At least once a year I am compelled to dedicate this newsletter to the articles flooding our medical journals reiterating the importance of the gut in health and disease.
I WROTE A BOOK ABOUT THIS. VISIT hugorodier.com for more information.
In this issue you will find the raw data on how an imbalance of gut flora caused by antibiotics, pollutants, drugs, bad foods, and even C sections leads to practically all diseases, from simple gut issues to joint problems, arthritis, asthma, heart disease, brain problems and even cancer.
At least read the titles, ok? They are highlighted for you. I hope you find this information useful; but, as always, the most practical application is that you become more active, eat more veggies, quit eating processed foods and stop treating your symptoms with pharmaceuticals.
Hugo Rodier, MD
The Gut Microbiota and Host Health J.Gut. 2016;65(2):330-339.
Over the last 10–15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new ‘omic’ technologies that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.
Imagine the scenario: a scientist at a conference claims to have found a new organ in the human body. It is comparable to the immune system in as much as it is made up of a collection of cells, it contains a 100 times more genes than the host, is host-specific, contains heritable components, can be modified by diet, surgery or antibiotics, and in its absence nearly all aspects of host physiology are affected. While this may seem far-fetched, it is the current situation in which we find ourselves. We now realise that the human microbiota is an overlooked system that makes a significant contribution to human biology and development. Moreover, there is good evidence that humans co-evolved a requirement for their microbiota.
In the past decade, partly because of high resolution observational studies using next-generation sequencing technologies and metabolite profiling (see Box 1), the gut microbiota has become associated with promotion of health and the initiation or maintenance of different GI and non-GI diseases. As we enter the postmetagenomic era, we need to move away from simple observations to determine what are merely correlations and what are causal links—and focus efforts and resources on the latter. This postmetagenomic era is starting to provide new therapeutic targets based on a better understanding of how the microbiota interacts with the host’s physiology. Ultimately, we aim to integrate an individual’s microbiota into some form of personalised healthcare and, by better understanding its role, treat an individual’s diseases more efficiently and in a more targeted fashion. With a more complete understanding of the disease process, we will be able to more accurately stratify different disease states and determine whether or not the gut microbiota is a potential therapeutic target which we can modulate in order to treat specific diseases.
This review gives a much needed update on current understanding of the gut microbiota in GI diseases and metabolic disorders, and gives an insight into how this might impact on clinical practice. The evidence for the preventive and therapeutic benefit of different ways of modulating the gut microbiota, such as probiotics, prebiotics, antibiotics and faecal microbiota transplantation (FMT) (see Box 2), is reviewed.
Current Understanding of the Gut Microbiota
In the last decade, several large-scale projects, for example, the human microbiome project, have investigated the microbiota of a variety of bodily niches, including the skin as well as the oral, vaginal and nasal cavities. While some of these are relatively easy to access, the GI tract remains a challenging environment to sample, and to describe. Currently the majority of research is focused on the gut microbiota, since this is where the greatest density and numbers of bacteria are found, with most data being derived from faecal samples and, to a lesser extent, mucosal biopsies. While it is relatively easy to obtain fresh faecal samples, the information obtained from them does not represent the complete picture within the gut. From a number of limited studies, we know that the small intestine contains a very different abundance and composition of bacteria, with much more dynamic variation compared with the colon. The colonic microbiota is largely driven by the efficient degradation of complex indigestible carbohydrates but that of the small intestine is shaped by its capacity for the fast import and conversion of relatively small carbohydrates, and rapid adaptation to overall nutrient availability. While faeces are not an ideal proxy for the GI tract, they do give a snapshot of the diversity within the large intestine. Furthermore, the majority of the data comes from North American and European studies with very few studies in Asia, Africa or South America. Hence we have a somewhat biased view of the gut microbiota.
This rapid increase in interest in the microbiome has also been driven by the application of multi-‘omic’ technologies; we refer the reader to Lepage et al for more detailed explanation of these
What do we Know About the Gut Microbiota?
Bearing in mind the limitations above, the GI tract is often seen as a two phylum system (the Firmicutes and Bacteroidetes) although it should be noted that members of at least 10 different phyla can also have important functional contributions (see Box 3). We are also very bacteria-centric when we look at the gut microbiota; only a handful of papers have looked at the viral component (or virome) and micro-eukaryotes (protozoa and fungi). When the gut microbiota of relatively large cohorts of individuals (eg, more than 100) is analysed, it can be seen that the ratio of the Firmicutes:Bacteroidetes is not the same in all individuals. Currently we do not know the significance of being at either end of this continuum, especially as a large shift in the relative abundance of a group of organisms translates to a modest change in bacterial numbers. Yet there is evidence that depletion of a single species, for example, Faecalibacterium prausnitzii, belonging to the Firmicutes phylum, has been associated with IBD. But in the scientific literature, we see counterarguments for any involvement of this species in IBD. This disparity highlights the current status of understanding. We know that the gut microbiota is essential to the proper function and development of the host but we are unsure which are keystone species and whether the microbiota’s function is more important than any individual member of the community. But this is too simplistic a view. In several cases, strain differences within a species can be the difference between being a pathogen/pathobiont and being a probiotic: for example, Escherichia coli is associated with IBD and colorectal cancer (CRC)[7,8] yet an E. coli strain is used as a probiotic.
In fact, five phyla represent the majority of bacteria that comprise the gut microbiota. There are approximately 160 species in the large intestine of any individual and very few of these are shared between unrelated individuals. In contrast, the functions contributed by these species appear to be found in everybody’s GI tract, an observation that leads us to conclude that function is more important than the identity of the species providing it. Yet differences in the gut microbiota may matter because these may result in differences in the effectiveness of a function. For example, while the ability to synthesise short chain fatty acids (SCFAs) is found in all humans, their amounts can vary.
Dietary Modulation of the Gut Microbiota
Metabolic Activities of the Gut Microbiota
Carbohydrate fermentation is a core activity of the human gut microbiota, driving the energy and carbon economy of the colon. Dominant and prevalent species of gut bacteria, including SCFA-producers, appear to play a critical role in initial degradation of complex plant-derived polysaccharides, collaborating with species specialised in oligosaccharide fermentation (eg, bifidobacteria), to liberate SCFAs and gases which are also used as carbon and energy sources by other more specialised bacteria (eg, reductive acetogens, sulfate-reducing bacteria and methanogens). Efficient conversion of complex indigestible dietary carbohydrates into SCFA serves microbial cross-feeding communities and the host, with 10% of our daily energy requirements coming from colonic fermentation. Butyrate and propionate can regulate intestinal physiology and immune function, while acetate acts as a substrate for lipogenesis and gluconeogenesis. Recently, key roles for these metabolites have been identified in regulating immune function in the periphery, directing appropriate immune response, oral tolerance and resolution of inflammation, and also for regulating the inflammatory output of adipose tissue, a major inflammatory organ in obesity. In the colon, the majority of this carbohydrate fermentation occurs in the proximal colon, at least for people following a Western style diet. As carbohydrate becomes depleted as digesta moves distally, the gut microbiota switches to other substrates, notably protein or amino acids. Fermentation of amino acids, besides liberating beneficial SCFAs, produces a range of potentially harmful compounds. Some of these may play a role in gut diseases such as colon cancer or IBD. Studies in animal models and in vitro show that compounds like ammonia, phenols, p-cresol, certain amines and hydrogen sulfide, play important roles in the initiation or progression of a leaky gut, inflammation, DNA damage and cancer progression. On the contrary, dietary fibre or intake of plant-based foods appears to inhibit this, highlighting the importance of maintaining gut microbiome carbohydrate fermentation. Recognition of carbohydrate fermentation as a core activity of the gut microbiota provides the scientific basis for rational design of functional foods aimed at improving gut health and also for impacting on microbiota activities linked to systemic host physiology through newly recognised interkingdom axes of communication such as the gut:liver axis, the gut:brain axis and the gut:brain:skin axis.
Three ‘P’s’ for Gut Health: Probiotics, Prebiotics and Polyphenols
A number of dietary strategies are available for modulating either the composition or metabolic/immunological activity of the human gut microbiota: probiotics, prebiotics and polyphenols are among the most well established.
There are many examples of positive results with different probiotic strains against a range of disease states in animal models, however the human data are equivocal. This may partly be due to poor study design and poor choice of strain. However, there is also a persistent lack of understanding as to the very nature of probiotics, which cannot be considered a ‘class’ of bioactives, amenable to traditional efficacy assessments such as the meta-analysis (unless restricted to one strain), since they are all unique living organisms and their health-promoting traits are strain-specific. Rarely have probiotic strains been selected with specific mechanisms of effect in mind; this has led to conflicting observations and damaged the reputation of this area of science. A few exceptions do exist, most notably the work of Jones et al who selected a bile salt-hydrolysing Lactobacillus reuteri strain, to study its ability to reduce cholesterol levels in hypercholesterolaemic individuals. In two well powered, randomised, placebo-controlled and double-blinded studies, they demonstrated that ingestion of this strain significantly lowered total and low density lipoprotein (LDL)-cholesterol. Moreover, they suggested an underlying novel mechanism linked to reduced fat absorption from the intestine via the nuclear receptor farnesoid X receptor (FXR).
Prebiotics represent a specific type of dietary fibre that when fermented, mediate measurable changes within the gut microbiota composition, usually an increase in the relative abundance of bacteria thought of as beneficial, such as bifidobacteria or certain butyrate producers. As with probiotics, despite convincing and reproducible results from animal studies showing efficacy in prevention or treatment of many diseases (eg, IBD, IBS, colon cancer, obesity, type 2 diabetes (T2D) and cardiovascular disease), the data in humans remain ambiguous. Fewer well powered or well designed clinical studies have been conducted with prebiotics compared with probiotics, and there may be an issue with prebiotic dose. Human studies rarely, if ever, employ prebiotics. A prebiotic is shown to be efficacious in animal studies: typically 10% w/w of the diet, which in humans equates to about 50 g per day. However, as we learn more about the ecology of the gut microbiota, it is becoming clear that the prebiotic concept has tapped into the underlying fabric of the gut microbiota as a primarily saccharolytic and fermentative microbes community evolved to work in partnership with its host’s digestive system to derive energy and carbon from complex plant polysaccharides which would otherwise be lost in faeces.
Polyphenols are a diverse class of plant secondary metabolites, often associated with the colour, taste and defence mechanisms of fruit and vegetables. They have long been studied as the most likely class of compounds present in whole plant foods capable of affecting physiological processes that protect against chronic diet-associated diseases. The gut microbiota plays a critical role in transforming dietary polyphenols into absorbable biologically active species, acting on the estimated 95% of dietary polyphenols which reach the colon. Recent studies show that dietary intervention with polyphenol extracts, most notably dealcoholised red wine polyphenol extract and cocoa-derived flavanols, modulate the human gut microbiota towards a more ‘health-promoting profile’ by increasing the relative abundance of bifidobacteria and lactobacilli. These data again raise the possibility that certain functional foods tap into the underlying ecological processes regulating gut microbiome community structure and function, contributing to the health of the gut microbiota and its host.
Obesity-related Diseases and the Gut Microbiota
Starting around 2004, the hallmark studies of Gordon et al demonstrated a potential relationship between the gut microbiome and development of an obese phenotype. An increase in relative abundance of Firmicutes and a proportional decrease in Bacteroidetes were associated with the microbiota of obese mice, which was confirmed in a human dietary intervention study demonstrating that weight loss of obese individuals (body mass index, BMI>30) was accompanied by an increase in the relative abundance of Bacteroidetes. Nevertheless, based on most human studies, the obesity-associated decrease in the ratio of Bacteroidetes to Firmicutes (B:F) remains controversial.[24,25] This is likely due to heterogeneity among human subjects with respect to genotype and lifestyle. Recent studies have identified diet, especially fat, as a strong modulator of the microbiota, particularly in inbred and age-standardised laboratory animals. The sources of variation in the microbiota are mainly limited to the experimental diets used, and there is growing evidence that the high fat intake rather than obesity per se had a direct effect on the microbiota and linked clinical parameters. However, in humans the microbiome is exposed to fundamentally different ‘environmental’ factors in obese and lean individuals that go beyond BMI alone, including diet and host hormonal factors. In addition, the aetiology of obesity and its metabolic complications, including low grade inflammation, hyperlipidaemia, hypertension, glucose intolerance and diabetes, reflect the complex interactions of these multiple genetic, behavioural and environmental factors. Lastly, the accuracy of BMI as an indicator for obesity is limited; 25% of obese people could in fact be regarded as metabolically ‘healthy’ (ie, with normal lipid and glucose metabolism). Therefore, linking GI tract microbial composition directly and exclusively to obesity in humans will remain challenging due to the various confounding factors within the heterogeneous population.
This complexity has led to a shift from treating obesity as a single phenotype, to attempts at correlating microbial signatures to distinct or multiple features associated with (the development of) metabolic syndromes such as T2D. Recently, two (meta)genome-wide association studies were performed, with 345 Chinese individuals and 145 European women. In both studies, de novo generated metagenomic species-level gene clusters were employed as discriminant markers which, via mathematical modelling, could better differentiate between patients and controls with higher specificity than a similar analysis based on either human genome variation or other known risk factors such as BMI and waist circumference. At the functional level, membrane transporters and genes related to oxidative stress were enriched in the microbiota of patients, while butyrate biosynthesis was decreased. Although both studies observed high similarities in microbial gene-encoded functions, the most discriminant metagenomic species-level gene clusters differed between the cohorts (Akkermansia did not contribute to the classification in the European cohort whereas Lactobacillus showed no contribution in the Chinese study population), indicating that diagnostic biomarkers could be specific to the population studied.
In another metagenomic study, a bimodal distribution of microbial gene richness in obese individuals was observed, stratifying individuals as High Gene Count or Low Gene Count (HGC and LGC). HGC individuals were characterised by higher prevalence of presumed anti-inflammatory species such as F. prausnitzii, and an increased production potential of organic acids (including butyrate). In contrast, LGC individuals showed higher relative abundance of potentially proinflammatory Bacteroides spp and genes involved in oxidative stress response. Remarkably, only biochemical obesity-associated variables, such as insulin resistance, significantly correlated with gene count while weight and BMI did not, underscoring the inadequacy of BMI as an indicator for ‘Obesity and its Associated Metabolic Disorders’ (OAMD). An accompanying paper demonstrated that a diet-induced weight-loss intervention significantly increased gene richness in the LGC individuals which was associated with improved metabolic status. Although gene richness was not fully restored, these findings support the reported link between long-term dietary habits and the structure of the gut microbiota. It also suggests permanent adjustment of the microbiota may be achieved through diet.
Most studies involving the microbiome have been solely correlative but recently a causal relationship was established between host glucose homoeostasis and gut microbial composition. FMT from lean donors to individuals with metabolic syndrome significantly increased their insulin sensitivity. The transplant produced an increase in faecal butyrate concentrations, microbial diversity and the relative abundance of bacteria related to the butyrate-producing Roseburia intestinalis.
Together, these studies produce a body of evidence that the microbiome plays a role in host energy homoeostasis and the establishment and development of OAMD, although the exact mechanisms remain obscure. Previous contradictory findings might be attributed to miscellaneous approaches, and also heterogeneity in genotype, lifestyle and diet of humans combined with the complex aetiology of OAMD. Nonetheless, a clearer picture is emerging. The gut of individuals with OAMD is believed to harbour an inflammation-associated microbiome, with a lower potential for butyrate production and reduced bacterial diversity and/or gene richness. Although the main cause of OAMD is excess caloric intake compared with expenditure, differences in gut microbial ecology might be an important mediator and a new therapeutic target or a biomarker to predict metabolic dysfunction/obesity in later life.
Liver Disease and the Gut Microbiota
The liver receives 70% of its blood supply from the intestine via the portal vein, thus it is continually exposed to gut-derived factors including bacterial components, endotoxins (lipopolysaccharide, flagellin and lipoteichoic acid) and peptidoglycans. Multiple hepatic cells, including Kupffer cells, sinusoidal cells, biliary epithelial cells and hepatocytes, express innate immune receptors known as pathogen-recognition-receptors that respond to the constant influx of these microbial-derived products from the gut. It is now recognised that the gut microbiota and chronic liver diseases are closely linked. Characterising the nature of gut dysbiosis, the integrity of the gut barrier and mechanisms of hepatic immune response to gut-derived factors is potentially relevant to development of new therapies to treat chronic liver diseases. Furthermore the field of bile acid signalling has thrown open the concept of the gut:liver axis as being active and highly regulated.
Non-alcoholic Fatty Liver Disease
The pathophysiology of NAFLD is multifactorial with strong genetic and environmental contributions. Recent evidence demonstrates that gut microbiota dysbiosis can result in the development of obesity-related non-alcoholic fatty liver disease (NAFLD), and patients with NAFLD have small intestinal bacterial overgrowth and increased intestinal permeability. In the 1980s, development of non-alcoholic steatohepatitis (NASH) and small intestinal bacterial overgrowth was observed in humans after intestinal bypass and, interestingly, regression of hepatic steatosis after metronidazole treatment, suggesting a possible role for the gut bacteria in NAFLD. Disruption of the murine inflammasomes (see Box 1) is associated with an increase in Bacteroidetes and reduction in Firmicutes and results in severe hepatic steatosis and inflammation. Faecal microbiota analysis of patients with NAFLD and NASH has produced variable results due to significant variation of patient demographics, severity of liver disease and methodology. A lower proportion of Ruminococcaceae was noted in patients with NASH compared with healthy subjects and a study which characterised gut microbiota of children with NASH, obesity and healthy controls showed that patients with NASH had a higher proportion of Escherichia compared with other groups. Patients with NAFLD also have increased gut permeability suggesting that translocation of bacteria or microbe derived products into the portal circulation contributes to the pathogenesis.
Alcoholic Liver Disease
Since not all alcoholics develop liver injury, it appears that chronic alcohol abuse is necessary but not sufficient to cause liver dysfunction. Numerous animal model and human observational studies indicate that gut bacterial products like endotoxin may mediate inflammation and function as cofactors for the development of alcohol-related liver injury. Serum endotoxin levels are elevated in humans and rats with alcoholic liver disease, and monocytes from alcoholics are primed to produce cytokines after endotoxin exposure. Alcohol causes intestinal bacterial overgrowth in humans and bacterial numbers were significantly higher in jejunal aspirates from patients with chronic alcohol abuse compared with controls, with similar findings in patients with alcohol-induced cirrhosis. The degree of overgrowth correlates with the severity of cirrhosis. Tsukamoto-French model mice fed intragastrically with alcohol for 3 weeks showed increased relative abundance of Bacteroidetes and Akkermansia spp and a reduction in Lactobacillus, Leuconostoc, Lactococcus and Pediococcus while control mice showed a relative predominance of Firmicutes. Patients with alcoholic liver disease also show increased gut permeability, allowing translocation of bacteria and bacterial products to the liver.
Autoimmune Liver Diseases
These consist of primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) and autoimmune hepatitis and represent at least 5% of all chronic liver diseases. They are presumed autoimmune conditions but the expectation is that the gut microbiota is relevant to pathogenesis, particularly because (A) PSC is associated with IBD and aberrant lymphocyte tracking, and (B) significant gut:liver axes exist through bile acid signalling. Patients with PSC develop a distinct form of IBD thus understanding the relationship between PSC and IBD is essential in uncovering the pathogenesis of PSC, which remains largely undetermined. However, it is likely that in genetically susceptible individuals, intestinal bacteria could trigger an abnormal or inadequate immune response that eventually leads to liver damage and fibrosis. Recently it was shown that patients with PSC have distinct gut microbiota. Analysis of colon biopsy microbiota revealed that patients with PSC-IBD and IBD showed reduced abundance of Prevotella and Roseburia (a butyrate-producer) compared with controls.[48,49] Patients with PSC-IBD had a near-absence of Bacteroides compared with patients with IBD and control patients, and significant increases in Escherichia, Lachnospiraceae and Megasphaera. Randomised controllled trials (RCTs) investigating antibiotic therapy in PSC have shown these to be superior in improving biochemical surrogate markers and histological parameters of disease activity compared with ursodeoxycholic acid alone. In a recent prospective paediatric case series, oral vancomycin was shown to normalise or significantly improve liver function tests. There is evidence that mucosal integrity is compromised in patients with PSC, supporting the traditional leaky gut hypothesis of microbe-derived products translocating to the liver and biliary system to trigger an inflammatory reaction. It was also demonstrated that tight junctions of hepatocytes were impaired in patients with PSC and infusion of non-pathogenic E. coli into portal circulation caused portal fibrosis in animal models. These findings collectively suggest that bacterial antigens translocate across a leaky and possibly inflamed gut wall into the portal and biliary system to induce an abnormal immune response and contribute to PSC pathogenesis.
PBC is a chronic cholestatic liver disease with an uncertain aetiology. It is generally believed to be an autoimmune disease triggered by environmental factors in individuals with genetic susceptibility. As yet, there have been no studies directly characterising the gut microbiota in patients but molecular mimicry has been suggested as a proposed mechanism for the development of autoimmunity in PBC, with serum antibodies of patients cross-reacting with conserved bacterial pyruvate dehydrogenase complex component E2 (PDC-E2) homologues of E. coli, Novosphingobium aromaticivorans, Mycobacterium and Lactobacillus species. Hence it has been speculated that these bacteria (of possible GI origin) may initiate molecular mimicry and development of PBC in genetically susceptible hosts.
Modulation of the Microbiota as a Therapy in Liver Disease
Probiotics have shown promise in ameliorating liver injury by reducing bacterial translocation and hepatic inflammation. A recent meta-analysis concluded that probiotics can reduce liver aminotransferases, total cholesterol, tumour necrosis factor α and improve insulin resistance in patients with NAFLD. A recent study in patients with cirrhosis with ascites showed that the probiotic VSL#3 significantly reduced portal hypertension. A further study evaluated the role of FMT in modulating liver disease by transferring the NAFLD phenotype from mice with liver steatosis to germ-free mice. There remains a need for detailed descriptive and interventional studies focused on bacterial diversity and mechanisms linking gut dysbiosis with inflammatory, metabolic and autoimmune/biliary liver injury.
BD and the Gut Microbiota
Early studies implicating bacteria in IBD pathogenesis focused on identifying a potential culprit that could initiate the inflammatory cascade typical of IBD. Many organisms have been proposed: Mycobacterium avium subsp paratuberculosis and a number of Proteobacteria including enterohepatic Helicobacter, non-jejuni/coli Campylobacter and adherent and invasive E. coli. The focus has recently shifted with the realisation that the gut microbiota as a whole is altered in IBD. The concept of an altered gut microbiota or dysbiosis is possibly the most significant development in IBD research in the past decade. A definitive change of the normal gut microbiota with a breakdown of host-microbial mutualism is probably the defining event in IBD development.
Changes in the gut microbiota have been repeatedly reported in patients with IBD, with certain changes clearly linked to either Crohn’s disease (CD) or UC: the most consistent change is a reduction in Firmicutes. This has been balanced by reports of increased levels of Bacteroidetes phylum members, although a reduction in Bacteroidetes has also been reported. There is a suggestion that there may be spatial reorganisation of the Bacteroides species in patients with IBD, with Bacteroides fragilis being responsible for a greater proportion of the bacterial mass in patients with IBD compared with controls.
Reduction in the Firmicutes species F. prausnitzii has been well documented in patients with CD, particularly those with ileal CD, although an increase in F. prausnitzii has been shown in a paediatric cohort, suggesting a more dynamic role for the species that merits further study. Other studies have also demonstrated a decrease in Firmicutes diversity, with fewer constituent species detected in patients with IBD compared with controls. Changes in the two dominant phyla, Firmicutes and Bacteroidetes, are coupled with an increase in abundance of members of the Proteobacteria phylum, which have been increasingly found to have a key role in IBD. Studies have shown a shift towards an increase in species belonging to this phylum, suggesting an aggressor role in the initiation of chronic inflammation in patients with IBD. More specifically, increased numbers of E. coli, including pathogenic variants, have been documented in ileal CD. The IBD metagenome contains 25% fewer genes than the healthy gut with metaproteomic studies showing a correlative decrease in proteins and functional pathways. Specifically, ileal CD has been shown to be associated with alterations in bacterial carbohydrate metabolism and bacterial-host interactions, as well as human host-secreted enzymes. A detailed investigation of functional dysbiosis during IBD built on this by including inferred microbial gene content from 231 subjects and an additional 11 metagenomes. This study identified enrichment in microbial pathways for oxidative stress tolerance, immune evasion and host metabolite uptake, with corresponding depletions in SCFA biosynthesis and typical gut carbohydrate metabolism and amino acid biosynthetic processes. Intriguingly, similar microbial metabolic shifts have been observed in other inflammatory conditions such as T2D, suggesting a common core gut microbial response to chronic inflammation and immune activation. In addition, recent work suggests a role for viruses in IBD, with a significant expansion of Caudovirales bacteriophage in patients.
Modulation of the Microbiota as a Therapy in IBD
Several clinical trials have examined the approach of modulating the microbiota in patients with IBD, many of which predate the ‘omics’ era. Such trials provide a ‘proof of concept’ for the importance of the role of the gut microbiota in IBD, but marrying up individual approaches with the complex multifactorial nature of IBD remains a challenge, particularly in addressing the different phenotypes and genotypes of disease and the different ‘phases’ of the disease process: for example, prophylaxis, maintenance of remission, treatment of relapses.
In terms of probiotic research, one of the largest clinical trials in IBD was the use of E. coli Nissle 1917 in the setting of remission maintenance in UC. Patients (n=327) were assigned to a double-blind, double-dummy trial to receive either the probiotic or mesalazine. Both treatments were deemed equivalent with regards to relapse. E. coli Nissle is now considered an effective alternative to 5-aminosalicylate for remission maintenance in UC. There are two published clinical trials of the multistrain probiotic VSL#3 in the setting of mild to moderate flares of UC. Both demonstrate that high doses improve disease activity scores but whether such improvements in scores are clinically meaningful for patients, particularly compared with other treatment options, remains to be clarified. An alternative approach is transplantation of the whole gut microbiota from a healthy donor: FMT. In IBD, a recent systematic review and meta-analysis has shown that of nine cohort studies, eight case studies and one randomised controlled trial, overall 45% (54/119) achieved clinical remission. When only cohort studies were analysed 36% achieved clinical remission. Since that meta-analysis, two randomised controlled trials in UC show discrepant results. One trial, in which two faecal transplants were given via the upper GI route, showed no difference in clinical or endoscopic remission between the faecal transplant group and the control group (given autologous stool). A second trial, in which patients with UC were randomised to weekly faecal enemas from healthy donors or placebo enemas for 6 weeks, demonstrated remission in a greater percentage of patients given FMT compared with the control group (given water enema). There are unanswered questions regarding mode of delivery, frequency of delivery and optimal donor/host characteristics.
Antibiotics demonstrate efficacy in particular groups of patients with CD but some antibiotics may be detrimental, showing a complex interplay between host and microbiota. Patients who have had a resection for CD have a decreased rate of endoscopic and clinical recurrence when metronidazole or ornidazole are used as prophylactic therapies. Several studies have assessed the specific role of antimycobacterial therapies in CD treatment but overall results are disappointing. There is no clinically relevant evidence base for the use of probiotics in CD and in terms of prebiotics, although an open label trial of fructo-oligosaccharide in CD showed promise, and a subsequent randomised placebo-controlled trial of fructo-oligosaccharide did not support any clinical benefit.
Restorative proctocolectomy with ileal-pouch anal anastomosis is the operation of choice for patients with UC requiring surgery. Pouchitis has an incidence of up to 50% of patients although it is a significant clinical problem for only about 10%. Antibiotics are used as primary therapy; if single antibiotics fail, dual antibiotics used for longer periods of time or antibiotics tailored to the microbiota in an individual patient can be used. VSL#3 reduced the risk of disease onset and maintained an antibiotic-induced disease remission in pouchitis. A meta-analysis has shown that VSL#3 significantly reduced the clinical relapse rates for maintaining remission in patients with pouchitis.[82
CRC and the Gut Microbiota
Many microbiome studies have focused on colitis-associated cancers or rodent preclinical models. Despite this, there is increasing evidence that the colonic microbiota plays an important role in the cause of sporadic CRC. Reduced temporal stability and increased diversity has been shown for the faecal microbiota of subjects with established CRC and polyposis, and now metagenomic and metatranscriptomic studies have identified an individualised oncogenic microbiome and specific bacterial species that selectively colonise the on-tumour and off-tumour sites.
Several competing theories of the microbial regulation of CRC have emerged (figure 1) to explain these observations. The keystone-pathogen hypothesis and the α-bug hypothesis both state that certain, low abundance microbiota members (such as enterotoxigenic B. fragilis) possess unique virulence traits, which are pro-oncogenic and remodel the microbiome and in turn promote mucosal immune responses and colonic epithelial cell changes. Tjalsma et al have also proposed the ‘driver-passenger’ model for CRC: a first hit by indigenous intestinal bacteria (‘bacterial drivers’), which drive the DNA damage that contributes to CRC initiation. Second, tumorigenesis induces intestinal niche alterations that favour the proliferation of opportunistic bacteria (‘bacterial passengers’). For example, CRCs have an increased enrichment of opportunistic pathogens and polymicrobial Gram-negative anaerobic bacteria but it is not yet clear whether these opportunistic pathogens merely benefit from the CRC microenvironment or influence disease progression. However, colonic polyps demonstrate higher bacterial diversity and richness when compared with control patients, with higher abundance of mucosal Proteobacteria and lower abundance of Bacteroidetes. This may in part be explained by the mucosal defensive strategies designed to manage the commensal microbiota. For example, α-defensin expression is significantly increased in adenomas resulting in an increased antibacterial activity compared with normal mucosa.
Proposed mechanisms of the gut microbiome in colon cancer aetiology.
At present, human studies have involved small patient numbers, with evidence of sampling heterogeneity, limited tumour phenotyping and oncological data. Despite this, a small number of specific pathobionts have now been linked with adenomas and CRC including Streptococcus gallolyticus,Enterococcus faecalis and B. fragilis.E. coli is also overexpressed on CRC mucosa; it expresses genes that confer properties relevant to oncological transformation including M cell translocation, angiogenesis and genotoxicity. Enrichment of Fusobacterium nucleatum has also been identified in adenoma versus adjacent normal tissue and is more abundant in stools from CRC and adenoma cases than in healthy controls. F. nucleatum’s fadA, a unique adhesin, allows it to adhere to and invade human epithelial cells, eliciting an inflammatory response and stimulating cell proliferation. Novel mechanisms from previously unassociated bacteria are also being described to explain how bacterial proteins target proliferating stem-progenitor cells. For example, AvrA, a pathogenic product of Salmonella, has been shown to activate β-catenin signals and enhance colonic tumorigenesis.
Work has also focused on the metabolic function of the gut microbiome and dietary microbiome interactions in the aetiology of CRC. It is likely that the metabolism of fibre is critical to this. Metagenomic analyses have consistently identified a reduction of butyrate-producers in patients with CRC, a finding replicated in animals. The microbiome also plays an important role in the metabolism of sulfate, through assimilatory sulfate-reduction to produce cysteine and methionine, and dissimilatory sulfate-reduction to produce hydrogen sulfide (H2S). H2S is likely to contribute to CRC development, as colonic detoxification of H2S is also reduced in patients with CRC; it also induces colonic mucosal hyperproliferation. There is also evidence that differences in host genotype, which affect the carbohydrate landscape of the distal gut, interact with diet to alter the composition and function of resident microbes in a diet-dependent manner. Therefore it is possible that patients genetically predisposed to CRC have a modified metabolically active microbiome, which is determined by their genes and by their family environment and dietary habits. There is other evidence from global studies of cancer risk, that the microbiome is important in cancer risk.
African Americans possess a colon dominated by Bacteroides, while in Africans Prevotella are more abundant. African Americans, who are at high risk of CRC, may have evolved a CRC-microbiota moulded by dietary habits and environmental exposures. Critically, mucosal Ki67 expression (a biomarker for cancer risk) may decrease or increase within 2 weeks of either a high fibre (>50 g/day) dietary intervention in African Americans or a high fat, high protein low fibre Westernised diet in African subjects. This short-term intervention leads to reciprocal changes in luminal microbiome co-occurrence network structures that overwhelm interindividual differences in microbial gene expression. Specifically, an animal-based diet increases the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreases the levels of Firmicutes that metabolise dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii).[105,106]
In the past decade, interest in the human microbiome has increased considerably. A significant driver has been the realisation that the commensal microorganisms that comprise the human microbiota are not simply passengers in the host, but may actually drive certain host functions as well. In sterile rodents, we see the dramatic impact that removing the microbiota has on nearly all aspects of the host’s ability to function normally. This review highlights some key disease areas in which the microbiota and its microbiome are thought to have not just an association, but also a key modulatory role. By better understanding the mechanisms and contribution the microbiota make to these diseases, we hope to develop novel therapeutics and strategies to modulate the microbiota to treat or prevent disease. Additionally, in some instances it may be possible to use the microbiome to detect gut-related diseases before conventional diagnostics can. In the future we hope to use this information to stratify patients more accurately and for more efficient treatment. A body of evidence also points to the gut microbiota being an environmental factor in drug metabolism, for example, inactivation of the cardiac drug digoxin by Eggerthella lenta in the gut. Thus, if we are to realise the vision of a personalised healthcare revolution, we must explore how the microbiome fits with this notion.
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THE GUT-JOINT AXIS
Medscape: When did the idea develop that our microbiota might play a role in rheumatologic disease?
Jose Scher, MD: This is a very old idea. The notion that gut material has a particular link with rheumatic disease has been around for at least 100 years, if not more. This was based on something called the toxemic factor hypothesis. The whole idea was that there were enough anaerobic bacteria in the gut that produced some sort of toxic factor that, when absorbed, would cause systemic inflammation of the joints.
There are also historical data suggesting that rheumatoid arthritis is a disease that was passed from Native American tribes to European conquerors when they came in the mid-15th century. These data come from Rothschild and Woods and look specifically at skeletal remains in many different museums. Essentially, what they showed was that only remains from North American populations from 2000 or 3000 years ago had erosive disease related to rheumatoid-type damage. If you now go around the world and try to find similar skeletal remains with this phenotype, you won’t find it.
The literature never really described rheumatoid-type disease until the late 18th century into the 19th century, so there is no real description of the disease. Forget about calling it “rheumatoid arthritis.”
All of this information combined has suggested that there is a vector that actually transmits disease.
With all of this in mind, I always give the example of sulfasalazine. In the 1940s, sulfasalazine was the first rationally designed disease-modifying antirheumatic drug for rheumatoid arthritis. The idea was to combine a sulfa antibiotic with a salicylate, to provide anti-inflammatory medication at the same time as giving an antibiotic to target gut microorganisms.
Medscape: In the past 5 or 10 years, we have seen an explosion in microbiome research. How has this influenced rheumatology?
Dr Scher: The Human Microbiome Project started grew out of a fundamental idea from Joshua Lederberg—a very important microbiologist who was a Nobel Laureate at the age of 35 years—who said that the microbiome is a totality of microorganisms in our bodies that we haven’t paid enough attention to. He recognized that we have about 100 trillion microbial cells coding for about 3 million different genes, which is 100-fold higher than the human genome. They are there, and they are doing something. You can’t ignore them.
These microorganisms are essentially promoting health. With them, we have coevolved over thousands of years to live peacefully. The fundamental question is: If you alter the “normal” composition of the gut microbiota, can that lead to disease? Is there a triggering event or something downstream in terms of immune properties that these microorganisms now promote?
The answer, at least from animal models, is yes. I will give you the examples that have been out there. If you keep animals that are predisposed to get arthritis under germ-free environments—no microbes whatsoever—they typically don’t get disease. If you then take these animals and raise them in conventional cages where there are normal microbes, they start getting the arthritis phenotype. This is true whether it is an induced arthritis model or a spontaneous arthritis model. They have been implicated as triggering factors for inflammation of the joints
Medscape: We are starting to see human data in this area as well, correct?
Dr Scher: Yes. What we and some other groups have been doing is trying to take the animal information into the human world. There have been some advances. Mainly, they come from work in inflammatory bowel disease, where there was always this idea that an alteration of the gut microbiota led to Crohn disease or ulcerative colitis. That is pretty much advanced.
What we have been doing with some other groups is trying to look at the different mucosal types and see whether there are any differences in terms of the relative composition of these microbes.
Medscape: Can you speak about your work profiling the gastrointestinal microbes in patients with rheumatoid arthritis?
Dr Scher: Yes; they are different. Some other people have done this with what we call “low-throughput technology.” They have used polymerase chain reaction and some other approaches.
We have used high-throughput sequencing, which is essentially trying to get the entire population of microbes in any given niche. We have done that in oral mucosal periodontal disease. This is a chronic infection of the mouth or the gums.
Then, we moved into the intestinal microbe, where there are several correlations. We have seen a striking correlation with one particular species in rheumatoid arthritis.
There are similar data from a Chinese group, so now we have been trying to understand what it means. Essentially, these are correlative studies without necessarily showing causation just yet.
Medscape: Are clinicians beginning to sequence the microbiome in their patients with rheumatoid arthritis or other diseases?
Dr Scher: I know of a few companies that are doing it, but these are laboratory companies that are doing it without a complete scientific rationale. They are doing it for the public, which is a little concerning, because we haven’t established a causal relationship at this point.
Beyond rheumatoid arthritis is a fascinating story about subclinical gut inflammation in patients with spondyloarthritis. We know that patients with ankylosing spondylitis or psoriatic arthritis seem to have some gut inflammation that is not necessarily full-blown Crohn disease or ulcerative colitis. We know that Crohn disease and ankylosing spondylitis, or Crohn disease and psoriasis or psoriatic arthritis, have been linked for many, many years—mainly on the basis of the bidirectional correlation that lots of patients with Crohn disease will develop arthritis.
Typically, it is called “inflammatory bowel disease-related arthropathy,” which is part of the spondyloarthritis spectrum. These patients can also get ankylosing spondylitis and psoriasis. We also know that patients with psoriasis and psoriatic arthritis are at a higher risk of developing Crohn disease, so there is an association between all of these diseases.
We have seen that there is some sort of decrease in the overall commensals in the intestinal microbiome of both psoriasis and psoriatic arthritis, but if you look at the literature, these commensals are also absent or decreased in patients with inflammatory bowel disease.
Medscape: In the next few years, do you see microbiome alteration being an effective treatment for arthritis or other rheumatologic conditions?
Dr Scher: We are in this space in which we are trying to better understand these mechanisms. We have animal models of psoriatic arthritis right now and are trying to see what happens when you incorporate those microorganisms that are missing.
Medscape: So this would be akin to customized probiotics?
Dr Scher: Yes, in way. But it is not completely a probiotic approach, because the probiotics are swallowed. Such probiotics as Lactobacillus and a few others have exponentially grown the revenue of yogurt companies. Most support and funding for the microbiome is coming from Nestlé, Dannon, and other yogurt companies.
Another issue is with the metabolites. We know that certain metabolites have been produced by the microbes in downstream effects, so you don’t necessarily require these microorganisms. All you need is the metabolites that they produce. Some data show that if you incorporate some of the fatty acids that are missing in psoriasis and in Crohn disease in animals, they make disease either go away or get much better, particularly in psoriatic arthritis. So, it is not necessarily relevant to repopulate the microbes. What is important is to add the metabolites back into the intestine.
Something more relevant to clinicians is understanding the effects of our medications on the microbiota. Are biologic therapies or disease-modifying antirheumatic agents modifying the composition of the microbiota? If so, are they responsible for some of the side effects, the actual clinical effect, or the bioavailability of our drugs? In other words, if you take disease-modifying antirheumatic drugs and your microbiota is actually not altered, is it possible that your microbiota processes the drugs differently?
These are the more advanced ways of looking at the microbiota that are not necessarily related to etiology, mostly what we call “pharmacomicrobiotics.” How can we make use of the microbes to help us personalize medicine in rheumatology? In other words, can we predict who is going to respond to which medication on the basis of their microbiota?
Medscape: What about the mycobiota, or the fungi that in part make up the microbiota, which we’ve been hearing a bit about lately? Have you been studying this?
Dr Scher: We are studying this as well. There are animal models in arthritis that are fungus-driven. The SKG animal model, for instance, is an arthritis model that gets disease because of a fungal cell-wall component. But what is the microbiome doing in the intestine?
There are various aspects of what we are trying to do, especially in inflammatory bowel disease-related arthropathy. That seems to have some traction right now. Maybe it is more about the fungal microorganisms that are now part of the microbiome and are triggering inflammatory bowel disease-related arthritis.
Medscape: So this research is in its early stages?
Dr Scher: Very few data are available here yet. We are working with some of the new medications that are targeting the microbiota, and we think that the drug/microbiome interaction is what is causing the side effects, particularly in inflammatory bowel disease.
Medscape: Any final thoughts on the role of the microbiome and how it is going to influence rheumatology in the next 5 years?
Dr Scher: Let me be blunt here: Everything is about the microbiome now. It seems like every single disease will be caused by the microbiome, right? It is a hot topic in the same way that genome-wide association study was 10 years ago.
My responsible answer is that this needs to get done. There will be a lot of noise and a lot of correlative data that won’t take us further. Some of it will remain true, and that is what we are working on.
This also creates a lot of expectations and anxiety in patients. The way this comes across for the patient population is that a bug causes their disease, and they think that they are going to cure their disease through diet and antibiotics. It is not as simple as that. It is a different disease model. I am not so sure that we are going to find too many etiologic factors in the microbiome, and I am more enthusiastic about how the microbiome will help us understand how our treatments work and whether or not response to therapy is altered by having these microbes living with us.
This is kind of a cautionary note, because this is in the community and the next thing you know, my office is packed with people who want to be on the “leaky gut diet.” It creates a lot of expectations. This is just the beginning of the field. We are going to fail way more than we will succeed. The good news is that we will succeed in at least some aspects of this, and we will move this field forward—and that is great.
- Rothschild BM, Woods RJ. Symmetrical erosive disease in archaic Indians: the origin of rheumatoid arthritis in the New World? Semin Arthritis Rheum. 1990;19:278-284.
- Scher JU, Ubeda C, Equinda M, et al. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 2012;64:3083-3094.
- Zhang X, Zhang D, Jia H, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21:895-905.
THE GUT-BRAIN CONNECTION Medscape March 2016
The gut microbiome is a key component of our immune system and mediates a lot of the communication along our HPA axis. The gut microbiome has three different ways of communicating with the brain: hormonally, via the immune system, and via direct mechanisms. Some of the microorganisms in your gut actually release neurotransmitters that speak to your brain via the vagus nerve.[1-3]
Animal studies have shown that you can change a rodent’s behavior just by changing the microbiome. There are numerous ways to do this, including probiotics, antibiotics, prebiotics (fibers that feed the microbiota), and fecal transplants.
In human studies, probiotics have been shown to reduce negative thinking in healthy human subjects and reduce anxiety in subjects undergoing cancer treatment. One dramatic but rather small study showed that the administration of probiotics to babies significantly reduced the development of autism or ADHD 13 years later.
Right now, researchers are working on strains of so-called “psychobiotics” that we might be using as part of our armamentarium in the future to fight mental illness.
What can we do right now? We know that poor sleep, poor diet, chronic stress, and too much alcohol adversely affect our microbiome. The effect is almost immediate. You can have a 40% reduction in the diversity of your microbiome within 10-14 days of eating a highly processed food diet.
It is believed that this dietary interaction with the microbiome may explain why people who eat a traditional whole-foods diet are up to 40% more resilient to stress and developing mental illness than those who eat a processed Western foods diet.
Avoiding processed foods and reinforcing good sleep habits are strong evidence-based recommendations that you as a clinician can make today that can help your patients and their microbiomes at the same time.
If your patients have irritable bowel syndrome, there is now a large body of evidence showing that probiotics can help not only their irritable bowel but possibly anxiety and associated depression as well.
Every month, new and exciting studies emerge about the microbiome and mental health. We will be sure to stay on top of the evidence and report back to you here at Medscape Psychiatry. If you want to dive deeper, many of the references are open access and are great reads for you. Thank you and have a great day.
- Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014 May;38:1-12.
- Raison CL, Lowry CA, Rook GA. Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression. Arch Gen Psychiatry. 2010;67:1211-1224. Abstract
- Berk M, Williams LJ, Jacka FN, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Medicine. 2013;11:200.
- Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015;48:258-264. Abstract
- Yang H, Zhao X, Tang S, et al. Probiotics reduce psychological stress in patients before laryngeal cancer surgery. Asia Pac J Clin Oncol. 2014 Feb 20. [Epub ahead of print]
- Pärtty A, Kalliomäki M, Wacklin P, Salminen S, Isolauri E. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res. 2015;77:823-828.
Antibiotic-associated encephalopathy, J. Neurology March 8, 2016 vol. 86 no. 10 963-971. Antibiotics may upset the balance of gut flora with negative consequences on brain function
Migraines linked to Irritable Bowel Syndrome.February 23 2016 ahead of presentation in April at the American Academy of Neurology (AAN) 68th Annual Meeting in Vancouver, Canada.
THE GUT AND THE LUNGS
The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia Gut 2016;65:575
Gut to lung J. Gut 2016;65:544-545 doi:10.1136/gutjnl-2015-310599. Over the last few years, microbiome-focused studies have propelled our understanding of the importance and contribution of several species of gut microbes to immunity and tissue homeostasis.1 Certain microbiota were discovered to essentially shape the intestinal immune system, and changes in the composition of the gut microbiome were found associated with a wide range of diseases, including IBD, metabolic diseases such as diabetes or even neurological disorders like autism.1 These studies laid the foundation for novel therapeutic interventions like microbiome-tailored treatments. As a first, seemingly simple but nevertheless effective step, faecal microbiota transplantation (FMT) is increasingly recognised as a powerful means to treat conditions associated with dysbiosis, most notably Clostridium difficile enteritis. In a parallel attempt, the lungs moved into the focus of microbe-interested scientists and clinicians alike. As a result, the lung microbiome as its own unique habitat was explored, ending the century-old misconception that lungs are sterile sites. Empowered by more sophisticated technical tools like pyrosequencing, a number of studies established the composition of the lung microbiome in healthy people and discovered various degrees of alterations.
MICROBIOME, CHILDREN AND PREGNANCY
Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer Nature Medicine22,250–253(2016) Exposure of newborns to the maternal vaginal microbiota is interrupted with cesarean birthing. Babies delivered by cesarean section (C-section) acquire a microbiota that differs from that of vaginally delivered infants, and C-section delivery has been associated with increased risk for immune and metabolic disorders. Here we conducted a pilot study in which infants delivered by C-section were exposed to maternal vaginal fluids at birth. Similarly to vaginally delivered babies, the gut, oral and skin bacterial communities of these newborns during the first 30 d of life was enriched in vaginal bacteria—which were underrepresented in unexposed C-section–delivered infants—and the microbiome similarity to those of vaginally delivered infants was greater in oral and skin samples than in anal samples. Although the long-term health consequences of restoring the microbiota of C-section–delivered infants remain unclear, our results demonstrate that vaginal microbes can be partially restored at birth in C-section–delivered babies. COMMENT p231: Altered microbial colonization associated with cesarean section (C-section) birth could potentially have adverse effects on host development. The first interventional study of its kind attempts to reconfigure the early microbiota composition in C-section–delivered newborns to resemble that associated with vaginal birth.
The right gut microbes help infants grow J. Science 19 Feb 2016:Vol. 351, pp. 802. Most 180 million children across the globe are stunted, a severe, disabling consequence of malnutrition, repeated childhood infections, and sometimes irreversible damage. Now, new studies suggest the gut microbiome plays a critical role in infant growth—sometimes promoting it even in the absence of sufficient calories—providing tantalizing, if preliminary, clues about possible new interventions. They show that microbial communities change as an infant ages, and when they don’t poor nutrition leads to stunting and other problems. Work in germ-free mice shows providing the right human microbial communities can restore growth, likely by restoring the proper connections between growth hormone and insulinlike growth factor 1. And supplying young mice with certain sugars typically provided in breast milk helps to make sure the right microbial community gets established.
It’s in the Milk: Feeding the Microbiome to Promote Infant Growth Volume 23, Issue 3, p393–394, 8 March 2016 Journal Cell Metabolism
Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children J. Science 19 Feb 2016:Vol. 351, Issue 6275, pp. 854
Fungal Microbiota Dysbiosis Seen in Inflammatory Bowel Disease. Epub Feb 3 2016 J. Gut. Despite this article you will still hear most doctors say that an overgrowth of yeast in the gut (caused by poor diets and antibiotics) has nothing to do with intestinal problems.
Prevalence of probiotic use among inpatients: A descriptive study of 145 U.S. hospitals http://dx.doi.org/10.1016/j.ajic.2015.12.001
Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress
Gut 2016;65:595. Colitis, or inflammation of the intestines, causes poor absorption of B vitamins, which then aggravates colitis.
l-Glutamine Enhances Tight Junction Integrity by Activating CaMK Kinase 2–AMP-Activated Protein Kinase Signaling in Intestinal Porcine Epithelial Cells
J. Nutr. 2016 146: 501. The amino acid Glutamine helps heal Leaky Gut
The role of bile acids in metabolic regulation J Endocrinol 228 (3) R85 Their role in the pathogenesis of diabetes, obesity and other ‘diseases of civilization’ becomes even more clear. They also interact with the gut microbiome, with important clinical implications.
Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells
J. Nutr. 2016 146: 465. Foods must be metabolized by gut bacteria before they can render their salutary effect on all cells. This article is about the health of the lining of our arteries
Am J Gastroenterol 2016; 111:163–169; doi:10.1038/ajg.2015.301; The Link between the Appendix and Ulcerative Colitis: Clinical Relevance and Potential Immunological Mechanisms. The human appendix has long been considered as a vestigial organ, an organ that has lost its function during evolution. In recent years, however, reports have emerged that link the appendix to numerous immunological functions in humans. Evidence has been presented for an important role of the appendix in maintaining intestinal health. This theory suggests that the appendix may be a reservoir or ‘safe house’ from which the commensal gut flora can rapidly be reestablished if it is eradicated from the colon. However, the appendix may also have a role in the development of inflammatory bowel disease (IBD). Several large epidemiological cohort studies have demonstrated the preventive effect of appendectomy on the development of ulcerative colitis, a finding that has been confirmed in murine colitis models. In addition, current studies are examining the possible therapeutic effect of an appendectomy to modulate disease course in patients with ulcerative colitis. This literature review assesses the current knowledge about the clinical and immunological aspects of the vermiform appendix in IBD and suggests that the idea of the appendix as a vestigial remnant should be discarded.
Environ Health Perspect; 2016DOI:10.1289/ehp.124-A49 Inflammatory Bowel Disease in Asia: A Second Chance at Uncovering Environmental Factors
Increasing Evidence for an Association Between Periodontitis and Cardiovascular Disease
The Intestinal Immune System in Obesity and Insulin Resistance Journal Cell Metabolism Volume 23, Issue 3, p413–426, 8 March 2016 Obesity and insulin resistance are associated with chronic inflammation in metabolic tissues such as adipose tissue and the liver. Recently, growing evidence has implicated the intestinal immune system as an important contributor to metabolic disease. Obesity predisposes to altered intestinal immunity and is associated with changes to the gut microbiota, intestinal barrier function, gut-residing innate and adaptive immune cells, and oral tolerance to luminal antigens. Accordingly, the gut immune system may represent a novel therapeutic target for systemic inflammation in insulin resistance. This review discusses the emerging field of intestinal immunity in obesity-related insulin resistance and how it affects metabolic disease.
Strategies for Altering the Microbiome-Medscape March 16 2016
The gut microbiome, a dynamic feature of the gastrointestinal system, has the potential to dramatically influence health outcomes. Through complex interactions with the host immune system and signaling pathways, the gut microbiome can significantly influence the pathogenesis of disease states such as cancer, metabolic syndrome, inflammatory bowel disease, and nonalcoholic fatty liver disease.
Recent technological advances have vastly improved not only our understanding of the gut microbiome but also potential mechanisms through which we may confer health benefits by altering it. As what one eats partially determines the gut flora, there are very likely significant dietary effects on the gut microbiome and a likely interaction across a broad spectrum of systemic diseases. Furthermore, emerging data on factors such as sleep and exercise underline their potential role in affecting the microbiome. This review summarizes our current understanding of how microbiome health may be affected by these lifestyle factors.
A wide range of dietary carbohydrates, including prebiotic food ingredients, fermentable fibers, and milk oligosaccharides, have been shown to produce significant changes in the intestinal microbiota. These shifts in the microbial community are often characterized by increased levels of bifidobacteria and lactobacilli. A more recent study revealed that species of Faecalibacterium, Akkermansia, and other less well studied members may also be enriched.
Investigations of clinical outcomes associated with dietary modification of the gut microbiota have shown systemic as well as specific health benefits. Both prebiotic oligosaccharides comprised of a linear arrangement of simple sugars as well as fiber-rich foods containing complex carbohydrates have been clinically studied with variable benefit. However, inconsistency of response across study participants can make the outcome of dietary interventions less predictable and limit the value of making specific recommendations to individual patients.
Nondigestible food ingredients, prebiotics can beneficially affect the host by selectively stimulating the growth and/or activity of one or more bacteria in the colon. They do so via selectively fermented ingredients that can change the composition and/or activity in the gastrointestinal microflora. In order for a food to be classified as a prebiotic, it must resist gastric acidity, hydrolysis by mammalian enzymes, and absorption in the upper gastrointestinal tract, so that it is able to be fermented by the gut microbiota into short-chain fatty acids (including acetate, propionate, and butyrate) that can be used for energy. Thus, prebiotics not only can cause shifts in the microbiota by supporting growth of a particular intestinal microbiome but also serve as substrates for production of biologically active metabolites. The primary prebiotics are the inulin-type fructans oligofructose and fructo-oligosaccharides, yet there are a number of others, including the galactan galacto-oligosaccharide. Fermentation of prebiotic carbohydrates yields butyrate and other short-chain fatty acids as well as other end products that lower the local pH, stimulate mucin production by colonocytes, and induce immunomodulatory cytokines, all of which may have potential disease modulation effects.
Prebiotic fibers are often natural constituents of a variety of foods, especially whole grains, fruits, root vegetables, and legumes. Although some foods contain appreciable concentrations of these prebiotics, they are probably found too infrequently in most Western diets to contribute much fermentable fiber to the colon. Prebiotic fiber products such as psyllium have been commonly used to supplement where needed. As a practical strategy, consumption of fermentable fiber or combinations of prebiotics may enrich for a larger and more diverse population of gut microbes and should be a standard recommendation for most disease states.
In order for a live micro-organism to be classified as a probiotic, it must satisfy the following criteria: (1) exert a beneficial effect on the host; (2) be nonpathogenic and nontoxic; (3) contain a large number of viable cells; (4) be capable of survival and metabolism within the gut; (5) remain viable during storage and use; (6) have good sensory properties; and (7) be isolated from the same species as the intended host.
Probiotics have long been used as therapeutic agents for improving gastrointestinal health. Although several microbial taxa or genera have been suggested as being beneficial to the host, there is still no actual definition of what constitutes a healthy gut microbiome to a specific patient. Most available information concerns Bifidobacterium and Lactobacillus spp; consequently, most commercially available products generally contain bacteria from one or both of these species.
Probiotics have been shown to provide a number of health benefits and can potentially be used to alter the gut microbiome and thereby treat certain gastrointestinal conditions. Within the gastrointestinal tract, probiotics play a number of functional roles, including maintaining the intestinal barrier integrity, regulating mucin secretion, controlling immunoglobulin A secretion, and producing antimicrobial peptides, which influence cytokine production. In clinical trials, probiotics have shown beneficial effects in nonalcoholic fatty liver disease and ulcerative colitis, but a favorable effect has not been consistently demonstrated to date. The combined physiologic and clinical data strongly support the continued research of probiotics as a potential therapy for manipulating the gut microbiome.
Introduced over a century ago, artificial sweeteners were designed to enhance taste without the effects of caloric intake, theoretically benefiting health by weight reduction and enhanced glycemic control. These agents are commonly used in a broad array of foods, beverages, and candy designed for diabetics and those actively dieting. However, recent information shows that these formulations drive the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota, which in fact promote glucose intolerance. These agents may therefore have directly contributed to enhancing the very obesity epidemic they were intended to combat
Similar to other organ systems, the gastrointestinal tract operates on a 24-hour circadian schedule that anticipates and prepares for changes in the physical environment associated with day and night. These circadian rhythms regulate a number of gastrointestinal functions, ranging from gastric acid production to small intestinal nutrient absorption to colonic motility. These rhythms are also strong regulators of immunologic processes and the gut microbiome (abundance, speciation, and function), which fluctuates in accordance with their influence. This occurs via bidirectional communication between the central nervous system and an immune system and is mediated by shared signals (neurotransmitters, hormones, and cytokines [the brain-gut axis]) and direct innervations of the immune system by the autonomic nervous system.
Prolonged sleep curtailment and the accompanying stress response invoke a persistent unspecific production of proinflammatory cytokines, which results in a low-grade chronic inflammatory state. Epidemiologic studies have established the best amount of sleep to target as approximately 7 hours. This is the range that best correlates with lower prevalence of cardiovascular disease.
Recent attention has also focused on the sleep disruption-related upregulation of provocative cytokines, such as tumor necrosis factor alpha in patients with inflammatory bowel disease, which can increase the risk of inducing a disease flare or perpetuating disease activity.
There has long been a connection between exercise and gut symptomatology. Exercise and fitness modulate vagal tone, which is an integral component of the brain-gut microbiome axis. With exercise contraction of skeletal muscle, there is an innate immunity enhancement created by the release of muscle-related anti-inflammatory cytokines or myokines. Additionally, there is an associated reduction of toll-like receptors (involved in many inflammatory and cancer pathways) on monocytes and macrophages. Exercise and the gut microbiome share many immunometabolic and physiologic processes that are well established in cardiovascular health and other areas beyond the gut.
Although there is an intuitive role for exercise in the prevention and treatment of gastrointestinal conditions such as irritable bowel syndrome, nonalcoholic fatty liver disease, and obesity, among others, the recommendation to include exercise and fitness is not yet standard for specific disease state management.
As the microbiota has an established role in the development and homeostasis of the gastrointestinal tract, the potential impact of exercise and fitness on the gut microbiota has attracted recent attention. However, more research is required to quantify the anti-inflammatory and metabolic effects of moderate exercise and to weigh these against the potential hazards of excessive exercise.
The effects of prebiotics, probiotics, and even antibiotics on the gut microbiome will continue to remain a mainstay of investigation and will hopefully advance our knowledge of the intricacies of the gut microbiome while improving clinical outcomes. Supplemental focus on exercise and sleep function will likely have an added beneficial effect. My prediction is that enhancing our disease management protocols will require us soon to all be in the “gut microbiome business.” This will likely be directed toward “dysbiosis” management using multiple approaches, often in combination.
Exciting work from the Weizmann Institute in Israel highlights the need to develop new nutritional strategies tailored to the individual patient, whereby unique diet and exercise protocols are used to correct the microbiome. In taking such an approach, we may no longer rely on empiricism or published clinical trial data but instead more accurately address each patient’s needs in order to restore microbiome balance.
- Krumbeck JA, Maldonado-Gomez MX, Ramer-Tait AE, Hutkins RW. Prebiotics and synbiotics: dietary strategies for improving gut health. Curr Opin Gastroenterol. 2016;32:110-119.
- Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514:181-186.
- Rosselot AE, Hong CI, Moore SR. Rhythm and bugs: circadian clocks, gut microbiota, and enteric infections. Curr Opin Gastroenterol. 2016;32:7-11.
- Cronin O, Molloy MG, Shanahan F. Exercise, fitness, and the gut. Curr Opin Gastroenterol. 2016;32:67-73.
- Zeevi D, Korem T, Zmora N, et al. Personalized nutrition by prediction of glycemic responses. Cell. 2015;163:1079-1094.