Dietary restrictions modulate the gut microbiota: Implications for health and disease

The health benefits of carefully restricting the energy intake in a strategic manner whilst avoiding malnutrition are widely discussed. In the recent years, the great impact of the gut microbiota on its host has been clarified more and more. Since the gut microbiota produces a number of metabolites and molecules that can affect host metabolism, modulating it with dietary restriction can influence the health and the progression of disease of its host on various levels. This review comprises 15 studies investigating the effect of different variants of fasting and caloric restriction on the gastrointestinal microbiome and its metabolites. The data suggest that changing the gut microbiota composition by dietary restriction has the potential to positively influence the progression of several diseases such as obesity, diabetes, neurological diseases or inflammatory bowel disease. Finally, the relevance of the findings for clinical practice is evaluated and approaches for future research are proposed.     

The public health rationale for increasing dietary fibre: Health benefits with a focus on gut microbiota

Dietary fibre can be considered an essential macronutrient which feeds our gut microbiota, thus enabling the optimal functioning of this ‘virtual organ’. Recommended daily intakes range from 25 to 38 g/day. However, most individuals fail to reach this target and may consume <50% of the recommended amount. Poor dietary fibre intake is associated with an imbalanced gut microbiota leading to reduced diversity and increased abundance of non‐beneficial microorganisms at the expense of beneficial ones. Inflammation is a recognised physiological effect of such a microbiome structure and is a common denominator in several non‐communicable diseases associated with the Western lifestyle/developed world including obesity, cardiovascular disease, type 2 diabetes and colorectal cancer. Yet increasing dietary fibre intake can reduce risk factors associated with these diseases and may even improve prognosis. Several food manufacturers have now developed strategies to increase the fibre content of foods. However, research gaps still remain. In particular, dietary fibre is composed of various non‐digestible carbohydrates and the exact effect of each of these on the gut microbiota is currently unknown. The links between dietary fibre and disease risk are generally associative. Understanding the biological mechanisms will require deeper insight into the impact of the gut microbiota on health. Furthermore, gut microbiota research has shown significant inter‐individual variation meaning that some individuals may not respond to certain dietary fibres owing to the absence of specific microorganisms. Understanding how the different fibre types influence the microbiota, combined with knowledge of an individual’s microbiota, should lead to fibre‐led, microbiota‐based dietary advice.     

Intestinal microflora of human infants and current trends for its nutritional modulation

Diet, among other environmental and genetic factors, is currently recognised to have an important role in health and disease. There is increasing evidence that the human colonic microbiota can contribute positively towards host nutrition and health. As such, dietary modulation has been proposed as important for improved gut health, especially during the highly sensitive stage of infancy. Differences in gut microflora composition and incidence of infection occur between breast- and formula-fed infants. Human milk components that cannot be duplicated in infant formulae could possibly account for these differences. However, various functional food ingredients such as oligosaccharides, prebiotics, proteins and probiotics could effect a beneficial modification in the composition and activities of gut microflora of infants. The aim of the present review is to describe existing knowledge on the composition and metabolic activities of the gastrointestinal microflora of human infants and discuss various possibilities and opportunities for its nutritional modulation.     

Probiotics and prebiotics in infant nutrition

The human colonic microflora has a central role in health and disease, being unique in its complexity and range of functions. As such, dietary modulation is important for improved gut health, especially during the highly-sensitive stage of infancy. Diet can affect the composition of the gut microflora through the availability of different substrates for bacterial fermentation. Differences in gut microflora composition and incidence of infection exist between breast-fed and formula-fed infants, with the former thought to have improved protection. Historically, this improvement has been believed to be a result of the higher presence of reportedly-beneficial genera such as the bifidobacteria. As such, functional food ingredients such as prebiotics and probiotics could effect a beneficial modification in the composition and activities of gut microflora of infants by increasing positive flora components. The prebiotic approach aims to increase resident bacteria that are considered to be beneficial for human health, e.g. bifidobacteria and lactobacilli, while probiotics advocates the use of the live micro-organisms themselves in the diet. Both approaches have found their way into infant formula feeds and aim to more closely simulate the gut microbiota composition seen during breast-feeding.     

Food matrix and the microbiome: considerations for preclinical chronic disease studies

Animal models of chronic disease are continuously being refined and have evolved with the goal of increasing the translation of results to human populations. Examples of this progress include transgenic models and germ-free animals conventionalized with human microbiota. The gut microbiome is involved in the etiology of several chronic diseases. Therefore, consideration of the experimental conditions that may affect the gut microbiome in preclinical disease is very important. Of note, diet plays a large role in shaping the gut microbiome and can be a source of variation between animal models and human populations. Traditionally, nutrition researchers have focused on manipulating the macronutrient profile of experimental diets to model diseases such as metabolic syndrome. However, other dietary components found in human foods, but not in animal diets, can have sizable effects on the composition and metabolic capacity of the gut microbiome and, as a consequence, manifestation of the chronic disease being modeled. The purpose of this review is to describe how food matrix food components, including diverse fiber sources, oxidation products from cooking, and dietary fat emulsifiers, shape the composition of the gut microbiome and influence gut health.     

Prebiotic effects: metabolic and health benefits

The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.     

Influence of Mediterranean Diet on Human Gut Microbiota

Gut microbiota changes correlate with health status. Literature data on gut microbiota show that all dietary changes can induce the alteration of gut microbiota composition. Mediterranean diet (MD) is associated with a reduction of all-cause mortality and in this review, we analyzed its interactions with human microbiota. In particular, we explored the modulation of the human microbiota, in response to MD adherence, focusing the attention on polyphenols, polyunsaturated fatty acids (PUFA) ω-3 and fiber. Evidences suggest that MD is able to modulate the gut microbiota, increasing its diversity. In fact, a Mediterranean-type dietary pattern is associated with specific gut microbiota characteristics. The available evidence, suggests that gut microbiota of subjects that follow a MD is significantly different from subjects that follow a Western diet model. In fact, the latter show an increased gut permeability, which is responsible for metabolic endotoxemia. For this reason, we can speculate that the gut microbiota of the subjects following a MD is able to prevent the onset of chronic non-communicable degenerative diseases, such as cardiovascular diseases and some types of cancer. However, in order to understand these correlations with dietary patterns, controlled intervention studies on the gut microbiota composition and activity are needed.     

The Nutrition-Microbiota-Physical Activity Triad: An Inspiring New Concept for Health and Sports Performance

The human gut microbiota is currently the focus of converging interest in many diseases and sports performance. This review presents gut microbiota as a real “orchestra conductor” in the host’s physio(patho)logy due to its implications in many aspects of health and disease. Reciprocally, gut microbiota composition and activity are influenced by many different factors, such as diet and physical activity. Literature data have shown that macro- and micro-nutrients influence gut microbiota composition. Cumulative data indicate that gut bacteria are sensitive to modulation by physical activity, as shown by studies using training and hypoactivity models. Sports performance studies have also presented interesting and promising results. Therefore, gut microbiota could be considered a “pivotal” organ for health and sports performance, leading to a new concept: the nutrition-microbiota-physical activity triad. The next challenge for the scientific and medical communities is to test this concept in clinical studies. The long-term aim is to find the best combination of the three elements of this triad to optimize treatments, delay disease onset, or enhance sports performance. The many possibilities offered by biotic supplementation and training modalities open different avenues for future research.     

HDHL-INTIMIC: A European Knowledge Platform on Food,Diet, Intestinal Microbiomics,and Human Health

Studies indicate that the intestinal microbiota influences general metabolic processes in humans, thereby modulating the risk of chronic diseases such as type 2 diabetes, allergy, cardiovascular disease, and colorectal cancer (CRC). Dietary factors are also directly related to chronic disease risk, and they affect the composition and function of the gut microbiota. Still, detailed knowledge on the relation between diet, the microbiota, and chronic disease risk is limited. The overarching aim of the HDHL-INTIMIC (INtesTInal MICrobiomics) knowledge platform is to foster studies on the microbiota, nutrition, and health by assembling available knowledge of the microbiota and of the other aspects (e.g., food science and metabolomics) that are relevant in the context of microbiome research. The goal is to make this information findable, accessible, interoperable, and reusable (FAIR) to the scientific community, and to share information with the various stakeholders. Through these efforts a network of transnational and multidisciplinary collaboration has emerged, which has contributed to further develop and increase the impact of microbiome research in human health. The roles of microbiota in early infancy, during ageing, and in subclinical and clinically manifested disease are identified as urgent areas of research in this knowledge platform.     

Ultra-processed Foods and Cardiovascular Diseases: Potential Mechanisms of Action

Ultra-processed foods are industrially manufactured ready-to-eat or ready-to-heat formulations containing food additives and little or no whole foods, in contrast to processed foods, which are whole foods preserved by traditional techniques such as canning or pickling. Recent epidemiological studies suggest that higher consumption of ultra-processed food is associated with increased risk of cardiovascular disease (CVD). However, epidemiological evidence needs to be corroborated with criteria of biological plausibility. This review summarizes the current evidence on the putative biological mechanisms underlying the associations between ultra-processed foods and CVD. Research ranging from laboratory-based to prospective epidemiological studies and experimental evidence suggest that ultra-processed foods may affect cardiometabolic health through a myriad of mechanisms, beyond the traditionally recognized individual nutrients. Processing induces significant changes to the food matrix, for which ultra-processed foods may affect health outcomes differently than unrefined whole foods with similar nutritional composition. Notably, the highly degraded physical structure of ultra-processed foods may affect cardiometabolic health by influencing absorption kinetics, satiety, glycemic response, and the gut microbiota composition and function. Food additives and neo-formed contaminants produced during processing may also play a role in CVD risk. Key biological pathways include altered serum lipid concentrations, modified gut microbiota and host–microbiota interactions, obesity, inflammation, oxidative stress, dysglycemia, insulin resistance, and hypertension. Further research is warranted to clarify the proportional harm associated with the nutritional composition, food additives, physical structure, and other attributes of ultra-processed foods. Understanding how ultra-processing changes whole foods and through which pathways these foods affect health is a prerequisite for eliminating harmful processing techniques and ingredients.     

Do Interactions Between Gut Ecology and Environmental Chemicals Contribute to Obesity and Diabetes?

Background: Gut microbiota are important factors in obesity and diabetes, yet little is known about their role in the toxicodynamics of environmental chemicals, including those recently found to be obesogenic and diabetogenic.Objectives: We integrated evidence that independently links gut ecology and environmental chemicals to obesity and diabetes, providing a framework for suggesting how these environmental factors may interact with these diseases, and identified future research needs.Methods: We examined studies with germ-free or antibiotic-treated laboratory animals, and human studies that evaluated how dietary influences and microbial changes affected obesity and diabetes. Strengths and weaknesses of studies evaluating how environmental chemical exposures may affect obesity and diabetes were summarized, and research gaps on how gut ecology may affect the disposition of environmental chemicals were identified.Results: Mounting evidence indicates that gut microbiota composition affects obesity and diabetes, as does exposure to environmental chemicals. The toxicology and pharmacology literature also suggests that interindividual variations in gut microbiota may affect chemical metabolism via direct activation of chemicals, depletion of metabolites needed for biotransformation, alteration of host biotransformation enzyme activities, changes in enterohepatic circulation, altered bioavailability of environmental chemicals and/or antioxidants from food, and alterations in gut motility and barrier function.Conclusions: Variations in gut microbiota are likely to affect human toxicodynamics and increase individual exposure to obesogenic and diabetogenic chemicals. Combating the global obesity and diabetes epidemics requires a multifaceted approach that should include greater emphasis on understanding and controlling the impact of interindividual gut microbe variability on the disposition of environmental chemicals in humans.     

Potential mechanisms for the emerging link between obesity and increased intestinal permeability

Recently, increased attention has been paid to the link between gut microbial composition and obesity. Gut microbiota is a source of endotoxins whose increase in plasma is related to obesity and insulin resistance through increased intestinal permeability in animal models; however, this relationship still needs to be confirmed in humans. That intestinal permeability is subject to change and that it might be the interface between gut microbiota and endotoxins in the core of metabolic dysfunctions reinforce the need to understand the mechanisms involved in these aspects to direct more efficient therapeutic approaches. Therefore, in this review, we focus on the emerging link between obesity and increased intestinal permeability, including the possible factors that contribute to increased intestinal permeability in obese subjects. We address the concept of intestinal permeability, how it is measured, and the intestinal segments that may be affected. We then describe 3 factors that may have an influence on intestinal permeability in obesity: microbial dysbiosis, dietary pattern (high-fructose and high-fat diet), and nutritional deficiencies. Gaps in the current knowledge of the role of Toll-like receptors ligands to induce insulin resistance, the routes for lipopolysaccharide circulation, and the impact of altered intestinal microbiota in obesity, as well as the limitations of current permeability tests and other potential useful markers, are discussed. More studies are needed to reveal how changes occur in the microbiota. The factors such as changes in the dietary pattern and the improvement of nutritional deficiencies appear to influence intestinal permeability, and impact metabolism must be examined. Also, additional studies are necessary to better understand how probiotic supplements, prebiotics, and micronutrients can improve stress-induced gastrointestinal barrier dysfunction and the influence these factors have on host defense. Hence, the topics presented in this review may be beneficial in directing future studies that assess gut barrier function in obesity.     

Diet‐derived microbial metabolites in health and disease

The gut microbiota helps us digest food and has been associated with both good health and risk of disease. Although compositions of the gut microbiota are highly divergent, the gut microbiota exhibits a high level of functional redundancy making it difficult to reliably link gut microbiome patterns to health and diet across individuals. Thus, there is a need to move beyond profiling of the gut microbial composition to the assessment of gut microbial metabolic activity in order to expand knowledge on the impact of the gut microbiota on health. Metabolomics has already proven its utility in identifying gut‐derived microbial metabolites, which may be mediators of diet‐induced host–microbial crosstalk important for health. These diet‐derived metabolites include, among many others, the short‐chain fatty acids originating from bacterial degradation of dietary fibres and proteins, secondary bile acids derived from primary bile acids, microbial tryptophan catabolites resulting from proteolysis, imidazole propionate produced from histidine and trimethylamine N‐oxide, a host–microbial co‐metabolite of nutrients such as phosphatidylcholine, choline and L‐carnitine, present in high‐fat foods. These co‐metabolites have been associated with beneficial and detrimental effects in the host. However, the vast majority of metabolites measured by untargeted metabolomics in human blood and excreta remain unknown and may include additional microbial molecules of importance for health. Thus, there is great potential, yet to be explored, for identifying additional diet‐derived microbial products that affect the host. Herein, we review key advances, challenges and limitations in our understanding of diet–microbiome interactions and diet‐derived microbial metabolites in relation to human health and discuss how metabolomics may shed light on inter‐individual differences in dietary responses.     

Protein Intake,Metabolic Status and the Gut Microbiota in Different Ethnicities: Results from Two Independent Cohorts

Background: Protein intake has been associated with the development of pre-diabetes (pre-T2D) and type 2 diabetes (T2D). The gut microbiota has the capacity to produce harmful metabolites derived from dietary protein. Furthermore, both the gut microbiota composition and metabolic status (e.g., insulin resistance) can be modulated by diet and ethnicity. However, to date most studies have predominantly focused on carbohydrate and fiber intake with regards to metabolic status and gut microbiota composition. Objectives: To determine the associations between dietary protein intake, gut microbiota composition, and metabolic status in different ethnicities. Methods: Separate cross-sectional analysis of two European cohorts (MetaCardis, n = 1759; HELIUS, n = 1528) including controls, patients with pre-T2D, and patients with T2D of Caucasian/non-Caucasian origin with nutritional data obtained from Food Frequency Questionnaires and gut microbiota composition. Results: In both cohorts, animal (but not plant) protein intake was associated with pre-T2D status and T2D status after adjustment for confounders. There was no significant association between protein intake (total, animal, or plant) with either gut microbiota alpha diversity or beta diversity, regardless of ethnicity. At the species level, we identified taxonomical signatures associated with animal protein intake that overlapped in both cohorts with different abundances according to metabolic status and ethnicity. Conclusions: Animal protein intake is associated with pre-T2D and T2D status but not with gut microbiota beta or alpha diversity, regardless of ethnicity. Gut microbial taxonomical signatures were identified, which could function as potential modulators in the association between dietary protein intake and metabolic status.     

The human gut microbiota and its interactive connections to diet

The microbiota of the gastrointestinal tract plays an important role in human health. In addition to their metabolic interactions with dietary constituents, gut bacteria may also be involved in more complex host interactions, such as modulation of the immune system. Furthermore, the composition of the gut microbiota may be important in reducing the risk of contracting particular gut infections. Changes in the microbiota during an individual's lifespan are accompanied by modifications in multiple health parameters, and such observations have prompted intense scientific efforts aiming to understand the complex interactions between the microbiota and its human host, as well as how this may be influenced by diet.     

The impact of nutrition on the human microbiome

Diet-derived carbohydrates that are not fully digested in the upper gut, known as nondigestible carbohydrates, provide a major source of energy for bacteria that colonize the human large intestine. It is well established that dietary intake of nondigestible carbohydrates influences microbial fermentation and total bacterial numbers in the colon. Recent evidence from molecular ecology has also shown that the amount and type of nondigestible carbohydrates (e.g., resistant starch, non-starch polysaccharides, and prebiotics) influences the species composition of the intestinal microbiota both in short-term dietary interventions and in response to habitual long-term dietary intake. Interindividual variation in gut microbiota may, in part, reflect differences in dietary intake, but the response of the gut microbiota to dietary change can also differ among individuals. As a better understanding is gained of the impact of different groups of bacteria on host metabolism, the ability to manipulate the microbiota through diet should provide a route for delivering health benefits.     

Designing future prebiotic fiber to target metabolic syndrome

The metabolic syndrome (MetS), characterized by obesity, hyperlipidemia, hypertension, and insulin resistance, is a growing epidemic worldwide, requiring new prevention strategies and therapeutics. The concept of prebiotics refers to selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host. Sequencing the gut microbiome and performing metagenomics has provided new knowledge of the significance of the composition and activity of the gut microbiota in metabolic disease. As knowledge of how a healthy gut microbiota is composed and which bacterial metabolites are beneficial increases, tailor-made dietary interventions using prebiotic fibers could be developed for individuals with MetS. In this review, we describe how dietary fibers alter short-chain fatty acid (SCFA) profiles and the intrinsic and extrinsic effects of prebiotics on host metabolism. We focus on several key aspects in prebiotic research in relation to MetS and provide mechanistic data that support the use of prebiotic fibers in order to alter the gut microbiota composition and SCFA profiles. Further studies in the field should provide reliable mechanistic and clinical evidence for how prebiotics can be used to alleviate MetS and its complications. Additionally, it will be important to clarify the effect of individual differences in the gut microbiome on responsiveness to prebiotic interventions.     

Prebiotics and the Human Gut Microbiota: From Breakdown Mechanisms to the Impact on Metabolic Health

The colon harbours a dynamic and complex community of microorganisms, collectively known as the gut microbiota, which constitutes the densest microbial ecosystem in the human body. These commensal gut microbes play a key role in human health and diseases, revealing the strong potential of fine-tuning the gut microbiota to confer health benefits. In this context, dietary strategies targeting gut microbes to modulate the composition and metabolic function of microbial communities are of increasing interest. One such dietary strategy is the use of prebiotics, which are defined as substrates that are selectively utilised by host microorganisms to confer a health benefit. A better understanding of the metabolic pathways involved in the breakdown of prebiotics is essential to improve these nutritional strategies. In this review, we will present the concept of prebiotics, and focus on the main sources and nature of these components, which are mainly non-digestible polysaccharides. We will review the breakdown mechanisms of complex carbohydrates by the intestinal microbiota and present short-chain fatty acids (SCFAs) as key molecules mediating the dialogue between the intestinal microbiota and the host. Finally, we will review human studies exploring the potential of prebiotics in metabolic diseases, revealing the personalised responses to prebiotic ingestion. In conclusion, we hope that this review will be of interest to identify mechanistic factors for the optimization of prebiotic-based strategies.