Intestinal microbiota, diet and health

Recent omics level studies are confirming what pioneers in gut microbiology have been saying for some time, that diet:microbe interactions impact on human health and disease risk (Midtvedt, 1974; Rowland, 1988). The post genomics technologies of metagenomics and metabolomics are decoding the detailed cross-talk between the structure and function of the intestinal microbiome and host physiology, with diet:microbe interactions now shown to impact on the risk of cardio-metabolic disease, cancers, immune diseases and psychiatric disorders (Nicholson et al, 2012). The gut microbiota is becoming recognised as an important metabolic and immunological organ in its own right, intricately linked to the functioning of other organs most notably the liver, adipose tissue and the brain. Evidence mainly from animal studies describe important roles for gut microbiota metabolites and/or microbiota immunological regulation of metabolic and inflammatory pathways critical for maintenance of host defences. Indeed, such studies hint at common underlying pathological processes linking diet:microbe interactions in the gut with a spectrum of chronic diseases along the gut:liver:fat:brain axis. Indeed, different aspects of this gut:liver:fat:brain axis are currently receiving much attention for their role in obesity, the diseases of obesity (cardiovascular-disease, type 2 diabetes, non-alcoholic fatty liver disease, Alzheimer’s disease) and psychiatric conditions such as autism, Schizophrenia and importantly, depression. Many of these diseases are characterised by loss of metabolic homeostasis and unresolved systemic inflammation. While the gut microbiota have been shown to produce toxic compounds for example trimethylamine-N-oxide and N-nitroso compounds derived from amino acid/protein fermentation n the gut, many microbial metabolites impact beneficially on host health, especially those which derive from the breakdown and fermentation of plant macromolecules, fibers and polyphenols. Short chain fatty acids and small phenolic compounds derived from colonic carbohydrate fermentation and plant polyphenol catabolism respectively, have been shown to play a critical role in establishment and maintenance of host defences, especially immune function (both within the gut and systemically) and gut barrier integrity. Moreover, plant fibers and polyphenols can influence the quantity of bile acids entering the distal ileum and colon, and also the profile of bile salt hydrolyzing bacteria therein, and thus may influence microbial involvement in the enterohepatic circulation of bile acids. Bile acids, apart from their role in regulating fat uptake are now being recognised for their important cell signalling role, acting as ligands for nuclear receptors like FXR, VDR, PXR, CAR and g-coupled receptors like TGR5, which in turn regulate inflammation, glucose and lipid metabolism, nutrient absorption, intestinal permeability and thermogenesis. Gut bacteria also produce biologically active compounds like B vitamins (niacin and folate for example), vitamin K, and conjugated linoleic acids, all powerful bioactive agents targeting regulation of various inflammatory and metabolic pathways in man. Moreover, both the physiological concentrations of these compounds and their biological activity change throughout life, driven both by diet and successional development of the gut microbiota, identifying diet:microbe interactions as an important extra-genomic epigenetic mediator capable of impacting on physiological processes linked to chronic disease risk and the ageing process itself. Recent studies indicate that processes within the gut play a critical role in the persistent low grade systemic inflammation common to many chronic human diseases associated with modern diet and life-style. Increased intestinal permeability leads to translocation of inflammatory molecules such as lipopolysaccharide, which then act as continuous triggers for unresolved systemic inflammation. This intestinal permeability and emergence of aberrant microbiota profiles is strongly influenced by diet, with high fat - low fiber diets (the modern or Western style diet) contributing to gut wall permeability. Conversely, ancestral or traditional dietary patterns high in fermentable fiber, prebiotics, fruit and vegetables (and indeed certain probiotic or fermentative microorganisms) support microbiome structure and function and improve gut barrier integrity (Figure 1). A number of gut bacteria, including species of bifidobacteria and lactobacilli commonly used as probiotics, SCFA and the bile acid regulated nuclear receptor, FXR, have all been shown to control gut permeability via induction of tight junction proteins between epithelial cells. Similarly gut inflammation and oxidative damage play their part in gut “leakiness”, and are themselves impacted by both diet and the gut microbiome. Indeed, this diet induced intestinal damage and gut permeability, which is also characteristic of certain chronic disease states like obesity strongly mirrors the gut leakiness and chronic low grade systemic inflammation observed in the elderly, and at least in models of ageing, harbingers unresolved inflammation, metabolic derangement, diabetes and eventually death (Rena et al. 2012). Of course the ancients knew this all along - “death sits in the bowel” Hippocrates c. 400 BC. However, we are now providing the mechanistic understanding of how the gut microbiota may constitute a lynch-pin upon which the destructive degenerative processes of aberrant metabolic and inflammatory pathway activation are held at bay until overwhelmed by advancing age or aberrant diet. When this occurs, or what chronic disease expresses itself, is of course determined by host genetic predisposition, but it appears that diet:microbiota interactions in the gut contribute significantly to the environmental pressure driving these metabolic and inflammatory disease processes. Diet is one disease risk factor we can modify, and understanding on the one hand, what dietary components contribute to disease risk, and on the other hand, those which reduce disease risk is critical if we are to reduce the burden of chronic non-communicable diseases. Adherence to the Mediterranean style diet has been proven to protect against these chronic non-communicable diseases and improve mental well-being (Bonaccio et al. 2013) and indeed, recent studies are showing that components of the Mediterranean diet may mediate, at least part of their protective effects, through the gut microbiome (Figure 1, Tuohy and Del Rio, 2014). This lecture will provide an insight into recent studies illustrating how diet:microbe interactions in the gut not only contribute to chronic disease risk, but also hold great potential of reducing the socioeconomic impact of these diseases through rational modulation of dietary patterns throughout life.