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Thursday, March 23, 2017

The health-promoting and microbiota-modulating properties of the fermented beverage kefir


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

"Kefir is a complex fermented dairy product created through the symbiotic fermentation of milk by lactic acid bacteria and yeasts contained within an exopolysaccharide and protein complex called a kefir grain. As with other fermented dairy products, kefir has been associated with a range of health benefits such as cholesterol metabolism and angiotensin-converting enzyme (ACE) inhibition, antimicrobial activity, tumor suppression, increased speed of wound healing, and modulation of the immune system including the alleviation of allergy and asthma. These reports have led to increased interest in kefir as a focus of research and as a potential probiotic-containing product. Here, we review those studies with a particular emphasis on the microbial composition and the health benefits of the product, as well as discussing the further development of kefir as an important probiotic product."


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



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

"The purpose of this review has been to collate and summarize that which is known about the microbial composition of kefir and how this composition plays a role in the health benefits associated with kefir consumption. Kefir is a dynamic fermented dairy product with many different factors affecting the benefits associated with its consumption. These factors include the variable yeast and bacterial species present, as well as metabolites such as kefiran and other exopolysaccharides. While kefir has been associated with health benefits for 100s of years, the exact form of these benefits has, until recently, not been studied. The use of animal models and other in vitro analyses has allowed for the elucidation of how kefir positively impacts host health. Whole kefir, as well as specific fractions and individual organisms isolated from kefir, provide a multitude of positive effects when consumed. These range from improved cholesterol metabolism and wound healing, to the modulation of the immune system and microbiome, and even the potential alleviation of allergies and cancers. Further studies into the mechanisms behind these effects will allow scientists to better understand exactly how kefir and other fermented dairy products confer these benefits as well as how to harness these traits outside of kefir itself.

The wide range of potential health promoting effects of kefir could lead to a further expansion on the popularity of both traditional fermented kefir and products that are manufactured with kefir fractions or organisms. In order to fully exploit the beneficial characteristics of kefir, a more in-depth understanding of the composition of kefir is critical. With advances in metagenomic analysis through the development of high-throughput sequencing technology, this is a very realistic prospect. Armed with this knowledge, it should be possible to more readily isolate and examine the phenotypic characteristics of individual organisms present in a kefir blend while also providing a greater insight into the evolution of these organisms and how they became specialized to the kefir ecosystem. The additional knowledge gained can also provide crucial information relating to the mechanisms and exact agents responsible for beneficial effects that have been attributed to kefir (Atalan et al., 2003; Rodrigues et al., 2005; Huseini et al., 2012; Rahimzadeh et al., 2014).

The need for further research does not only apply to the mechanisms by which kefir consumption exerts these effects but also which organisms or parts of kefir are responsible for each benefit. By determining which organisms and metabolites are essential for each process, the possibility arises for the commercial manufacturing of kefir that is specifically designed to create the most profound effect in those that consume it. As it stands currently, the highly variable nature of the organisms and metabolites present in traditional kefir requires health claims to be verified individually in each grain and kefir beverage. The ability to combine the best possible strains of the best organisms from multiple sources of kefir would create the potential for greater benefits than have been previously observed, with a measure of control over these effects that has not been possible in traditional kefir."


Full-text access of the referenced scientific work:

Bourrie BC, Willing BP, Cotter PD. The Microbiota and Health Promoting
Characteristics of the Fermented Beverage Kefir. Front Microbiol. 2016 May
4;7:647. doi: 10.3389/fmicb.2016.00647. Review. PubMed PMID: 27199969; PubMed
Central PMCID: PMC4854945.

Traditional use of medicinal plants to combat disease: special journal issue


Submission is open for an ethnopharmacology-focused special issue of the journal Frontiers in Pharmacology (IF=4.4, Q1), guest edited by Atanas G. Atanasov, Judith Maria Rollinger, Judit Hohmann, and Anna Karolina Kiss.

With emphases of traditional European medicine, the special issue encourages submissions related to phytochemistry, clinical studies with herbal preparations, bioactivities and mechanism of action studies with natural products, pharmacokinetics and biotransformation of phytochemicals, field and observational studies on the use of local and traditional medicinal plants etc.



The submission of the following article types is particularly encouraged: Original Research, Methods, Protocols, Technology Reports, Reviews, Mini-Reviews, Hypothesis & Theory, Perspectives, Data Reports, General Commentary, Opinions, and Book Reviews.

The full text of the submission call with all further details and requirements can be viewed at:

http://journal.frontiersin.org/researchtopic/6024/ethnopharmacology-in-central-and-eastern-europe-in-the-context-of-global-research-developments



Sunday, March 19, 2017

The novel dietary supplement methylsulfonylmethane (MSM): applications and safety


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

"Methylsulfonylmethane (MSM) has become a popular dietary supplement used for a variety of purposes, including its most common use as an anti-inflammatory agent. It has been well-investigated in animal models, as well as in human clinical trials and experiments. A variety of health-specific outcome measures are improved with MSM supplementation, including inflammation, joint/muscle pain, oxidative stress, and antioxidant capacity. Initial evidence is available regarding the dose of MSM needed to provide benefit, although additional work is underway to determine the precise dose and time course of treatment needed to provide optimal benefits. As a Generally Recognized As Safe (GRAS) approved substance, MSM is well-tolerated by most individuals at dosages of up to four grams daily, with few known and mild side effects. This review provides an overview of MSM, with details regarding its common uses and applications as a dietary supplement, as well as its safety for consumption."


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



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

"MSM is a naturally occurring organosulfur compound with broad biological effects. Human absorption and biosynthesis of this compound likely depends heavily on the co-metabolism between microbiota and host. Whether naturally produced or manufactured, MSM exhibits no biochemical differences in its ability to intermediate oxidative stress and inflammation. This micronutrient is well tolerated for arthritis and a number of other conditions related to inflammation, physical function, and performance. Emerging research suggests that MSM may one day aid in the treatment of various types of cancer [49,99,100,101,119,120,121,122,123,125,126,181,184,185,186,194] or metabolic syndromes [195]."


Full-text access of the referenced scientific work:

Butawan M, Benjamin RL, Bloomer RJ. Methylsulfonylmethane: Applications and
Safety of a Novel Dietary Supplement. Nutrients. 2017 Mar 16;9(3). pii: E290.
doi: 10.3390/nu9030290. Review. PubMed PMID: 28300758.
http://www.mdpi.com/2072-6643/9/3/290/htm


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Thursday, March 16, 2017

Stress-induced despair behavior and intestinal microbiota: can eating yogurt combat depression?


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

"Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress."


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



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

"Taken together, our results demonstrate that microbiome homeostasis was robustly altered in animals undergoing UCMS, with a consistent decrease in Lactobacilli. This finding was shared across three strains of mice (C57BL/6J, as BALB/cJ and C57BL/6N). Moreover, our data suggest that the production of H2O2 by Lactobacillus may be protective against the development of despair behavior by direct inhibition of intestinal ido1 expression and decrease in the circulating level of kynurenine, a metabolite associated with depression26.

Our results are in agreement with recent literature demonstrating that microbiome composition is modified with acute and chronic stress20,33,34. Microbiome dysbiosis is also detected in humans affected by major depressive disorders and the transplantation of the biota from these patients in germ free mice can induce despair behavior9. Beyond describing microbiome fluctuation as a consequence of UCMS, we further demonstrated that levels of Lactobacillus correlate with the susceptibility to and severity of despair behaviors. Indeed, animals exhibiting low (i.e. Taconic C57BL/6N mice) intestinal Lactobacillus levels present with a basal despair phenotype, when compared to animals with higher levels of Lactobacillus (i.e. Jackson C57BL/6J mice). Accordingly, therapeutic administration of a probiotic Lactobacillus species during UCMS was sufficient to improve the despair symptoms. Further works will be needed to explore the role of other populations of bacteria affected by UCMS, as well as Lactobacillus strain differences and their abilities to improve behavior.

Recently, members of the Lactobacillus genus have been shown to affect a multitude of aspects of human physiology, as they colonize several sites of the body, including the skin, the vagina, and the entirety of the gastrointestinal tract, starting with the oral cavity35. Perhaps best studied in the vagina, Lactobacilli protect against infection by producing a diversity of antimicrobial factors, including lactic acid, peroxide, bacteriocins, as well as by resource competition35,36,37. Although in a few contexts increased levels of Lactobacilli are associated with pathology, e.g. dental cavities38, the bacteria are largely non-pathogenic or beneficial. From dysbioses or probiotic studies, Lactobacilli are associated with protection against infection, improved recovery after enteric infections, decreased colitis pathology, and better cognitive function25,39,40,41.

While Lactobacilli are able to control other microbial communities through secretion of antimicrobial factors, genetic limitations make them more sensitive to environmental conditions. In particular, many Lactobacillus genus members are unable to synthesize amino acids and purines and thus rely on nutrient rich environments and other bacteria for supply of essential building blocks42,43,44,45. We hypothesize that, in the context of a faster intestinal transit, such as the one observed in stressed animals, fluctuating availability of nutrients and symbiotic bacteria will impact the renewal of the Lactobacillus niche46. Further studies will be able to determine whether there is indeed a causal relationship between increased intestinal motility and microbiota alteration in the context of stress, or rather if the dysbiosis induced during stress causes altered intestinal physiology.

We found that the level of kynurenine is increased after chronic stress, in a manner dependent on Lactobacillus levels. Kynurenine can readily cross the blood-brain barrier to drive depression within the CNS by disrupting neurotransmitter balance and driving neuroinflammation27,47. A recent study by Agudelo et al.26 identified this pathway as also being disrupted in stressed mice using the same model of UCMS. Taken together, these new findings point to disruptions in tryptophan-kynurenine metabolism as an important factor in mediating despair behavior. IDO1 is the main enzyme responsible for conversion of tryptophan to kynurenine outside of the liver, and its expression and activity can be directly inhibited by reactive oxygen species (ROS)32. Members of the Lactobacillus family have the capacity to produce high levels of ROS, as a means of maintaining their niche36,37. In our study, we have shown that decreased levels of ROS in stressed animals correlate with an increase in intestinal ido1 transcripts, thus potentially explaining our observed increase in circulating kynurenine. Moreover, several studies have shown that inhibiting IDO1 activity (such as with the small molecule 1-methyl tryptophan) has potent effects in ameliorating depressive-like behaviors both in chronic stress and inflammation-induced sickness behavior models48,49,50.

The inhibition of IDO1 by Lactobacillus-derived ROS is likely just one of the mechanisms through which Lactobacilli, and L. reuteri in particular, contribute to host physiology and modulate behavior. Our findings are in accordance with the previously reported beneficial effect of L. reuteri administration on despair and anxiety-like behaviors25. Nevertheless, in their study, Bravo and colleagues have shown that L. reuteri can modulate GABA receptor expression in the CNS, via the vagus nerve25. The vagus nerve has been shown to carry peripheral signals and modulate inflammatory and stress reponses51,52,53,54. Whether the two results are connected remains to be investigated. It is possible that intestinal kynurenine can signal on the afferent vagal terminals and modulate its effects in the CNS, including its modulation of the hypothalamus-pituitary adrenal (HPA) axis. To this point, it is important to consider the contribution of liver TDO to peripheral kynurenine levels. TDO expression and activity are increased by glucocorticoids and in response to acute stress, and play a role in glucocorticoid levels homeostasis55,56,57. Whether TDO levels decrease chronically in our long-term stress model (following an expected decrease of corticosterone) or what effect the Lactobacillus administration has remains to be investigated. We have also considered other possible mechanisms for the behavioral effects of L. reuteri supplementation, mediated by the immune system, or other populations of commensals affected by the treatment. Further studies will be necessary to assess the chronological and the hierarchical role of each pathway during despair behavior development, as well as how these pathways affect the CNS.

Altogether, our results indicate that the microbiome can play a causative role in the development and symptomatology of depression. Further studies are needed to prove a causal relationship between intestinal Lactobacillus levels and depressive-like behavior. Moreover, investigation of whether Lactobacilli can play a similar function in human biology and if manipulation of Lactobacillus levels and/or local induction of ROS production in the gut could be used to treat psychiatric disorders is warranted."


Full-text access of the referenced scientific work:
Marin IA, Goertz JE, Ren T, Rich SS, Onengut-Gumuscu S, Farber E, Wu M,
Overall CC, Kipnis J, Gaultier A. Microbiota alteration is associated with the
development of stress-induced despair behavior. Sci Rep. 2017 Mar 7;7:43859. doi:
10.1038/srep43859. PubMed PMID: 28266612; PubMed Central PMCID: PMC5339726.
https://www.researchgate.net/publication/314302451_Microbiota_alteration_is_associated_with_the_development_of_stress-induced_despair_behavior


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Monday, March 13, 2017

The stomach in health and disease


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

"The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer."


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






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

"Healthy stomach: future approach to gastric diseases

The stomach occupies the central role in orchestrating the digestive process, and this is frequently underestimated. Moreover, gastric acid secretion in the last decades has been seen as a ‘bystander’ with little function but with deleterious potential for itself and adjacent organs, the oesophagus and duodenum. As a consequence, the pharmacological approach has been towards the development of more potent drugs for acid inhibition. Due to the increasing awareness of GI functional disorders, the role of the stomach has been revisited in its role as site of origin for dyspeptic symptoms. More recently, attention has focused on the stomach for its control function in food intake and for contributing to maintenance of metabolic balance (figure 10).

The future approach to gastric diseases (box 3) is directed to maintaining a healthy stomach, which is free from discomfort, ulceration and the risk of complications and malignancy. The main challenge remains the elimination of H. pylori infection from individual patients and from populations. An estimated 20% of H. pylori-infected people will continue to suffer from overt clinical upper GI symptoms and complications over their lifetime, and some may develop extra-digestive diseases. The individual outcome of anyone infected with H. pylori cannot be predicted. Therefore, a public health approach should be directed towards ‘screen and treat’ strategies that will have to be adapted to the needs of different populations according to the prevalence of H. pylori infection and gastric cancer risk stratification. Gastric disease prevention programmes should be integrated with more comprehensive GI prevention strategies. The combination of H. pylori screening and eradication programmes with colorectal cancer screening is an initiative promoted and coordinated by the Healthy Stomach Initiative (HSI) (http://www.hsinitiative.org).

Gastric cancer is still a major challenge worldwide, and because detection is frequently made only at an advanced stage, mortality has remained high.216 ,217 Gastric cancer prevention programmes by H. pylori eradication have been shown of benefit in high-risk populations.193 The best results from gastric cancer prevention strategies are obtained when H. pylori eradication is performed before advanced atrophic gastritis with pre-neoplastic changes becomes established and thus implementation of H. pylori screening and treatment in early adulthood is required. Secondary prevention by H. pylori eradication following endoscopic resection of early gastric cancer has major limitations.218 With pre-neoplastic conditions such as atrophy and IM already present, carcinogenic pathways are more likely to progress in spite of the eradication of H. pylori infection. Future research will need to focus on unravelling mechanisms involved in progression from pre-neoplastic lesions to cancer.

The recent definition of H. pylori gastritis as an infectious disease by the Kyoto global consensus conference, January 2014, is expected to raise concern and engender support from regulatory authorities towards the global elimination of H. pylori infection and its serious sequelae.150

Despite these important indications and calls for a widespread approach to the eradication of H. pylori infection, there remain substantial challenges. The first includes achieving the ideal effective therapy without significant side effects and no antibiotic resistance. Such an ideal therapy is not yet available, and therefore, H. pylori eradication therapy, beyond the established specific clinical indications, should embark on selected screen and treat strategies. For the time being, these strategies will have to address populations with a high to moderate incidence of gastric cancer. The search for a ‘golden treatment bullet’ continues to remain one option while the second option is an intensified search for a vaccine.

Second, H. pylori infection may confer some benefits to those who do not have gastroduodenal symptoms, nor present with gastroduodenal disease or complications. The reduced prevalence of atopic diseases, such as asthma in patients infected with H. pylori up to young adulthood, requires intensive investigation to understand the mechanism of this phenomenon. Epidemiological and experimental evidence is still limited and cannot yet offer any conclusions about a causal relationship.93 ,219 ,220 Studies on the relationship of H. pylori gastritis will lead to better understanding of both local and systemic immune responses and their impact on gastric diseases.

In addition to the initiatives and strategies to eradicate H. pylori infection, studies are required to better understand the role of the stomach in food intake, accommodation, pre-digestion and the delivery of nutrient for intestinal digestion.38 Research should focus on ways to modulate gastric functions and their role as ‘weight watcher’ and their integration in the balance of hunger and satiety. Studies will need to address to what extent gastric acid should be inhibited and for how long during the 24 h period in patients who suffer from acid-related diseases. Moreover, it will be important to define just how much acid is required to preserve a ‘healthy’ gut microbiome. The role of the gastric microbiota in the presence and absence of H. pylori infection on the diversity of microbiota in the small bowel will be of enormous relevance in understanding and tackling gastric, hepatic and intestinal diseases.221–223

Last, but by no means least, education with effective presentation of new knowledge to the general public to ensure gastric health and prevent disease is a major task to be accomplished and the creation of the HSI for public awareness is a step in this direction."


Full-text access of the referenced scientific work:

Hunt RH, Camilleri M, Crowe SE, El-Omar EM, Fox JG, Kuipers EJ, Malfertheiner P, McColl KE, Pritchard DM, Rugge M, Sonnenberg A, Sugano K, Tack J. The stomach in health and disease. Gut. 2015 Oct;64(10):1650-68. doi:10.1136/gutjnl-2014-307595. Review. PubMed PMID: 26342014; PubMed Central PMCID: PMC4835810.
https://www.researchgate.net/publication/281510130_The_stomach_in_health_and_disease


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At



Sunday, March 12, 2017

How beneficial is Silymarin/Silybin use in chronic liver disease?


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

"
Silymarin is the extract of Silybum marianum, or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma."


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



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

"
The “marriage of many years” that links silymarin/silybin to liver diseases, derives from the progressive evidence that, with the passing of time, has led to investigation of, firstly empirically and then scientifically, the mechanisms through which they act in carrying out the therapeutic effect. The studies of pharmacokinetics and pharmacodynamics on silymarin have improved, in the last few years, its applicability in different pathologies, especially liver diseases, allowing, through the use of conjugates compounds, a more efficient application. Through the analysis of literature, it has been demonstrated that silymarin has an effect that allows its use in all of the most frequent causes of liver damage. Indeed, silymarin has three important activities: anti-inflammatory, antioxidant and pro-apoptotic, which represent the “functional triad” that allows for antagonizing the onset and the progression of mechanisms of damage that are responsible for the progression of hepatitis to cirrhosis and HCC. However, it is clear that, also in the end stages of liver pathologies, silymarin can act by limiting de-novo fibrogenesis and antagonizing procarcinogenic mechanisms that cause HCC. Nevertheless, the treatment with silymarin/silybin in routine clinical practice is strongly limited, since it is necessary to obtain scientific data deriving from well-structured trials based on large populations of patients, and to achieve a standardization of methods used for evaluating the therapeutic efficacy, especially in an NAFLD context, that is particularly promising."


Full-text access of the referenced scientific work:

Federico A, Dallio M, Loguercio C. Silymarin/Silybin and Chronic Liver
Disease: A Marriage of Many Years. Molecules. 2017 Jan 24;22(2). pii: E191. doi: 
10.3390/molecules22020191. Review. PubMed PMID: 28125040.
http://www.mdpi.com/1420-3049/22/2/191


Webmaster:


Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At



Thursday, March 9, 2017

Role of intestinal microbiota and metabolites in human diseases


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

"
BACKGROUND:
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.
METHODS:
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).
RESULTS:
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.
CONCLUSIONS:
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:
PMC5219689.
https://www.researchgate.net/publication/312145121_Role_of_intestinal_microbiota_and_metabolites_on_gut_homeostasis_and_human_diseases


Webmaster:


Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At