the fermented-food group. The levels of 19 inflammatory proteins measured in blood samples also decreased. One of these proteins, interleukin 6, has been linked to conditions such as rheumatoid arthritis, Type 2 diabetes and chronic stress.

“Microbiota-targeted diets can change immune status, providing a promising avenue for decreasing inflammation in healthy adults,” said Christopher Gardner, PhD, the Rehnborg Farquhar Professor and director of nutrition studies at the Stanford Prevention Research Center. “This finding was consistent across all participants in the study who were assigned to the higher fermented food group.”

Microbe diversity stable in fiber-rich diet
By contrast, none of these 19 inflammatory proteins decreased in participants assigned to a high-fiber diet rich in legumes, seeds, whole grains, nuts, vegetables and fruits. On average, the diversity of their gut microbes also remained stable.

“We expected high fiber to have a more universally beneficial effect and increase microbiota diversity,” said Erica Sonnenburg, PhD, a senior research scientist in basic life sciences, microbiology and immunology.

“The data suggest that increased fiber intake alone over a short time period is insufficient to increase microbiota diversity.”

The study published online July 12 in Cell. Justin and Erica Sonnenburg and Christopher Gardner are co-senior authors. The lead authors are Hannah Wastyk, a PhD student in bioengineering, and former postdoctoral scholar Gabriela Fragiadakis, PhD, who is now an assistant professor of medicine at UC-San Francisco.

A wide body of evidence has demonstrated that diet shapes the gut microbiome, which can affect the immune system and overall health. According to Gardner, low microbiome diversity has been linked to obesity and diabetes.

“We wanted to conduct a proof-of-concept study that could test whether microbiota-targeted food could be an avenue for combatting the overwhelming rise in chronic inflammatory diseases,” Gardner said.

The researchers focused on fiber and fermented foods due to previous reports of their potential health benefits. While high-fiber diets have been associated with lower rates of mortality, the consumption of fermented foods can help with weight maintenance and may decrease the risk of diabetes, cancer and cardiovascular disease.

The researchers analyzed blood and stool samples collected during a three-week pre-trial period, the 10 weeks of the diet, and a four-week period after the diet when the participants ate as they chose.

The findings paint a nuanced picture of the influence of diet on gut microbes and immune status. On one hand, those who increased their consumption of fermented foods showed similar effects on their microbiome diversity and inflammatory markers, consistent with prior research showing that short-term changes in diet can rapidly alter the gut microbiome.

On the other hand, the limited change in the microbiome within the high-fiber group dovetails with the researchers’ previous reports of a general resilience of the human microbiome over short time periods.

Designing a suite of dietary and microbial strategies
The results also showed that greater fiber intake led to more carbohydrates in stool samples, pointing to incomplete fiber degradation by gut microbes. These findings are consistent with other research suggesting that the microbiome of people living in the industrialized world is depleted of fiber-degrading microbes.

“It is possible that a longer intervention would have allowed for the microbiota to adequately adapt to the increase in fiber consumption,” Erica Sonnenburg said. “Alternatively, the deliberate introduction of fiber-consuming microbes may be required to increase the microbiota’s capacity to break down the carbohydrates.”

In addition to exploring these possibilities, the researchers plan to conduct studies in mice to investigate the molecular mechanisms by which diets alter the microbiome and reduce inflammatory proteins. They also aim to test whether high-fiber and fermented foods synergize to influence the microbiome and immune system of humans.

Another goal is to examine whether the consumption of fermented food decreases inflammation or improves other health markers in patients with immunological and metabolic diseases, and in pregnant women and older individuals.

“There are many more ways to target the microbiome with food and supplements, and we hope to continue to investigate how different diets, probiotics and prebiotics impact the microbiome and health in different groups,” Justin Sonnenburg said.

Other Stanford co-authors are Dalia Perelman, health educator; former graduate students Dylan Dahan, PhD, and Carlos Gonzalez, PhD; graduate student Bryan Merrill; former research assistant Madeline Topf; postdoctoral scholars William Van Treuren, PhD, and Shuo Han, PhD; Jennifer Robinson, PhD, administrative director of the Community Health and Prevention Research Master’s Program and program manager of the Nutrition Studies Group; and Joshua Elias, PhD..

The microbiota exerts a marked influence on the host during homeostasis linked with metabolic diseases in humans, but demonstration of causality remains a challenge [1].

Humans as hosts have co-evolved with microorganisms over millions of years, and each body habitat has a unique set of microorganisms shaping its microbiota [2].

These bacteria live on the skin, in the corners of the eyes, in the oral cavity, under fingernails, and most importantly, in the guts. Several perinatal determinants, such as caesarean section delivery, type of feeding, the use of antibiotics, gestational age or environment can affect the pattern of bacterial colonization, resulting in gut dysbiosis. The establishment and development of the gut microbiota over the lifecycle moved from the previous accepted dogma that the mammalian healthy placenta and foetus were germ-free and considered to be sterile, and that these conditions were critical to the developing newborn’s immune system, to the actual knowledge that in utero humans are now known to harbour unique prenatal microbiomes [3,4].

Amniotic fluid may contain microorganisms, increasing the complexity of fetal microbiota, and having implications for the long-term health and susceptibility to disease, as placental microbiota could trigger immune responses in the fetus. Early gut microbiota settlement influences the maturation of the infant’s immune system [5] and subsequent health, although the evidence in support of the “in utero colonization hypothesis” is considered extremely weak by some authors [6].

Health authorities are now becoming fully aware that one cannot be considered to be in good health without a well-balanced microbiota composition in the gut, our “forgotten organ” [7], and of the fundamental role of a diverse and healthy gut microbiota on the subsequent maintenance of future health and well-being of the host [8,9]. Indeed, although it is broadly mentioned that there are 10 times more cells from microorganisms in our bodies than there are human cells [10], this claim has been challenged, and others have estimated that the number of bacteria is similar to that of human cells [11].

Many species of bacteria, specifically those found in the invisible universe of the human microbiota, e.g., composed of nonpathogenic commensal microbiota from the Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia phyla [12], are unsusceptible to petri dish cultivation. They can be successfully cultivated in association with other microbes, meaning in communities of different bacteria species. But without being able to isolate them, research is difficult [13]. Commensal microbiota gradually deteriorates in sick patients. Therefore, research is being conducted to generate new technologies to study the rest of the human microbiome using advances in DNA-sequencing technologies and associated computational methods [14]. Metagenomic sequencing of total fecal DNA samples offers complementary support to classical microbiology, and enables researchers to access previously-inaccessible genomic information from gut bacteria [15,16].

In recent years, a number of functional species and strains have been identified in human metabolic diseases [17]. Gut bacteria can produce various bioactive metabolites which can be detrimental to the host’s health, such as those with cytotoxicity, genotoxicity, or immunotoxicity [18], shifting the paradigm of understanding the root cause of the onset and progression of several human metabolic diseases [19].

Gut microbiota modulates the expression of many genes in the human intestinal tract [20], including genes involved in immunity, nutrient absorption, energy metabolism, and intestinal barrier function. It is important to understand genomic diversity of specific members of the gut microbiota if precise nutrition-based approaches are to be realized [21].

In the oral use of live bacteria, there is more research concerning isolated probiotic commercial supplements than there is work concerning health benefits of common fermented foods, since major industries usually do not fund this type of research [22]. Many studies suggest that probiotics may help with diarrhea or symptoms of irritable bowel syndrome, but strong evidence to support their use for most health conditions is lacking in people with sepsis, and probiotics are no panacea [23,24].

Probiotics should not be universally given as a ‘one-size-fits-all’; most trials were based on stool samples, which may not really reflect the bacteria living in the gut, as shedding takes place continuously [25]. Besides, taking probiotics after treatment with broad spectrum antibiotics may actually delay the return of normal gut microbiome, a new potential adverse side effect [26].

The One Health concept, introduced at the beginning of the 2000s [27], is a worldwide strategy for promoting multidisciplinary partnerships and information in all facets of health care sciences, perceiving the interrelationship between humans, animals, plants, and their common environment [28]. By working with physicians, veterinarians, osteopathic physicians, dentists, pharmacists, nurses, ecologists, wildlife professionals, and other scientific-health and environmentally-related specialists, it will be possible to monitor and control public health threats and learn how diseases spread among people, animals, and the environment [29].

The point of this mini review is to highlight if the requirement for multiconvergence of the research fields of One Health (Human-Animal-Environment), the relationship between microbiota-nutrition and fermented foods, and to underline the idea that future gut-brain research is feasible and achievable (Figure 1).

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Figure 1
A general picture of the One Health (Human-Animal-Environment) concept as a trans-disciplinary effort. Contribution of the three branches of public health. Microbiota and human metabolic diseases, animal health, and environmental epidemiology.

Microbiota and General Health
Having an active and natural variety of microorganisms in the gut may improve general health [30]. The good, healthy bacteria make food more digestible through their enzymes, increased vitamin synthesis, and the preservation of nutrients, and also help to reduce sweet cravings, maintain the immune system, and benefit overall gut wellness [31].

The microbiome, consisting of microorganisms and their collective genomes, modulates the host metabolic phenotype, and influences the host immune system. It is now well established that gut bacteria are closely tied to immune health [32]. The gut microbiota regulates l-tryptophan metabolism and identifies the underlying molecular mechanisms of these interactions [33].

A large majority of the immune system resides in the tonsils and gut, so when gut health is imbalanced, it is hard for the body’s immune system to function properly [34]. There are also a number of common factors in modern life that can throw human gut bacteria off, such as processed foods and antibiotics. The use of antibiotics does have several short and long-term implications in the ecology of the normal microbiota and gut motility [35].

Research on the health benefits of probiotics is still emerging, mainly from the food and beverage industries and their commercial interests. In contrast, strong, independent scientific evidence to support specific uses of probiotics for most health conditions is still lacking [36].

The administration of probiotics/prebiotics has been shown to alter the composition and functionality of the gut microbiota [37]. Recent evidence indicates that the effects of probiotics are likely to be different from one person to the next [38].

In addition, probiotics might be ineffective, and possibly counterproductive, in restoring the baseline gut microbiome after it has been altered by antibiotic treatment. Indeed, probiotics may not be quite as good as was commonly thought, and they could even be harmful if taken after antibiotics [39].

Serious disorders such as obesity, anorexia, irritable bowel syndrome, autism, and posttraumatic stress disorder—which have been thought to be solely psychological—share a common symptom: a hypersensitivity to gut stimuli [40,41,42].

The role of environmental factors in the development of autism is a crucial and an important area of research concerning how the environment influences and interacts with genetic susceptibility. Factors such as parental age at conception, maternal nutrition, infection during pregnancy, and premature birth are risk factors [43]. Autism (ASD, autism spectrum disorder), a developmental disorder characterized by disturbance in language, perception, and socialization, with no exact known cause, is usually linked with bioenergetic metabolism deficiency [44] and neuro-inflammatory conditions [45], and immune system dysregulation and dreadful gut concerns may improve with better diet and fermented foods (e.g., fermented raw coconut milk) [46,47].

Specific benefits from the direct dietary modulation of the human gut microbiota has been described [48]. Despite the wide array of beneficial mechanisms deployed by probiotic bacteria and fermented foods and beverages, relatively few effects have been supported by clinical data [49].

The interactions (Figure 2) between ingested fermented food and intestinal microbiota, and their correlations to metabolomics profiles and health, represent an important perspective, and independent research on health benefits is still emerging [50,51]. Microbiota is specific to each individual, despite the existence of several bacterial species shared by the majority of adults. A diverse and propitious microbial ecosystem (e.g., Bacteroides fragilis, Bifidobacterium spp. and Faecalibacterium spp.) favors homeostasis, particularly at the level of the disease–immune dialogue [52,53].

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Figure 2
Interactions between dynamics of microbiota in humans, animals, and the associated environment with disease occurrence, salubrity, and well-being.

Fermented Foods, Probiotics, Body and Mind
The use of fermentation in conserving food and beverage as a means to provide better taste, improve nutrition and food safety, organically preserve foodstuffs, and promote health properties, is a well-known ancient practice. The reasons for fermenting foods and beverages include improvements of a product’s storage time, safety, functionality, organoleptic quality, and nutritional quality properties [54]. Not only is this process beneficial for extending shelf-life, but also, fermentation can enhance nutritional properties in a safe and effective manner [55].

Many types of food groups, including dairy, vegetables, legumes, cereals, starchy roots, and fruits, as well as meat and fish, can be fermented [56]. Fermented foods and beverages can comprise anywhere from 5–40% of the human diet in some populations [57].

Phytochemicals, defined as the non-nutritive, naturally-occurring chemicals found in fruits, vegetables, wholegrains, legumes, beans, herbs, spices, nuts, and seeds, are responsible for producing physiological properties, as well as protecting against various environmental stressors of the plant crops. There are more than one thousand known phytochemicals (e.g., lycopene in tomatoes, isoflavones in soy, and flavanoids in fruits). The microbiota comes into contact with a wide variety of dietary components that escape gut digestion and may be affected by phytochemicals [58].

Substantial confusion exists between fermented foods and beverages and the probiotic concept. It is important to address the common misconception that fermented foods are the same thing as probiotics [59]. They are not probiotics, although they may contain them, as their live microbial content is undefined. The term “probiotic” was first coined [60] in 1974, and many authors have described the history and the progress of probiotics and their different applications. Ilya Ilyich Metchnikoff, the Nobel Prize winner in Medicine in 1908, was the first who observed the effect of what is called now “probiotic” [61]. FAO/WHO redefined the term “probiotics”, which is now widely accepted as constituting “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [62]. Different types of bacteria (e.g., Lactobacillus, Bifidobacterium, Streptococcus, Bacillus) and yeast or mold (e.g., Saccharomyces, Aspergillus, Candida) are used as probiotics. Probably, the first real use of food containing probiotics was fermented milk, but today we have to differentiate between probiotics and probiotic-containing foods (e.g., fermented foods) [63]. The scope and appropriate use of the term “probiotic” has been well clarified (Figure 3) [64].

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Figure 3
Overall framework for probiotic products [64].

Probiotics are able to renew, restore, and grow affected tissues lining the digestive tract with beneficial microorganisms neutralizing the harmful ones. Useful live microorganisms will regenerate our microflora fermenting our food correctly and improving our health [65,66].

Despite the impact of fermented foods and beverages on gastro-intestinal well-being and diseases, their health benefits or recommended consumption have not been widely translated to global inclusion in world food guidelines [67]. When fermented foods and beverages are supplemented with probiotic bacteria, they provide numerous extra nutritional and health characteristics [68].

Fermented foods and beverages are more popular than ever before, while research into the health benefits of fermented foods is relatively new. Not all fermented foods contain live organisms; beer and wine, for example, undergo steps that remove the organisms, and other fermented foods like bread are heat-treated and the organisms are inactivated. The strain composition and stability of the microbes in fermented foods is not well understood [69].

Fermentation generates adjustments in yeast and live microorganisms cultures in the absence of air, but retains the enzymes, vitamins, and minerals in foods and beverages, which are usually destroyed by processing [70]. The fermenting microorganism, bacteria or yeast, plays a precious role in the functional property of fermented foods and beverages [71]. One the biggest benefits of fermented foods comes from the probiotics they might contain [72]. There are currently no authorized European health claims for probiotics, and the application of probiotics is controversial, since the European Food Safety Authority (EFSA) rejected all submitted health claims related to the term “probiotic”, while accepting the term “live microorganism cultures” in yoghurt [73].

Traditional and modern dietary practices utilize fermented foods and beverages, contributing significantly to the food chain value and belonging to a category of foods called “functional foods” (e.g., probiotics, prebiotics, stanols and sterols) by having an additional characteristic, i.e., health-promotion or disease prevention effect [74].

Fermentation converts sugars, in the absence of oxygen, into organic acids, gases, alcohols, and carbon dioxide, and provides several benefits such as new and desirable tastes and textures, enhancement of nutrients (e.g., linoleic acid; bioactive peptides), removal of toxic or undesirable food constituents (e.g., phytic acid; bitter-tasting phenolic compounds), delivery of probiotic bacteria (e.g., Lactobacillus delbrueckii subsp. bulgaricus; Streptococcus thermophilus), and inhibition of foodborne pathogens [75,76].

Fermented foods and beverages are useful because they help provide a spectrum of probiotics to foster a vigorous microbiome. Fermented foods with unidentified microbial content cannot be considered probiotic suppliers. The two main effects of the daily consumption of fermented foods are upon the immune system and upon metabolic function [77].

Dealing with fermented foods has parallels with One Health, since it involves the links between human, animal, environment, foods and microbiota that impacts the organoleptic and physicochemical characteristics of foods as well as human health [78].

There are well documented effects of how adverse early life influences on the gut-brain axis and the use of fermented foods and beverages, mainly with probiotic bacteria, can restore a disturbance of the normal luminal habitat, and so change the effects of the central nervous system on the microbiota [79].

Our guts control and deal with every aspect of our health. How we digest our food, and even the food sensitivities we have are linked to our mood, behavior, energy, weight, food cravings, hormone balance, and immunity [80]. The interaction of nutrients with the microbiota is essentially what determines overall health. Eating and drinking fermented foods and beverages, especially organic unpeeled and unpasteurized fruits and vegetables, improves the bioaccessibility and bioavailability of food bioactive components, supplying dietary fibers and essential micronutrients such as trace-elements and phytochemicals, together with enzymes, lactic acid bacteria, and organic acids, all of which are crucial for good health [81].

Changes in the human colonic microbiota fingerprint are associated with the major causes of morbidity and mortality worldwide, diabetes and cardiovascular diseases, due to imbalances between beneficial and pathogenic bacteria [82].

Physiologically-active peptides with different functionalities are produced from food proteins during fermentation and food digestion by lactic acid bacteria. In some fermented products, bioactive peptides (e.g., immunoglobulins, antibacterial peptides, antimicrobial proteins, oligosaccharides, lipids, and other “minor” components) have the potential to be used in the formulation of health-enhancing nutraceuticals [83], and include short amino acid sequences that, upon release from the parent protein, may play different physiological roles, including antioxidant, antihypertensive, antimicrobial, and other bioactivities [84,85].

Fermentation may enhance the benefits of a wide variety of foods, dairy products, herbs, and beverages, acting upon the absorption and activity of their secondary metabolites and chemical elements [86]. However, it is not always possible to clearly distinguish the potential contribution of the microbial content from that of the food matrix. There is recent evidence and consumer perception of the health benefits of fermented foods and beverages [87], beyond the popular recognized effects on the impairment of gastrointestinal function, namely, their relevance on gut microbiota, correlated to human health and to several infectious [88], inflammatory, and neoplastic disease processes [89], as well as to brain functionality [90].

Despite disagreement among mental health practitioners and researchers pertaining to the aetiology, categorization, and medical care of several mental disorders [91], current research regarding fermented foods, the microbiome, and their effect on human health, particularly the global epidemic of mental health [92], describes problems associated with the modern lifestyle, and with the western diet being high in sugar and saturated fat [93].

The degradation of the intestinal mucous membrane, weakening the tight barrier against the ingress of harmful substances, and the protection against a reaction to omnipresent harmless compounds, is a primary cause of several disturbances [94].

Ingestion of vibrant probiotics, especially in fermented foods, is found to cause significant positive improvements in balancing intestinal permeability and barrier function [95], with direct effects on metabolic syndrome, atherosclerosis, inflammatory bowel diseases, and colon cancer [96] and indirect effects on depression, anger, anxiety, and levels of stress hormones [97].

Young individuals with autism often have a reduced number of microorganisms in the gut [98], and atypical digestive health conditions may occur, like chronic gastrointestinal and functional bowel disorder, causing discomfort, diarrhea and bloating, abdominal pain and cramping, collectively described as irritable bowel syndrome [99]. Children with autism spectrum, besides having a genetic predisposition, show a disruption of the indigenous gut flora and an elevated number of potentially pathogenic (toxin-producing) Clostridia in the gut [100,101]. The effectiveness of fermented foods, mushroom biomass, and probiotics in relieving gut symptoms in autistic children has been studied [102,103,104].

The involvement of the microbiota in inflammatory diseases may contribute to altered mood via intestinal permeability, systemic and local lipopolysaccharide burden, and even direct-to-brain microbial communication [105]. In future, insights based upon omics techniques will increase our knowledge between pathogens and healthy strains, thereby explaining food ecosystems and their dynamics [106,107].

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306734/

Original Research: Closed access.
“Gut-microbiota-targeted diets modulate human immune status” by Hannah Wastyk et al. Cell


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