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Thursday, March 9, 2017

Role of intestinal microbiota and metabolites in human diseases

Abstract (as presented by the authors of the scientific work):

A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health.
This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA).
In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction.
A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Conclusions (as presented by the authors of the scientific work):

Intestinal microbiota is normally indispensable for shaping host gut immune system and thus contributing to gut homeostasis maintenance, and is also a key mediator in keeping metabolic functions in the peripheral tissues including liver and pancreas. Accumulating evidence has indicated that intestinal microbiota not only induces and reinforces pro-inflammatory immune responses but also elicits immunosuppressive responses. Abnormal microbial-elicited immunosuppression may result in dysregulation in host metabolism and/or impairment in anti-cancer immunity.

Data with regard to commensal bacteria have integrated, which leads up to a conclusion that a number of microbes are fluctuating on the boundary of virulence. B. fragilis is a representative of this phenomenon. This bacterium is able to improve the development of the host adaptive immune system while being confined to the lumen of the intestinal tract, but becomes enterotoxigenic while it contingently traverses the gut epithelial mucosa. Mazmanian et al [103] showed that during colonization of B. fragilis in animals, a bacterial polysaccharide A (PSA) was presented by DCs, which could direct and promote the maturation of the developing immune system [103]. Subsequent work by the same group substantiated the above finding and further explored the mechanisms of its immunomodulatory effects [129]. Not belonging to dominant members of the gut microbiota, B. fragilis is normally absent in conventionally raised SPF mice. Inoculation with B. fragilis has been found to protect mice from colitis in the T-cell-transferred and TNBS-treated animal models. It appeared that the purified B. fragilis PSA was sufficient to act on host analogous to the live bacterium, including the initiation of IL-10 production by Tregs, suppression of Th17 cell production, disease protection from colitis, and colonization of the host [129, 200]. On the other hand, B. fragilis is capable of producing Bft (Bacteriodes fragilis toxin), which acts indirectly by eliciting high levels of ROS and the ensuing damage of host DNA [201]. Sustained high-leveled ROS, once exceeding the host’s DNA repair capacity, may lead to DNA damage and thereby culminating in cell death or oncogenic mutations [202]. Thus B. fragilis is considered to be a risky factor for colorectal cancer in mammals. Such example also illustrates that a subtle balance is maintained between mammal hosts and microbial kingdom [203].

Mucosal surface barriers are essential for host-microbial symbiosis, the former of which are vulnerable to persistent microbial insults and dietary antigenic components, and must be repaired to re-establish homeostasis. Compromised flexibility of the host or microbiota may place itself on a “death tunnel” to malignancy [202]. In addition, manifestations that immunotherapies are displaying efficacy in malignancies of organs such as melanoma, bladder, renal and lung cancers rather than cancer of the colon, the latter being highly-populated by microbes, have garnered extensive attention as to whether and how the microbiota influences immunotherapy’s efficacy [202]. So the interplays of microbiota and immunotherapy efficacy/toxicity need further investigation.

Among the metabolic disorders, NAFLD, which is characteristic of hepatic triglyceride (TG) accumulation rather than being arisen from alcohol abuse, is linked up with ectopic fat accumulation, especially in the liver. T2D is characterized by persistent hyperglycemia. Pathophysiologic mechanisms of NAFLD and T2D in common are believed to be relevant to insulin resistance, lipotoxicity, and inflammation [171]. Insulin resistance is a multi-organ manifestation as observed at the level of the liver, muscle and adipose tissues. Moreover, adipose tissues and the liver can secrete proinflammatory cytokines. In addition to insulin resistance and inflammation, other risk factors may contribute to the elevated incidence of metabolic diseases including lifestyle (high-fat/sugar diets and poor physical activity), gut microbiota alterations and environmental pollutants.

Based on data heretofore, it is hypothesized that the gut microbiota may mediate the influence of lifestyle factors triggering development of NAFLD and T2D [171]. A metagenome-wide association study on 345 Chinese patients with T2D versus healthy individuals has revealed that T2D sufferers exhibited a moderate degree of gut microbial dysbiosis, referring to a dearth of some butyrate-producing bacteria and an elevation in some opportunistic pathogens [204]. As afore-described in Section of “Liver diseases”, an increased prevalence of Firmicutes, a representation of dysbiosis, is found to be linked to NAFLD [168, 169, 205]. Of particular interest, these two metabolic disorders, NAFLD and T2D, to some extent, share similar mechanisms of etiology: being associated with dysbiosis. These novel findings would broaden our knowledge about metabolic influences of a shifted intestinal microbiota beyond the gut and thus benefit our exploration of therapeutic targets for metabolic diseases.

Close to the completion of this manuscript, an interesting paper has been published demonstrating the link of atherosclerosis etiology with abnormal gut microbiota [206]. Studies with low-density lipoprotein receptor (LDLR) −/− mice, an atherosclerotic murine model, revealed that 12-week supplementation of high-fat diet could lead to evident aortic lesions, macrophage infiltration, and collagen level increase, concurrent with an up-regulation of inflammatory factors [206]. This finding suggests that gut microbiota, combined with metabolisms of fatty acids and vitamin B3, could play a profound role in the onset and development of atherosclerosis [206] (Fig. 3).

A growing body of novel “omics” technologies based on next-generation sequencing, nuclear magnetic resonance (NMR) spectroscopy and gas chromatography coupled with flame ionization detector/mass spectrometry (GC–FID/MS) is gaining wide popularity in the field of cardiometabolic diseases in association with microbiota dysbiosis. The integration and comparison of omics-mode data and molecular biological data would offer comprehensive insight into the mechanisms by which microbiota and metabolites thereof influence host immunity and metabolism. Commensal microbiota in the intestine may serve as a consortium with immunologic and endocrine-like activities to modulate the epigenetic status of host cells. Owing to the advances in genome-wide epigenetic analysis, for instance, chromatin immunoprecipitation sequencing (CHIP-Seq), researchers can determine and analyze these epigenetic modifications, thereby deciphering the intrinsic intestinal microbiota–host interactions and unraveling the impacts of microbiota within and beyond the gut such as liver, cardiovascular system, and even CNS."

Full-text access of the referenced scientific work:

Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut
homeostasis and human diseases. BMC Immunol. 2017 Jan 6;18(1):2. doi:
10.1186/s12865-016-0187-3. Review. PubMed PMID: 28061847; PubMed Central PMCID:


Prof. Atanas G. Atanasov (Dr. habil., PhD)

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