Good or bad: gut bacteria in human health and diseases

ABSTRACT The human gastrointestinal tract is estimated to be colonised by over 1014 bacteria, approximately 10-fold of the total number of cells in the human body. Recently, an important role of the gut microbiota composition in many areas, such as normal development, immune system maturation, CNS functions, has been discovered. Also, accumulating evidence suggests that gut bacteria play critical roles in maintaining human health in many aspects. Gut microbiota dysbiosis may lead to a number of diseases, including gastrointestinal disorders, obesity, cardiovascular diseases, allergy and central nervous system-related diseases. In this review, we propose that novel effective and safe therapy methods for human diseases based on modulation of gut microbiota would attract more attention from both scientists and clinicians.


Introduction
The human gastrointestinal tract is estimated to be colonised by over 10 14 bacteria, approximately 10-fold of the total number of cells in the human body [1]. Disruptions to the microbiome have been associated with severe pathologies of the host, including metabolic disease, cancer and inflammatory bowel disease [2][3][4]. Recent studies based on 16 s ribosomal-RNA gene sequencing and metagenomic analysis have started to explore the species diversity of the intestinal microbiome within and between the individuals [5][6][7][8]. Among about 1000 bacterial species colonised in human guts, the dominant genera include Bacteroides, Clostridium, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus and Bifidobacterium [9]. Other genera, like Escherichia and Lactobacillus, are also present in the gut but to a lower degree. There are still many species that have not been identified, because many of them cannot be cultured in vitro.
The composition of the gut microbiota is determined and influenced by a number of endogenous and exogenous factors, such as geographic origin, age, genetics, diet and the use of prebiotics and antibiotics. For instance, antibiotics would disturb the gut microbiota either in septic patients or in a murine model, leading to the alteration of the immune system [10,11]. Yatsunenko et al. compared the bacterial species of faecal samples from individuals of different geographic origins (three populations from the United States and Malawi) and different ages (0-70 years) [12]. Their study shows that the diversity of the gut microbiota within individuals is much higher in adults than in children, but that the inter-individual differences are significantly higher in children than in adults. The composition of the bacterial community shifts to the adult-like pattern within the first three years after birth. Dietary components can also shape the bacterial composition [13]. For example, the Bacteroides genus is highly associated with the consumption of animal proteins, amino acids and saturated fats, which are typical components of Western diet, while the Prevotella genus is associated with the consumption of carbohydrates and simple sugars, which are typical of agrarian societies [13,14]. People with a Bacteroidesdominated gut microbiome will gain a Prevotella-dominated microbiome by switching from a Western diet to a carbohydrates-based diet for an extended period of time. Another study reported that the European microbiome was dominated by taxa typical of the Bacteroides, whereas the African microbiome was dominated by the Prevotella [15]. It has also been shown that the consumption of non-caloric artificial sweeteners, which are widely used as common food additives, can change gut microbiota composition [16].

Gut bacteria and health
Accumulating evidence suggests that gut bacteria play critical roles in maintaining human health in many aspects. For example, gut bacteria could train the immune system, prevent the growth of pathogenic bacteria, regulate the gut development, maintain epithelial integrity, and shape the neuronal development [17][18][19].
It has been proposed that gut bacteria are required to maintain epithelial integrity by regulating tight junction permeability. Lactobacillus plantarum, for example, was reported to regulate tight-junction proteins to protect against chemical-induced disruption of the epithelial barrier [20]. Loss of gut epithelial integrity will allow gut bacteria, bacterial toxins, incompletely digested fats and proteins, and wastes to pass the epithelium into the blood stream, triggering inflammatory responses and leading to gastrointestinal problems, such as abdominal bloating, excessive gas and cramps, and food sensitivities. These symptoms are characteristic of leaky gut syndrome, which exhibits intestinal hyperpermeability. A recent study in mice has identified commensal bacteriaderived short chain fatty acids (SCFAs) as modulators of the epithelial barrier function [21]. SCFAs derived from bacterial metabolism, particularly butyrate, stimulate consumption of intracellular oxygen to form a hypoxia state in the colon, resulting in stabilisation of the transcription factor HIF-1 and increase of epithelial integrity.
It is known that colonising gut bacteria are critical to the normal development of host defense [22]. Germ-free mice have low immunoglobulin concentrations; lymphopenia of lymphoid structures; reduced bone marrow leukocyte pools; and aberrant innate and adaptive immune functions [23]. Strikingly, fully functional development of the GALT (gut-associated lymphatic tissue), a sophisticated set of immune tissues, critically depends on the interactions with an intact bacterial gut flora. In germfree animals, the GALT cannot fully develop into mature tissue, with no Peyer's patches and only sparse lymphoid infiltrations [24]. By transiently colonising pregnant female mice, the maternal microbiota shapes the immune system of the offspring [23]. Consequently, the immune system, both innate as well as adaptive, and the commensal microbiota share a mutual and interactive evolution. Specifically, the immune system has a major role in containing the microbiota safely within their gut lumen, and conversely, the microbiota signals essentially to govern the development and functional integrity of the immune system [24]. Using animal models, two studies have shown that metabolites derived from gut bacteria, including butyrate, can induce the differentiation of peripheral regulatory T-cells to adjust the balance between pro-and anti-inflammatory responses [25,26].
Moreover, commensal bacteria in the colon can prevent the invasion of pathogenic bacteria either by competing for nutrients and living space on the mucosal surface, or by producing toxic metabolites, such as bacteriocins, acids and phenols, to inhibit pathogenic bacteria growth [9,27].
Gut bacteria benefit the host in a number of other ways, including regulating gut motility, producing vitamins and controlling the maturation and function of the microglia in the central nervous system (CNS) [28,29]. The gut microbiota is essential for normal CNS development. Generally, the absence of gut microbiota is associated with several CNS developmental problems [30]. Heiitz et al. [19] reported that compared with conventionally-raised mice, germ-free animals had an increased expression of PSD-95, and synaptophysin in the striate nucleus changed the microglia properties. Moreover, colonisation with a complex microbiota partially restores microglia features, highlighting the role of gut microbiota in conditioning normal CNS development [31]. Long-range interactions between the gut microbiota and the brain underlie the ability of microbe-based therapies to treat symptoms of multiple sclerosis and depression in mice, and the reported efficacy of probiotics in treating emotional symptoms of chronic fatigue syndrome and psychological distress in humans [32]. Recent studies suggest that the gut microbiota influences CNS development and function, and that gut dysbiosis is associated with significant neurological problems. However, most of these results have been collected in experimental animals and cannot be transferred to humans immediately [31]. In summary, commensal bacteria play numerous important roles in maintaining human health, and they also affect a variety of complex behaviours, including social, emotional and anxiety-like behaviours, and contribute to brain development and function.

Gut bacteria and diseases
Increasing evidence suggests that gut microbiota dysbiosis would lead to a number of diseases, including gastrointestinal disorders [2,[33][34][35], obesity [36][37][38], cardiovascular diseases [39][40][41], allergy [42][43][44] and CNS-related diseases [30,45], which affect a large population in the world. Besides, mood and behaviour are also susceptible to alterations in the gut microbiota [3]. Experimental and clinical trials for treatment of these diseases based on modulating gut bacteria composition have shown promises as a therapeutic strategy of gut microbiota on human diseases.
Inflammatory bowel disease (IBD) is a group of inflammatory conditions in the digestive tract, affecting about 3 million people in the United States [46]. Two major types of IBD are ulcerative colitis (UC) and Crohn's disease (CD), both of which have been shown to be associated with dysbiosis of the gut microbiota [47]. By comparing the predominant microbiota from 127 UC patients and 87 age and sex-matched controls, studies have shown that the abundance of two bacterial species, Roseburia hominis and Raecalibacterium prausnitzii, is significantly lower in UC patients than in controls [48]. Another twin study showed that UC patients have a different gene expression profile (e.g. genes related to oxidative and immune responses) in the colon mucosa compared to their healthy twin siblings, suggesting that such differences are due to the dysbiotic microbiota in UC patients [49]. The dysbiosis in CD patients has been better characterized [50]. One study has identified five dysbiotic bacterial species by comparing the predominant microbiota in CD patients and their relatives [51]. Recent clinical studies based on faecal microbiota transplantation (FMT) for treatment of UC demonstrated that FMT could alter the composition greatly, and a microbiota composition highly similar to that of the donor is reconstituted in the patients with successful treatment. No severe adverse or side effects occur during the treatments and follow-ups [52].
Obesity is tightly associated with specific diets and life styles, both of which can influence the composition of the gut microbiota. Thus, an association between changes in the gut microbiota and the development of obesity has been proposed. An epidemiological study shows that yogurt consumption can prevent age-associated gain of weight, which may be due to the effects of probiotics in the yogurt [53]. Transplanting human faecal microbiota from obese and lean twins to germ-free mice provided direct evidence that the gut microbiota modulates host metabolism to regulate body weight. The mice that received faecal microbiota from the obese twins had increased total and fat mass and showed obesity-associated metabolic phenotypes, something not observed in the mice receiving faecal microbiota from the lean twins [54]. In addition, changes in the gut bacteria contribute to both type-1 diabetes (T1D) and type-2 diabetes (T2D). T1D is an autoimmune disease that results from the destruction of insulin-producing pancreatic beta-cells. One study, using the non-obese diabetic (NOD) mouse model, shows that germ-free NOD mice lacking MyD88 (an adaptor for innate immune receptors that recognise microbial stimuli) develop robust T1D, whereas associating these mice with a defined microbial community attenuates T1D development [55]. T2D is a metabolic disease that results from obesity-linked insulin resistance. Dysbiosis of gut microbiota has also been observed in T2D patients, but the cellular and molecular mechanisms leading to these phenotypes need to be further characterized [56].
Moreover, it has been demonstrated that bidirectional communication between the gastrointestinal tract and the CNS occurs continuously through several routes (including hormonal, immune and neuronal pathways) that are mostly conditioned by the microbiota composition, which has led to the emergence of the 'microbiotagut-brain axis' concept. Altered microbiota composition in the intestines could promote a stage of chronic inflammation that might exacerbate CNS inflammatory diseases, such as multiple sclerosis [57][58][59][60][61][62][63][64].
More and more evidence shows that changes in the composition and diversity of the gut microbiota have a substantial influence on the pathology of CNS disorders, and consequently there has been a growing attention to microbiota-based therapeutics, including probiotics, prebiotics and faecal microbiota transplants [65]. For example, recent studies demonstrate treatment with Bacteroides fragilis corrects levels of tight junction proteins and cytokines in mice neurological symptoms related to autism spectrum disorder (ASD) [66][67][68]. More recently, Liang et al. [69] reported that Lactobacillus helveticus NS8 supplementation could greatly improve the behavioural, cognitive, and biochemical aberrations caused by chronic restraint stress, both in rats and children. Together, these studies confirm and demonstrate the hypothesis that probiotic supplementation may be an effective and safe therapy for brain and behaviour disorders.

Perspectives
The human gut microbiota may be viewed upon as an organ [70], and contributes to the digestion of food and the breakdown of toxins and drugs, regulates lipid and glucose metabolism, plays a fundamental role in the induction, training and function of the host immune system, modulates gene expression, and reduces inflammation [70]. In addition, 20%-40% of the small molecules in the peripheral blood are microbial metabolites, many of which have profound effects on CNS development and function [31]. Although there are numerous diseases that have been linked to dysbiosis of gut bacteria, it is critical for future studies to distinguish whether dysbiosis is the cause or the result of these diseases, as it determines how intervention strategies would develop. Prebiotics and probiotics have been widely used to treat some diseases, and they have shown great benefits to human health. In some cases, the change of a single bacterial species plays a key role on disease development, while in other cases dysbiosis of multiple species (microbiota composition) underlies the diseases. In addition, there also could be a potential method for curing patients with their own healthy microbiota preserved in the youth. Thus, future studies should put efforts not only on the exploration of effects from individual bacteria (like mono-association studies), but also on the accurate quantitative analysis of each species in one bacterial community [71].
There is no doubt that the gut microbiota would affect the immune system of the host, and impact the host health and disease subsequently. Emerging evidence has shown that early microbiota colonisation may influence the occurrence of diseases (microbial programming) later [72]. It is not difficult to imagine that each disease could have a unique pattern of gut microbiota. Accordingly, the gut microbiota could be potent biomarkers for disease diagnosis. It is now clear that the interindividual diversity in microbiota composition plays an important role in determining the susceptibility to a wide variety of diseases [73]. However, identifying the precise changes in microbiota composition that play causal roles has remained a largely unrealised goal [73].
Not only do the diverse gut bacteria play a crucial role in the host health, but also the products of gut microbiota, containing proteins, small molecular chemicals and even DNAs could involve in a lot of events, e.g. the gut microbiota provides unique contributions to the diversity of bile acids in the bile acid pool [74,75]. Based on all these features, the gut microbiota may secrete various molecular signatures labelling different diseases. Meanwhile, identification of gut bacteria-derived molecules would greatly facilitate the treatment of these diseases.
Moreover, the host health consists of two aspects: the physiological health and the psychological health. Recently, numerous findings have supported that the gut microbiota participates in almost all of the host health issues, whereas the relationship between the gut bacteria and the psychological conditions is still limited. Thus, more attention should be paid on this area. For instance, children with ASDs who have gastrointestinal disorders may present with behavioural manifestations [76][77][78], and in the near future, the gut microbiota might become the new ID of each patient with disorders of psychology.

Conclusions
The gut microbiota is required for animal development and for organismal homeostasis in adults. Accumulating evidence suggests a tight association of alterations in intestinal microbiota composition with several chronic conditions, including both physiological and psychological diseases. Identification of microbiota composition and gut bacteria-derived molecules, as well as introducing novel methods for reconstituting the normal gut microbiota composition would greatly facilitate treatments of these diseases, among which preserving one's own healthy microbiota in the youth for disease treatment in the future should be a promising strategy.