Lifestyle & Longevity: The Human Gut Microbiome
Mounting research in the last two decades has uncovered the critical influence that the diverse microbes in our gut have on our overall health. Varied studies worldwide have linked a balanced gut microbiome to immune system competence, regulation of our metabolism and psychological wellbeing. Imbalances, by contrast, have been linked to the development of multiple inflammatory disorders, several other disease categories and ageing itself. In this article, we explore current scientific opinion on the integral role of gut microbiota in health, disease and longevity, the impact of lifestyle factors and furthermore, how in practical terms we can optimise the health and balance of our microbiome.
Imbalances… have been linked to the development of multiple inflammatory disorders, several other disease categories and ageing itself
We commonly associate microbes, including bacteria and viruses, with disease. However, in contrast with the pathogenic microbes that can invade our bodies, a huge number and diversity of microbes live in and on our bodies, with a significant beneficial role in our health. In fact, the population of such organisms is thought to be just above our own cell count [Sender R., et al 2016].
These beneficial microbes are found in several locations including the skin, gut, oral cavities, vaginal lining and respiratory airways, and in turn, they help support our normal tissue and organ functions. By far the greatest number are housed in the lining of the intestines. Their collective name is the gut microbiota, and their combined genes are referred to commonly as the gut microbiome. They constitute a complex ecosystem dominated by bacteria, but also another type of prokaryote, known as archaea. In addition, there are yeasts, other fungi and viruses. Bacteriophages, viruses that specifically infect bacteria, make up most of the viral count.
Over the last two decades, there has been a significant increase in research focusing on the gut microbiome, much of it trying to understand the nature of the continual ‘cross-talk’ between the constituent organisms in the gut and us, as hosts. Studies have identified an essential function for this interaction in maintaining good health, coupling the gut microbiome to immunity, digestion, energy metabolism, and blood glucose regulation.
Research has also firmly implicated an imbalance in the gut microbiome in diverse diseases. These include, but are not confined to, allergic conditions, neurodegenerative disease, anxiety, depression, inflammatory bowel conditions, obesity, type 2 diabetes and several cancers.
As such, the gut microbiome has become a significant target for therapeutics.
What then is the gut microbiome’s role in immunity and disease?
…a perturbed gut microbiome has been linked to several diseases that exhibit pro-inflammatory effects or auto-immune states… including allergies, atopic disease such as asthma, eczema, and atopic dermatitis, irritable bowel syndrome, ulcerative colitis, obesity, type 2 diabetes and several cancers
The gut forms a critical concentration point for many of our immune cells. In fact, a huge proportion of our immune system’s focus is aimed at controlling our body’s interaction with the gut microbiome. Immune cells congregate and work in conjunction with the linings of the intestine and a mucus layer to produce an effective ‘barrier’ against our microbiome. This is sometimes referred to as a ‘mucosal firewall’ and it acts to prevent an unintended immune response against beneficial microbes. The interactions and responses of our immune cells here are thought to have far-reaching beneficial consequences to our body’s immunity as a whole.
Hence, the constituents of our gut microbiota can control pathogenic invaders in diverse ways, including producing antimicrobial proteins and molecules that adversely affect the survival and virulence of pathogens or competing directly for nutrients. For example, short chain fatty acids, produced by our microbiome by a fermentation process in the colon (discussed further below) have an anti-inflammatory effect mediated via the immune system. Moreover, several beneficial or ‘commensal’ bacteria types in the gut are known to synthesise vitamins, including B2, B6 and B12 vitamins, known to be essential for immune functioning [Belkaid,Y 2014].
Chronic inflammation and auto-immune disease
There is a growing recognition that many of our major disease categories result from chronic inflammation caused by imbalances in the proper functioning of multiple bodily systems. Moreover, a perturbed gut microbiome has been linked in research studies to several diseases that exhibit pro-inflammatory effects or auto-immune states, where the immune system erroneously attacks non-pathogenic cells causing chronic inflammation. This implicates disease categories including allergies, atopic disease such as asthma, eczema, and atopic dermatitis, irritable bowel syndrome, ulcerative colitis, obesity, type 2 diabetes and several cancers.
Allergies and atopic disease
There has been a significant rise in the incidence of allergic and atopic diseases, specifically in developed countries, over the last few decades. Many research groups have hypothesised this may be due to excessive hygiene as part of a Western lifestyle, that reduce infant exposure to microbes, including the beneficial ones that populate our gut. Furthermore, this could go on to disrupt immune responses resulting in hypersensitivity and disease development [Noverr, MC et al., 2004]. This is an expansion on the original ‘hygiene hypothesis’ by Strachan in 1989, that attributed atopic diseases to a reduced exposure to infections in infancy.
A host of clinical research studies suggest a strong link between changes in the gut microbiota, as well as those of the skin and respiratory tract, to allergic and atopic diseases [Huang, YJ. et al.,2017]. A large scale cohort study in The Netherlands examining nearly 1000 infants, concluded there were distinct differences in the guts of infants that went on to develop atopic diseases versus their healthy counterparts. An increased population of Escherichia Coli was present in those who developed eczema, with a direct correlation between the levels found and disease development. In addition, increased levels of Clostridium Difficile were associated with all atopic diseases (eczema, asthma, allergies and atopic dermatitis) [Penders, J. et al., 2006].
To summarise, the maintenance of a healthy gut microbiome could be critical to combatting cancer and a patient’s treatment success
There is increasing evidence that the gut microbiome can significantly influence the development of certain cancers and a patient’s subsequent response to cancer therapies.
Several research studies have shown that dysbiosis in the gut microbiome can be a risk factor for developing colorectal cancer. An increased inflammatory state, altered immunity and the production of toxins from unhealthy bacteria are thought to contribute to the disease process. On the contrary, increased amounts of short-chain fatty acids (SCFAs), a metabolite produced by certain types of commensal bacteria in the gut have been shown to have a protective effect [Rowland L, et al 2018; Zou S., et al 2018]. We discuss SCFAs further below in the section on diet.
A cancer treatment known as immunotherapy, (covered in our previous paper), manipulates a patient’s own immune system so that it attacks and targets tumour cells. A recent study, showed that patients with a disrupted gut microbiome due to antibiotic consumption, had a poor response to cancer immunotherapy. The patients in the study were being treated for lung and kidney cancers, by a class of drugs known as immune checkpoint inhibitors (ICIs). All non-responding individuals were found to have low levels of a specific healthy bacterium Akkermansia muciniphila in their gut [Routy et al 2019].
In two other studies in melanoma patients, the best responses to immunotherapy were seen in those with a healthy gut microbiome. Conversely, non-responding patients had a disrupted or imbalanced gut microbiome [Matson et al., 2018].
Other research studies, that focussed on stem cell transplants for haematologic cancers (also known as blood cancers), showed patients with the best survival and response rates had a higher level of microbiome diversity when treatment started [Taur et al., 2014]. Some studies also showed the presence of known beneficial bacterial species in patients was associated with a reduced risk of relapse [Peled et al., 2017].
To summarise, the maintenance of a healthy gut microbiome could be critical to combatting cancer and a patient’s treatment success. The manipulation of gut microbiota through probiotics, prebiotics or fecal transplantation is currently under investigation through a number of ongoing clinical trials in cancer patients. The outcomes could prove critical in helping to improve outcomes and reduce the toxic effects of cancer therapies [Gopalakrishnan et al., 2018].
Several studies have shown that differences in gut microbiota are intrinsically linked with obesity and metabolic syndrome. A study in 2018 showed that fecal microbiota transfer (FMT) – literally a transfusion of fecal matter from one host to another* – from an obese mouse to populate the gut of a germ-free mouse resulted in rapid weight gain [Turnbaugh, P et al., 2006]. What’s more, other studies have shown that the microbiota from obese individuals have an increased capacity for energy harvest from nutrients, and may increase intestinal permeability and endotoxin levels in the blood.
* Fecal microbiota transfer is an infusion through the colon, or delivery through the upper gastrointestinal tract, of stool from a healthy donor to a recipient with a disease believed to be related to an unhealthy gut microbiome
There has been increased reference in the last 5 years of the potential application of FMT, to treat diseases beyond gastrointestinal disorders where a perturbed gut microbiome is implicated.
There have been several clinical trials for the treatment of atopic disease and allergies, and obesity with inconclusive results. Some preliminary success has been observed for inflammatory bowel disease (IBD), irritable bowel syndrome, ulcerative colitis and metabolic syndrome, but further research is needed before wider use in patients [König, J et al., 2017; Zeng, W. et al 2019]
The ‘leaky gut’ hypothesis
The leaky gut hypothesis has been touted in many lay and scientific publications as a mechanism for disease development. The assertion underlying the hypothesis is that physiologic stressors such as dietary components, anxiety, or intense exercise can enhance the permeability of the intestinal mucosal membrane, specifically the ‘tight junctions’ between cells, thereby increasing entry of pathogenic bacteria, bacterial toxins and even food matter into the body’s circulation, causing inflammation and triggering numerous diseases or allergic reactions. However, whilst some continue to support this hypothesis [Bischoff, SC. et al., 2014; Mu, Q et al., 2017; Chakaroun RM et al 2020], other groups argue that there is a distinct lack of high quality scientific data to support this theory at present [Hollander, D. et al., 2020].
The gut is therefore a new and emerging target for health interventions in the field of psychiatric disease
The relationship between the gut microbiome and the brain
There are many pathways elucidated by researchers that connect the gut and the brain. The latter is referred to as the ‘gut-brain-axis’. For example, some neurotransmitters and metabolites that affect the brain are synthesised in the gut.
The role of gut bacteria in mood disorders has been investigated in a number of studies showing that individuals suffering from depression had altered gut microbiome diversity and composition compared to healthy individuals [Zheng, P. et al., 2016; Jiang, H et al., 2015]. Furthermore, these changes were also related to depression-like symptoms seen in rodent models [Kelly JR, et al., 2015]. The gut is therefore a new and emerging target for health interventions in the field of psychiatric disease.
Animal studies have bolstered the idea that gut microbes can influence the brain. Rats given fecal transplants from people with depression went on to develop the rodent equivalents of those problems. Conversely, giving those animals fecal transplants from healthy people sometimes relieved their symptoms [Kelly JR, et al., 2016]. Similar studies have been carried out for other diseases affecting the nervous system, including Parkinson’s disease and schizophrenia with varied and inconclusive outcomes [Bastiaanssen, TSF. et al., 2019].
Having considered the critical importance of a healthy gut microbiome for good health and prevention of disease, what constitutes a healthy gut microbiome and how is it created and fostered?
…a dominance of beneficial microbial categories coupled with a high-degree of diversity is what constitutes a healthy gut microbiome
What constitutes a healthy adult gut microbiome?
It is interesting to note that whilst the function of the gut microbiota is conserved between individuals, the make-up of a healthy adult’s microbe population varies greatly. Therefore, there is no single blueprint. However, we do know that certain microbiota categories have beneficial effects in the gut, whilst others are detrimental.
Additionally, microbial diversity in the context of the gut microbiome is seen as beneficial — as when one population of commensal bacteria is affected, another similar strain can step into its role, minimising any disruption to health. Diet is a significant contributory factor to increasing microbial diversity, and the prevalent microbe populations in our gut, as we will discuss further below.
Simply put, a dominance of beneficial microbial categories coupled with a high-degree of diversity is what constitutes a healthy gut microbiome.
How is our gut microbiome populated?
There is increasing evidence that the gut is not sterile when we are born, and its population with microbes actually starts in the womb, possibly sourced from the amniotic fluid and the placenta [Walker, RW. et al., 2017]. However, studies indicate that the gut of infants only becomes more densely populated with microbes during and after birth. Mother-to-baby transmission of microbes is often observed, with a newborn’s gut flora being different based on delivery method. Vaginal delivery results in a transfer of Lactobacillus and Prevotella, whereas those children born via Caesarean section acquire more Staphylococcus, which are more characteristic of the skin microbiome [Korpela, K. et al 2018].
Infants have been shown to share up to 30% of their gut microbiome with their mothers, further supporting the notion of maternal transmission of the gut microbiome to infant [Palmer, C, 2007]. However, some bacterial strains that are present in a mother’s gut, like Clostridia are not seen in the infant, suggesting there is some degree of selection. Subsequent to delivery, the intake of colostrum, breast-feeding, and environmental exposure go on to further influence the microbial composition.
Our gut flora starts to stabilise at the end of our first year of age. In later childhood, the similarity of our bacterial population to that of our mother declines, and is influenced more by more diverse lifestyle factors including the wider family members, and environment [Korpela, K. et al 2018].
In addition to such early-stage life factors, the adult gut microbiome is influenced by diet, body mass index (BMI), age, genetics, exercise frequency, lifestyle factors, medication, environmental stress and cultural habits. Perhaps not surprisingly, diet is seen as the most prominent lifestyle factor in shaping and modulating the human gut microbiota.
Numerous clinical trials and studies have shown that a high-fibre diet increases the microbial diversity of healthy bacteria in the gut
Can we change and optimise the gut microbiome through our diet?
Complex carbohydrates, dietary fibre and short chain fatty acids
Carbohydrate digestion happens in two principal ways. First, non-resistant starch and simple sugars are digested in the small intestine, where they become available for metabolism by the body. Secondly, more complex carbohydrates and resistant starches, that are indigestible in the small intestine, require bacterial fermentation in the large intestine to be broken down, in effect nourishing the commensal microbes present there. Complex carbohydrates that follow this secondary process are typically high in dietary fibre and include whole-grain cereal, fibrous vegetables and fruit.
A low F/B ratio is associated with a lean body type and a high F/B ratio is associated with an obese body type
Numerous clinical trials and studies have shown that a high-fibre diet increases the microbial diversity of healthy bacteria in the gut [Candela, M. et al., 2016; García-Peris, P. et al., 2012; Hoschler, HD. et al., 2014]. What’s more, high dietary fibre intake has been known to reduce the ratio between two key types of bacteria in the gut — Firmicutes and Bacteroidetes —referred to as the “F/B ratio.” A low F/B ratio is associated with a lean body type and a high F/B ratio is associated with an obese body type. Obese individuals commonly show a perturbed gut microbiome, as discussed earlier in this paper.
Another benefit of high fibre intake is that it encourages the growth of bacterial species that ferment fibre into short chain fatty acids (SCFAs). There are several documented positive health effects of SCFAs that include improved immunity, blood–brain barrier integrity, anti-inflammatory activity in the gut, an anti-cancer role in the colon and glucose and cholesterol regulation [Rowland, L., et al 2018]
Prebiotics and probiotics
Prebiotics are a sub-category of the complex carbohydrates that help feed our commensal gut bacteria and increase SCFA production. Common foods that contain prebiotics include raw garlic, leeks, chicory, onion, asparagus, banana and apples. Probiotics, on the other hand, directly introduce ‘live’ commensal bacteria into our gut and are present in live yoghurt cultures and fermented foods such as kimchi, sauerkraut and miso. They have also been shown to be beneficial for overall gut health [Markowiak, P., et al 2017; Sergeev, IN., et al 2020]
Detrimental effects of saturated fat
Diets high in saturated or total fat have consistently been shown to have detrimental effects on the gut microbiome composition and diversity [Wolters M., et al., 2019]. In particular, studies show saturated fats, such as animal-derived fats, lower the levels of microbes associated with good gut health, whereas unsaturated fats, such as olive oil, both increase the abundance of good bacteria and reduce harmful bacteria.
Further studies have also linked excesses of saturated fats sourced from milk or meat products with higher levels of anaerobic bacteria that have been implicated in inflammation in the gut and colorectal cancer [Peck, SC et al., 2019].
Negative influences of animal-derived protein
Several clinical and preclinical studies suggest that both the type and amount of protein in the diet have diverse and considerable effects on the gut microbiome. Studies in humans showed that individuals consuming large amounts of animal protein, mainly from beef, that incidentally also contains high levels of saturated fats, showed reduced bacterial diversity due to the loss of those groups required to digest plant derived carbohydrate [David, LA, et al., 2014].
Additionally, studies in animal models indicate that a diet dominated by animal based-protein results in an increase in detrimental gut microbiota and is linked to a pro-inflammatory gut profile. Conversely, one that is high in plant-protein and complex carbohydrate shows beneficial diversification of gut microbes [Yang, Q, et al., 2020].
Evidence also suggests that very high protein diets, including those supplemented with high protein drinks can have harmful effects. In a 70-day study that followed healthy athletes who supplemented with a protein drink, adverse effects were seen with a significant decrease in health beneficial microbiota [Moreno-Pérez, D., 2018].
Beneficial effects of polyphenols
Animal and human clinical trials have shown that polyphenols, like flavonoids, phenolic acids, stilbenes, and lignans (commonly found in fruits, vegetables, tea, coffee, and red wine) are thought to have prebiotic-like activities in the gut, imparting health benefits and reducing inflammation [Santino, A. et al 2017]. Furthermore, the intake of Vitamin A, C, D, and E have been shown to have a positive influence on health-beneficial microbes [Yang, Q, et al., 2020].
What other major factors influence the gut microbiome?
Getting a good night’s sleep
A recent study in 40 participants found that gut microbiome richness and diversity, are positively correlated with increased sleep efficiency and total sleep time. Conversely, there was a negative correlation with subjects who experience fragmented sleep [Smith, RP et al., 2019].
Another study, which focused solely on 37 older participants >65 yrs, noted increases in diversity in different groups of bacteria were associated with better sleep quality and cognitive function in advanced age [Anderson, JR. et al., 2017].
Exercise – keeping it regular and moderate
An increasing body of evidence indicates that regular aerobic exercise confers an independent beneficial influence over the human gut microbiome. In human models, moderate exercise, over a longer time scale of weeks rather than days, has been linked to notable positive changes.
Regular moderate exercise has been shown to decrease inflammation and its mediators in the gut. Indeed, several groups have suggested moderate exercise as an intervention for multiple inflammatory conditions. [O’Sullivan, O, et al., 2015 and references therein] .
Alcohol – a general disruptor
Alcohol is another dietary disruptor of the intestinal microbiota. Numerous studies have shown changes in alcoholic individuals, with or without liver disease, that result in a pathogenic disruption in the gut microbiome. A multitude of effects, reviewed in Engen et al., 2015, included bacterial overgrowth in the small intestine and a significant increase in potentially dangerous bacteria and toxins.
The only positive correlation for gut health and alcohol was seen with a limited intake of red wine, either a standard or de-alcoholised version (max of 272 ml/day) in a randomized control trial that resulted in an increase in certain healthy bacteria that has been linked to the polyphenol content of red wine providing beneficial prebiotic effects [Queipo-Ortuño MI, et al., 2012].
Smokers – a disrupted microbiome
Smoking was shown to induce imbalances in the gut microbiome in a small cohort study by Bidderman et al. in 2013. Furthermore, it has proven links to some chronic disease associated with the gut. For example, cigarette smoking is considered to be one of the most important lifestyle risk factors in developing inflammatory bowel disease [Danese et al., 2004].
A large scale study in Korea compared the gut microbiome of men who had never smoked, had quit smoking, or were current smokers, whilst controlling for all other variables. They observed that current smokers had a high F/B* ratio. This is something that’s normally associated with being predisposed to metabolic disease and obesity. Those who were former smokers or had never smoked had similar gut microbiota, suggesting that your microbiome returns to normal after smoking cessation [Lee et al., 2018]. Animal models of smoking have also shown increases in inflammatory markers in the gut.
(*Firmicutes and Bacteroidetes ratio —referred to above in the section on ‘Complex carbohydrates, dietary fibre and short chain fatty acids)
Stress – problematic over the long term
A number of research groups have linked an elevated stress response and stress-related disorders to dysregulation of the gut microbiome. Conversely, treatment with prebiotics and probiotics has been shown to attenuate the stress response in animal and in human studies [Foster, JA. et al., 2017]. A recent study showed that introducing certain bacterium into the diet through probiotics helped reduce anxiety and the stress response in healthy volunteers. [Allen AP et al., 2016].
Antibiotic depletion and the role of other drugs
The use of antibiotics is known to deplete the gut microbiome. Although antibiotics have had a vital medical role and are prescribed to help control and rid our bodies of pathogenic bacteria, they inadvertently also target the indigenous microbiota present in our gut. They can reduce bacterial diversity, and change or redistribute the microbe composition, in a transient or permanent manner. It should be noted that antibiotic treatment also selects for resistant bacteria in the long-run. For example, Clostridium Difficile infection (CDI) is often prevalent in patients continuously taking antibiotics [Modi, SR. et al., 2014].
The interaction between our gut microbes and other commonly prescribed non-antibiotic drugs is complex and bidirectional. The gut microbiome composition can be influenced by drugs, but, conversely, the microbiota can also impact our individual response to a drug by altering it enzymatically, and/or changing its bioavailability, bioactivity or toxicity. In studies, some routinely used drugs known to influence the microbiome include beta-blockers, ACE inhibitors, lipid-lowering statins, laxatives, metformin, and the antidepressants known as selective serotonin reuptake inhibitors [Vich Vila, A, et al., 2020]
As we age, the gut microbiome is less diverse and unstable. It remains unknown whether this disruption of the microbiota is a cause or consequence of ageing. It has been linked in various studies to impaired sleep, changed lifestyle and dietary schedule, lesser mobility, weakened immune strength, chronic low-grade inflammation, recurrent infections and the increased use of medications [Nagpal, R. et al., 2018].
Although further studies are needed, some research has suggested that given that the gut microbiome composition is critical to healthy ageing, so its restoration can support longevity. Preliminary studies, in nematode worms nonetheless, have shown that genetically engineered probiotics could hold some promise as a new therapeutic to promote healthy ageing and longevity [Han, B et al 2017].
…strong evidence exists of the presence and diversity of specific beneficial microbes and how we as individuals can help support and promote their presence in our gut
Scientific reductionism has traditionally segregated the function of organs and systems in the human body. Health optimisations and interventions have often been siloed as a result. Increasing evidence supports the gut microbiome as a converging point and interface between our all our physiological systems. This favours a targeted approach, via the gut, to help maintain optimal health outcomes throughout our lifetimes and potentially protect against wide categories of disease.
Although no single blueprint of a healthy gut microbiome to attain exists, strong evidence exists of the presence and diversity of specific beneficial microbes and how we as individuals can help support and promote their presence in our gut. Dietary interventions, like consuming complex carbohydrates, fibre-rich foods, low levels of animal fats, plant-derived proteins, polyphenol-rich foods, probiotics and prebiotics can all contribute.
Other lifestyle factors, like optimising sleep, moderating alcohol, smoking cessation and maintaining regular levels of activity also have a role to play.
Whilst we cannot yet be sure of the causal or consequential relationship of the gut microbiome to disease development and ageing more generally, the disruption observed is recognised. This opens up the potential for ongoing clinical interventions, to help prevent and treat disease development and slow aspects of the ageing process. The targeted use of FMT, prebiotics and probiotics will no doubt have an ongoing role to play as new data emerges.
By Dr. Seema Sharma for SX2 Ventures © 2020
Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, Murphy E, Cryan JF, Dinan TG, Clarke G. Transl Psychiatry. 2016 Nov 1; 6(11):e939.
Arumugam, M., Raes, J., Pelletier, E. et al. Enterotypes of the human gut microbiome. Nature. 2011. 473, 174–180. https://doi.org/10.1038/nature09944
Biedermann L, Zeitz J, Mwinyi J, et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS One. 2013;8(3):e59260. doi:10.1371/journal.pone.0059260
Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability–a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189. Published 2014 Nov 18. doi:10.1186/s12876-014-0189-7
Bressa C, Bailén-Andrino M, Pérez-Santiago J, et al. Differences in gut microbiota profile between women with active lifestyle and sedentary women. PLoS One. 2017; 12(2):e0171352.
Brouwer ML, Wolt-Plompen SA, Dubois AE, van der Heide S, Jansen DF, Hoijer MA, Kauffman HF, Duiverman EJ. No effects of probiotics on atopic dermatitis in infancy: a randomized placebo-controlled trial. Clin Exp Allergy. 2006 Jul; 36(7):899-906..
Candela M., Biagi E., Soverini M., Consolandi C., Quercia S., Severgnini M., Peano C., Turroni S., Rampelli S., Pozzilli P. Modulation of gut microbiota dysbioses in type 2 diabetic patients by macrobiotic ma-pi 2 diet. Br. J. Nutr. 2016;116:80–93. doi: 10.1017/S0007114516001045
Chakaroun RM, Massier L, Kovacs P. Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders?. Nutrients. 2020;12(4):1082. Published 2020 Apr 14. doi:10.3390/nu12041082
Cheng M, Ning K. Stereotypes About Enterotype: the Old and New Ideas. Genomics Proteomics Bioinformatics. 2019;17(1):4‐12. doi:10.1016/j.gpb.2018.02.004
Clarke SF, Murphy EF, O’Sullivan O, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014; 63(12):1913–20.
Dao MC, Everard A, Aron-Wisnewsky J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016; 65(3):426–36.
Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmune Rev. 2004. 3 (5): 394–400
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. . Diet rapidly and reproducibly alters the human gut microbiome. Nature. (2014) 505:559–63. 10.1038/nature12820
Engen PA, Green SJ, Voigt RM, Forsyth CB, Keshavarzian A. The Gastrointestinal Microbiome: Alcohol Effects on the Composition of Intestinal Microbiota. Alcohol Res. 2015;37(2):223‐236.
Estaki M, Pither J, Baumeister P, et al. Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome. 2016; 4:42.
Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress. 2017;7:124‐136. Published 2017 Mar 19. doi:10.1016/j.ynstr.2017.03.001
García-Peris P., Velasco C., Lozano M., Moreno Y., Paron L., De la Cuerda C., Bretón I., Camblor M., García-Hernández J., Guarner F. Effect of a mixture of inulin and fructo-oligosaccharide on lactobacillus and bifidobacterium intestinal microbiota of patients receiving radiotherapy; a randomised, double-blind, placebo-controlled trial. Nutr. Hosp. 2012;27:1908–1915.
Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Cancer Cell. 2018;33(4):570-580. doi:10.1016/j.ccell.2018.03.015
Han B, Sivaramakrishnan P, Lin CCJ, Neve IAA, He J, Tay LWR, Sowa JN, Sizovs A, Du G, Wang J, Herman C, Wang MC. Microbial genetic composition tunes host longevity. Cell. 2017;169(13):1249–62.
Hollander, D., Kaunitz, J.D. The “Leaky Gut”: Tight Junctions but Loose Associations?. Dig Dis Sci 65, 1277–1287 (2020). https://doi.org/10.1007/s10620-019-05777-2
Holscher H.D., Caporaso J.G., Hooda S., Brulc J.M., Fahey Jr G.C., Swanson K.S. Fiber supplementation influences phylogenetic structure and Functional capacity of the human intestinal microbiome: Follow-up of a randomized controlled trial. Am. J. Clin. Nutr. 2014;101:55–64. doi: 10.3945/ajcn.114.092064.
Huang, YJ, Marsland BJ, Bunyavanich S, et al. The microbiome in allergic disease: Current understanding and future opportunities-2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. J Allergy Clin Immunol. 2017;139(4):1099-1110. doi:10.1016/j.jaci.2017.02.007
J. König, A. Siebenhaar, C. Högenauer et al., Consensus report: faecal microbiota transfer–clinical applications and procedures. Alimentary Pharmacology & Therapeutics, vol. 45, no. 2, pp. 222–239, 2017
Kalliomäki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet. 2003 May 31; 361(9372):1869-71.
Korpela K, Costea P, Coelho LP, et al. Selective maternal seeding and environment shape the human gut microbiome. Genome Res. 2018;28(4):561‐568. doi:10.1101/gr.233940.117
Lee SH, Yun Y, Kim SJ, et al. Association between Cigarette Smoking Status and Composition of Gut Microbiota: Population-Based Cross-Sectional Study. J Clin Med. 2018;7(9):282. Published 2018 Sep 14. doi:10.3390/jcm7090282
Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol. Lett. 2009; 294(1):1–8.
Mach N, Fuster-Botella D. Endurance exercise and gut microbiota: A review. J Sport Health Sci. 2017;6(2):179-197. doi:10.1016/j.jshs.2016.05.001
Markowiak P, Śliżewska K. Effects of Probiotics, Prebiotics, and Synbiotics on Human Health. Nutrients. 2017;9(9):1021. Published 2017 Sep 15. doi:10.3390/nu9091021
Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104-108. doi:10.1126/science.aao3290
Matsumoto M, Inoue R, Tsukahara T, et al. Voluntary running exercise alters microbiota composition and increases n-butyrate concentration in the rat cecum. Biosci. Biotechnol. Biochem. 2008; 72(2):572–6.
McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol. 2008;583(2-3):174‐185. doi:10.1016/j.ejphar. 2007.11.071
Medic G, Wille M, Hemels ME. Short- and long-term health consequences of sleep disruption. Nat Sci Sleep. 2017;9:151–61. 10.2147/NSS.S134864
Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124(10):4212-4218. doi:10.1172/JCI72333
Moreno-Pérez D., Bressa C., Bailén M., Hamed-Bousdar S., Naclerio F., Carmona M., Pérez M., González-Soltero R., Montalvo-Lominchar M.G., Carabaña C. Effect of a protein supplement on the gut microbiota of endurance athletes: A randomized, controlled, double-blind pilot study. Nutrition. 2018;10:337. doi: 10.3390/nu10030337
Mu Q, Kirby J, Reilly CM, Luo XM. Leaky Gut As a Danger Signal for Autoimmune Diseases. Front Immunol. 2017;8:598. Published 2017 May 23. doi:10.3389/fimmu.2017.00598
Nagpal R, Mainali R, Ahmadi S, et al. Gut microbiome and aging: Physiological and mechanistic insights. Nutr Healthy Aging. 2018;4(4):267-285. Published 2018 Jun 15. doi:10.3233/NHA-170030
Orla O’Sullivan, Owen Cronin, Siobhan F Clarke, Eileen F Murphy, Micheal G Molloy, Fergus Shanahan & Paul D Cotter (2015) Exercise and the microbiota, Gut Microbes, 6:2, 131-136, DOI: 10.1080/19490976.2015.1011875
Peck, SC., Denger, K., Burrichter, A, Irwin, SM., Balskus, EP., Schleheck, D., A glycyl radical enzyme enables hydrogen sulfide production by the human intestinal bacterium Bilophila wadsworthia. PNAS 2019. 116 (8): 3171–3176. doi:10.1073/pnas.1815661116.
Peled JU, Devlin SM, Staffas A, et al., Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J Clin Oncol. 2017 May 20; 35(15):1650-1659.
Penders J, Thijs C, van den Brandt PA, et al. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study. Gut. 2007;56(5):661-667. doi:10.1136/gut.2006.100164
Poroyko, V., Carreras, A., Khalyfa, A. et al. Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice. Sci Rep. 6, 35405 (2016). https://doi.org/10.1038/srep35405
Purohit V, Bode JC, Bode C, et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol. 2008;42(5):349-361. doi:10.1016/j.alcohol.2008.03.131
Queipo-Ortuño M.I., Boto-Ordoñez M., Murri M., Gómez-Zumaquero J.M., Clemente-Postigo M., Estruch R., Diaz F.C., Andres-Lacueva C., Tinahones F.J. Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am. J. Clin. Nutr. 2012;95:1323–1334. doi: 10.3945/ajcn.111.027847
Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5:e177
Routy B, Le Chatelier E, Derosa L et al., Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5; 359(6371):91-97
Rowland L, Gibson G, Heinken A, et al. Gut microbiota functions: metabolism of nutrients and other food components. Eur J Nutr. 2018;57(1):1‐24. doi:10.1007/s00394-017-1445-8
Savage DC. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 1977;31:107–133.
Santino A, Scarano A, De Santis S, De Benedictis M, Giovinazzo G, Chieppa M
Gut Microbiota Modulation and Anti-Inflammatory Properties of Dietary Polyphenols in IBD: New and Consolidated Perspectives. Curr Pharm Des. 2017; 23(16):2344-2351.
Savage DC. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 1977;31:107–133.
Sender R., Fuchs S., Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337–340. doi: 10.1016/j.cell.2016.01.013.
Sergeev IN, Aljutaily T, Walton G, Huarte E. Effects of Synbiotic Supplement on Human Gut Microbiota, Body Composition and Weight Loss in Obesity. Nutrients. 2020;12(1):222. Published 2020 Jan 15. doi:10.3390/nu12010222.
Smith RP, Easson C, Lyle SM, et al. Gut microbiome diversity is associated with sleep physiology in humans. PLoS One. 2019;14(10):e0222394. doi:10.1371/journal.pone.0222394
Tartar JL, Fins AI, Lopez A, Sierra LA, Silverman SA, Thomas SV, et al. Sleep restriction and delayed sleep associate with psychological health and biomarkers of stress and inflammation in women. Sleep health. 2015;1(4):249–56. 10.1016/j.sleh.2015.09.007
Taur Y, Jenq RR, Perales MA, Littmann ER et al., The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014 Aug 14; 124(7):1174-82.
Turnbaugh, P., Ley, R., Mahowald, M. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). https://doi.org/10.1038/nature05414
Vich Vila A, Collij V, Sanna S, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun 2020;11:362.doi:10.1038/s41467-019-14177
Walker RW, Clemente JC, Peter I, Loos RJF. The prenatal gut microbiome: are we colonized with bacteria in utero?. Pediatr Obes. 2017;12 Suppl 1(Suppl 1):3‐17. doi:10.1111/ijpo.12217
Weston S, Halbert A, Richmond P, Prescott SL. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child. 2005 Sep; 90(9):892-7.
Wolters, M., Ahrens J., Perez M.R., Watkins C., Sanz Y., Benítez-Páez A., Stanton C., Günther K. Dietary fat, the gut microbiota, and metabolic health–a systematic review conducted within the mynewgut project. Clin. Nutr. 2019;38:2504–2520. doi: 10.1016/j.clnu.2018.12.024.
Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105‐108. doi:10.1126/science.1208344
Yang Q, Liang Q, Balakrishnan B, Belobrajdic DP, Feng QJ, Zhang W. Role of Dietary Nutrients in the Modulation of Gut Microbiota: A Narrative Review. Nutrients. 2020;12(2):381. Published 2020 Jan 31. doi:10.3390/nu12020381
Yoon MY, Yoon SS. Disruption of the Gut Ecosystem by Antibiotics. Yonsei Med J. 2018;59(1):4-12. doi:10.3349/ymj.2018.59.1.4
Zeng W, Shen J, Bo T, et al. Cutting Edge: Probiotics and Fecal Microbiota Transplantation in Immunomodulation. J Immunol Res. 2019 :1603758. doi:10.1155/2019/1603758
Zou S., Fang L., Lee M.H. Dysbiosis of gut microbiota in promoting the development of colorectal cancer. Gastroenterol. Rep. 2018;6:1–12. doi: 10.1093/gastro/gox031