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The Role of Bacteria and Its Derived Metabolites in Chronic Pain and Depression: Recent Findings and Research Progress.
Li, S, Hua, D, Wang, Q, Yang, L, Wang, X, Luo, A, Yang, C
The international journal of neuropsychopharmacology. 2020;23(1):26-41
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Depression is closely associated with chronic pain yet the connection between these comorbidities is ambiguous. Recent studies have shown alterations in the gut microbiome may contribute to cognitive dysfunction via the microbiota-gut-brain axis. The aim of this systematic review is to summarize the existing evidence of the role of the gut microbiome in chronic pain and depression and explore potential mechanisms of gut dysbiosis in the development of these conditions. This review found metabolic products from the gut microbiota can mediate neuro-inflammation and neuro-immunity pathways in pain and depression, and that dysbiosis in the gut may contribute to the cause of chronic pain and depression. The authors conclude the metabolic products from the gut bacteria offer new insights to the connection between the gut microbiota and mechanisms of pain and depression, while showing potential as a therapeutic target.
Abstract
BACKGROUND Chronic pain is frequently comorbid with depression in clinical practice. Recently, alterations in gut microbiota and metabolites derived therefrom have been found to potentially contribute to abnormal behaviors and cognitive dysfunction via the "microbiota-gut-brain" axis. METHODS PubMed was searched and we selected relevant studies before October 1, 2019. The search keyword string included "pain OR chronic pain" AND "gut microbiota OR metabolites"; "depression OR depressive disorder" AND "gut microbiota OR metabolites". We also searched the reference lists of key articles manually. RESULTS This review systematically summarized the recent evidence of gut microbiota and metabolites in chronic pain and depression in animal and human studies. The results showed the pathogenesis and therapeutics of chronic pain and depression might be partially due to gut microbiota dysbiosis. Importantly, bacteria-derived metabolites, including short-chain fatty acids, tryptophan-derived metabolites, and secondary bile acids, offer new insights into the potential linkage between key triggers in gut microbiota and potential mechanisms of depression. CONCLUSION Studying gut microbiota and its metabolites has contributed to the understanding of comorbidity of chronic pain and depression. Consequently, modulating dietary structures or supplementation of specific bacteria may be an available strategy for treating chronic pain and depression.
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Coronavirus disease 2019 (COVID-19) and obesity. Impact of obesity and its main comorbidities in the evolution of the disease.
Cornejo-Pareja, IM, Gómez-Pérez, AM, Fernández-García, JC, Barahona San Millan, R, Aguilera Luque, A, de Hollanda, A, Jiménez, A, Jimenez-Murcia, S, Munguia, L, Ortega, E, et al
European eating disorders review : the journal of the Eating Disorders Association. 2020;28(6):799-815
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The Covid-19 pandemic has caused thousands of deaths worldwide. Being obese is associated with worse outcomes following infection with Covid-19. This review aimed to summarise the data available on the relationship between Covid-19 and obesity, and explored some of the possible reasons for this relationship. The researchers found that obesity is an independent and strong risk factor for severe infection, Intensive Care Unit (ICU) admission and death. The impact of obesity might be of particular relevance in males and in younger individuals. Long‐term complications of Covid‐19 could also be more frequent and severe in obese subjects. There are many potential mechanisms that could explain this relationship. These include the effects of obesity and related diseases such as diabetes, high blood pressure and heart disease on the immune system, lung function, vitamin D deficiency and male hormones. The researchers also discussed the possibility of fat cells acting as a possible reservoir for Covid-19 infection. Research into Covid-19 is still at a very early stage and more studies are needed.
Abstract
The COVID-19 pandemic is posing a great challenge worldwide. Its rapid progression has caused thousands of deaths worldwide. Although multiple aspects remain to be clarified, some risk factors associated with a worse prognosis have been identified. These include obesity and some of its main complications, such as diabetes and high blood pressure. Furthermore, although the possible long-term complications and psychological effects that may appear in survivors of COVID-19 are not well known yet, there is a concern that those complications may be greater in obese patients. In this manuscript, we review some of the data published so far and the main points that remain to be elucidated are emphasized.
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The Role of Lung and Gut Microbiota in the Pathology of Asthma.
Barcik, W, Boutin, RCT, Sokolowska, M, Finlay, BB
Immunity. 2020;52(2):241-255
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Over 300 million people suffer with asthma worldwide and it has emerged that microbiome analysis of the lung and gut bacteria, fungi, viruses, and archaea may help with disease management. This microbiome plays an important role in immune response. Disturbances to these microbes, known as dysbiosis, may influence onset of disease and the body’s ability to respond naturally, and/or to pharmaceutical treatments. Asthma is not a singular disease and there are great variations in symptom severity and underlying immune mechanisms. Patients are typically classified as type 2 or non-type 2. Type 2 patients tend to be allergic to common air-born allergens which can trigger an attack. Treatment usually consists of glucocorticosteroids or novel biologicals. Non type-2 asthma is associated with obesity-related asthma and typically responds poorly to steroid treatment. For a long time, researchers believed the human lungs to be sterile, so they were initially not included in the 2007 Human Microbiome Project. It has since been shown that, like the gut, the lungs and respiratory tract also host various microbes, and this healthy-airway microbiota influence innate and adaptive immune processes. The Gut-Lung axis also confers additional microbial benefits from the intestines. In asthma patients, there is often an over-dominance of pathogenic bacteria. Fungal dysbiosis is associated with high-risk asthma phenotypes in childhood. Viral infections have been shown as a primary cause of asthmatic episodes. Future diagnosis and treatment of patients with asthma should be assisted by analysis of the composition and metabolic activity of an individual’s microbiome.
Abstract
Asthma is a common chronic respiratory disease affecting more than 300 million people worldwide. Clinical features of asthma and its immunological and molecular etiology vary significantly among patients. An understanding of the complexities of asthma has evolved to the point where precision medicine approaches, including microbiome analysis, are being increasingly recognized as an important part of disease management. Lung and gut microbiota play several important roles in the development, regulation, and maintenance of healthy immune responses. Dysbiosis and subsequent dysregulation of microbiota-related immunological processes affect the onset of the disease, its clinical characteristics, and responses to treatment. Bacteria and viruses are the most extensively studied microorganisms relating to asthma pathogenesis, but other microbes, including fungi and even archaea, can potently influence airway inflammation. This review focuses on recently discovered connections between lung and gut microbiota, including bacteria, fungi, viruses, and archaea, and their influence on asthma.
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Effects of Yeast (1,3)-(1,6)-Beta-Glucan on Severity of Upper Respiratory Tract Infections: A Double-Blind, Randomized, Placebo-Controlled Study in Healthy Subjects.
Dharsono, T, Rudnicka, K, Wilhelm, M, Schoen, C
Journal of the American College of Nutrition. 2019;38(1):40-50
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Upper respiratory tract infections (URTIs) significantly impact the quality of life in susceptible individuals and account for considerable economic costs in days of work lost and medical visits. Previous studies have shown that URTIs may be reduced by the consumption of yeast beta-glucans through their affect on the immune system. This randomised double-blind placebo controlled study aimed to investigate whether the incidence and severity of the common cold could be altered by consumption of yeast (1,3)-(1,6)-beta-glucan. 291 subjects susceptible to URTI’s were randomly assigned to placebo or (1,3)-(1,6)-beta-glucan for 16-weeks. There were no statistically significant differences on overall symptom severity or duration of URTIs with beta-glucans at 16 weeks. Feelings of joy were significantly reduced with placebo. Further analysis showed that the beta-glucan group did experience reduced severity of symptoms in the first 7 days of contracting the URTI. Interesting to note was a significant reduction in blood pressure with beta-glucans, which was even more pronounced in subjects with clinically high blood pressure. Nutrition practitioners working with individuals suffering from chronic URTIs may wish to consider beta-glucans for their ability to reduce symptom severity in the first week of infection and increase feelings of wellbeing.
Abstract
OBJECTIVES Each year, adults suffer about two to four upper respiratory tract infections (URTIs), mostly in winter. The aim of the study was to evaluate the effects of brewers' yeast (1,3)-(1,6)-beta-glucan on incidence and severity of upper respiratory tract infections (URTIs). METHODS Generally healthy men and women (n = 299) reporting at least three URTIs during the previous year were randomized to receive either a placebo or 900 mg of yeast beta-glucan daily for 16 weeks during winter. In cases of acute URTI, the severity of URTI symptoms was assessed via the WURSS-21 questionnaire and the Jackson scale, and a clinical confirmation was implemented by the investigator. RESULTS Overall, 70 subjects under placebo and 71 subjects under yeast beta-glucan experienced at least one clinically confirmed URTI episode. The global severity using WURSS-21 had been quite similar between the study groups (p = 0.5267), whereas during the first days of URTIs the severity was less pronounced in the yeast beta-glucan group. On the episode level, the severity of physical symptoms was significantly lower for all investigated time intervals up to 7 days under yeast beta-glucan (WURSS (Q2-11) (days 1-2: p = 0.0465, days 1-3: p = 0.0323, days 1-4: p = 0.0248, days 1-7: p = 0.0278), also confirmed for the Jackson scale). The reduction of severity was accompanied by a significant increase in the joy subscore of the Perceived Stress Questionnaire (PSQ20) (p = 0.0148). In addition, there was a reduction of systolic (p = 0.0458) and diastolic (p = 0.1439) blood pressure. CONCLUSION Subjects supplementing with yeast beta-glucan benefit by a reduced severity of physical URTI symptoms during the first week of an episode, even though the incidence and global severity of common colds could not be altered in comparison to placebo. Furthermore, accompanying benefits in terms of blood pressure and mood were identified. Altogether, yeast beta-glucan supports the immune function.
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Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential.
Guo, R, Chen, LH, Xing, C, Liu, T
British journal of anaesthesia. 2019;123(5):637-654
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Acute pain serves to protect us from further tissue damage. Chronic pain is debilitating and significantly reduces the quality of life for affected individuals and their loved ones. The relationship between gut bacteria and various diseases, including chronic pain, is receiving increasing attention. This review article discusses the current understanding of the role of the gut microbiota in pain regulation and what the science says in relation to gut bacteria manipulation and chronic pain. The authors of the review discuss the role of various compounds and metabolites of gut bacteria in relation to inflammation, neuropathic pain, visceral pain and headache. Whilst a lot of the current findings are based on results of rodent studies, the emerging evidence suggests that gut dysbiosis participates in various chronic pain conditions in a number of ways. Therefore, modulation of the gut microbiome through diet and pro- and pre-biotics is warranted for use by Nutrition Practitioners.
Abstract
The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
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Impact of red meat, processed meat and fibre intake on risk of late-onset chronic inflammatory diseases: prospective cohort study on lifestyle factors using the Danish 'Diet, Cancer and Health' cohort (PROCID-DCH): protocol.
Rasmussen, NF, Rubin, KH, Stougaard, M, Tjønneland, A, Stenager, E, Lund Hetland, M, Glintborg, B, Bygum, A, Andersen, V
BMJ open. 2019;9(3):e024555
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Chronic inflammatory diseases (CIDs) can be considered as systemic diseases which primarily affect one organ such as the intestine, skin, joints or the brain. The primary aim of this study was to investigate the impact of fibre, red meat and processed meat on disease risk outcomes of late-onset CID in the ‘Diet, Cancer and Health’ (DCH) cohort. The study is an observational prospective cohort study. The study will use data from 57,053 persons from the prospective Danish cohort study ‘Diet, Cancer and Health’ together with National Health Registry data. The study does not only target one CID but it looks at several CIDs. Furthermore, the linkage to Danish health registries will ensure almost complete follow-up of the study population since the Danish health registries are considered the internationally most comprehensive with high validity.
Abstract
INTRODUCTION Chronic inflammatory diseases (CIDs) (Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis and multiple sclerosis) are diseases of the immune system that have some shared genetic and environmental predisposing factors, but still few studies have investigated the effects of lifestyle on disease risk of several CIDs. The primary aim of this prospective cohort study is to investigate the impact of fibre, red meat and processed meat on risk of late-onset CID, with the perspective that results of this study can contribute in supporting future diet recommendations for effective personalised prevention. METHODS AND ANALYSIS The study will use data from 57 053 persons from the prospective Danish cohort study 'Diet, Cancer and Health' together with National Health Registry data. The follow-up period is from December 1993 to December 2018. Questionnaire data on diet and lifestyle were collected at entry to the Diet, Cancer and Health study. The outcome CID is defined as having a diagnosis of one of the CIDs registered in the National Patient Registry or, for multiple sclerosis, in the Danish Multiple Sclerosis Registry during follow-up and being treated with a drug used for the specific disease. The major outcome of the analyses will be to detect variability in risk of late onset of any CID and, if power allows, disease risk of late onset of each CID diagnosis between persons with different fibre and red meat, and processed meat intake. The outcome will be adjusted for age, sex, body mass index, physical activity, energy, alcohol, fermented dairy products, education, smoking status, hormone replacement therapy and comorbidity. ETHICS AND DISSEMINATION The study is approved by the Danish Data Protection Agency (2012-58-0018). The core study is an open register-based cohort study. The study does not need approval from the Ethics committee or Institutional Review Board by Danish law. Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. TRIAL REGISTRATION NUMBER NCT03456206; Post-results.
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Bioactivity of soy-based fermented foods: A review.
Cao, ZH, Green-Johnson, JM, Buckley, ND, Lin, QY
Biotechnology advances. 2019;37(1):223-238
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Fermented foods are growing in popularity in the West due to their unique flavour and nutritional value. This review investigates the fermentation processes, health-associated bioactive components and underlying mechanisms of the popular fermented soy products Natto, fermented soy milk, Tempeh and soy sauce. Each fermented soy product is summarised based on functional activities. The existing literature points to an overall positive effect on bone health and immune activities. Interestingly, each fermented soy food exhibits different profiles of bioactive components and therefore different mechanisms of action. Based on this review, the authors conclude there is a need for further in-depth human studies with large sample sizes and long-term follow up to better understand these foods benefits and potential toxicity.
Abstract
For centuries, fermented soy foods have been dietary staples in Asia and, now, in response to consumer demand, they are available throughout the world. Fermentation bestows unique flavors, boosts nutritional values and increases or adds new functional properties. In this review, we describe the functional properties and underlying action mechanisms of soy-based fermented foods such as Natto, fermented soy milk, Tempeh and soy sauce. When possible, the contribution of specific bioactive components is highlighted. While numerous studies with in vitro and animal models have hinted at the functionality of fermented soy foods, ascribing health benefits requires well-designed, often complex human studies with analysis of diet, lifestyle, family and medical history combined with long-term follow-ups for each subject. In addition, the contribution of the microbiome to the bioactivities of fermented soy foods, possibly mediated through direct action or bioactive metabolites, needs to be studied. Potential synergy or other interactions among the microorganisms carrying out the fermentation and the host's microbial community may also contribute to food functionality, but the details still require elucidation. Finally, safety evaluation of fermented soy foods has been limited, but is essential in order to provide guidelines for consumption and confirm lack of toxicity.
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Nutritional strategies for psoriasis: current scientific evidence in clinical trials.
Zuccotti, E, Oliveri, M, Girometta, C, Ratto, D, Di Iorio, C, Occhinegro, A, Rossi, P
European review for medical and pharmacological sciences. 2018;22(23):8537-8551
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Psoriasis is an inflammatory skin disease that results in patches of dry, scaly skin that can be itchy or sore. This review looked at the evidence for a variety of nutritional and herbal strategies for reducing the risk and severity of psoriasis. Obesity is associated with both an increased risk of psoriasis, and increased severity of the disease, with obese patients being twice as likely to suffer from psoriasis as people of normal weight. Abdominal obesity in particular is associated with chronic low-grade inflammation that contributes to immune dysregulation. In obese patients, weight reduction via a low-calorie diet has been shown to reduce the severity of psoriasis. A Mediterranean-style diet, rich in extra virgin olive oil, fish, fruit vegetables, legumes, nuts and seeds is associated with a lower incidence of psoriasis. In contrast, a diet high in simple carbohydrates, high in arachidonic acid, and a low omega 3: omega 6 ratio is likely to drive inflammation, worsening severity of the disease. The microbiota plays a role in the development of psoriasis, with disruption of the gut and skin microbiomes both associated with psoriasis. In particular, psoriasis patients have a reduced abundance of Akkermansia muciniphilia in their gut. Several Lactobacillus strains have demonstrated potential for therapeutic effects in psoriasis patients when taken as a supplement. Common nutritional supplements used by psoriasis patients are fish oil, selenium, and zinc. In a review of the efficacy of fish oil supplementation, 12 of 15 trials showed a benefit. The evidence for zinc supplementation is less robust. There is limited data on the effectiveness of selenium supplementation, however low serum selenium levels are associated with increased psoriasis severity. Vitamin D levels are lower in psoriasis patients and correlate with disease severity. In individuals who are deficient, supplementing with vitamin D may prevent psoriasis-related comorbidities. Amongst the herbal and botanical remedies studied, neem, turmeric, Tripterygium wilfordii (Thunder God Vine), and the carotenoid-rich alga Dunaliella bardawil may reduce the severity of psoriasis. The review authors concluded that an integrated multidisciplinary approach should be considered for the management of psoriasis patients. Education to modify lifestyle and environmental risk factors is important. A collaboration between nutritionists and medical specialists with a holistic approach may be useful for psoriasis patients.
Abstract
OBJECTIVE Several nutritional strategies for the management of psoriasis are promising. Even if recent data support that nutrition may play a pivotal role in prevention and co-treatment and despite patient's concerns regarding the best nutritional habits, the consensus regarding the nutritional strategies to be adopted lacks in clinical settings. In this manuscript, the effects of several nutritional strategies for psoriasis patients such as hypocaloric diet, vitamin D, fish oil, selenium, and zinc supplementation were systematically reviewed. Randomized controlled trials (RCTs) on beneficial botanical oral supplements were also included in the analysis. MATERIALS AND METHODS For each topic, a search was conducted in MEDLINE electronic databases for articles published in English between January 1, 1990 and September 2018. Two independent reviewers assessed and extracted the data. Only controlled clinical trials were selected. RESULTS The evidence regarding the current nutritional strategies for psoriasis patients were summarized and translated into a global, comprehensible recommendation. CONCLUSIONS Weight loss combined with a healthy lifestyle was shown to be very beneficial for patients with moderate to severe disease with a significant reduction of the Psoriasis Area and Severity Index (PASI) score. Currently, oral vitamin D supplementation for prevention or treatment of psoriasis in adults with normal vitamin D levels is not recommended; however, psoriasis patients with a deficit in plasma vitamin D levels are advised to complement with oral supplements to prevent psoriasis-related comorbidities. Instead of zinc, selenium, and omega 3 supplements have been proven beneficial for psoriasis patients. Among botanical species, Dunaliella bardawil (D. bardawil), Tripterygium wilfordii (T. wilfordii), Azadirachta indica (A. indica), Curcuma longa (C. longa), and HESA-A are the most beneficial. In conclusion, a close cooperation between nutritionists and dermatologists may be useful for the management of psoriasis.
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A Review of Microbiota and Irritable Bowel Syndrome: Future in Therapies.
Rodiño-Janeiro, BK, Vicario, M, Alonso-Cotoner, C, Pascua-García, R, Santos, J
Advances in therapy. 2018;35(3):289-310
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Irritable bowel syndrome (IBS) is a common functional gut disorder characterised by abdominal pain and associated changes in bowel habits. Increasing evidence points to altered gut microbiota, dysbiosis, as a predominant factor in IBS development and has therefore become a primary target for therapeutic options in patients with IBS. This review evaluates existing literature on IBS interventions targeting the gut microbiota and suggests future approaches useful for diagnosis, prevention and treatment of IBS. Based on the current literature, this review suggests there is a strong role of dysbiosis in the pathophysiology of IBS. The authors conclude that there are promising therapeutic options available but further evidence is needed from larger controlled studies.
Abstract
Irritable bowel syndrome (IBS), one of the most frequent digestive disorders, is characterized by chronic and recurrent abdominal pain and altered bowel habit. The origin seems to be multifactorial and is still not well defined for the different subtypes. Genetic, epigenetic and sex-related modifications of the functioning of the nervous and immune-endocrine supersystems and regulation of brain-gut physiology and bile acid production and absorption are certainly involved. Acquired predisposition may act in conjunction with infectious, toxic, dietary and life event-related factors to enhance epithelial permeability and elicit mucosal microinflammation, immune activation and dysbiosis. Notably, strong evidence supports the role of bacterial, viral and parasitic infections in triggering IBS, and targeting microbiota seems promising in view of the positive response to microbiota-related therapies in some patients. However, the lack of highly predictive diagnostic biomarkers and the complexity and heterogeneity of IBS patients make management difficult and unsatisfactory in many cases, reducing patient health-related quality of life and increasing the sanitary burden. This article reviews specific alterations and interventions targeting the gut microbiota in IBS, including prebiotics, probiotics, synbiotics, non-absorbable antibiotics, diets, fecal transplantation and other potential future approaches useful for the diagnosis, prevention and treatment of IBS.
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Human Gut Microbiota and Gastrointestinal Cancer.
Meng, C, Bai, C, Brown, TD, Hood, LE, Tian, Q
Genomics, proteomics & bioinformatics. 2018;16(1):33-49
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In this article the authors review research on the influence of the human gut microbiota on the development and progression of gastrointestinal cancers, and go into significant detail about the molecular mechanisms involved. Helicobacter pylori is a known risk factor for gastric cancer (GC) but other dysbiotic changes in the gut microbiota are also observed in GC. On the other hand, H. pylori is associated with a decreased risk for oesophageal cancer (OC). An increase in gram-negative bacteria is associated with OC, whilst gram-positive bacteria are dominant in a healthy oesophagus. Dietary factors are associated with the risk for colorectal cancer (CRC) and may be due to their effect on the bacterial composition of the bowel. The authors explore possible mechanisms for these links. Although the liver is considered sterile, carcinogenesis can be influenced by the gut microbiota through pathogens and bacterial metabolites which can disturb metabolic pathways and immune responses in the liver. In pancreatic cancer (PC), the gut microbiota may influence carcinogenesis by promoting inflammation. In addition to various lifestyle factors, H. pylori is a risk factor for PC. The authors also review the use of prebiotics, probiotics, synbiotics (a combination of pre- and pro-biotics) and Traditional Chinese Medicine as an adjunct to conventional cancer treatment to reduce side effects, as well as their potential preventive mechanisms.
Abstract
Human gut microbiota play an essential role in both healthy and diseased states of humans. In the past decade, the interactions between microorganisms and tumors have attracted much attention in the efforts to understand various features of the complex microbial communities, as well as the possible mechanisms through which the microbiota are involved in cancer prevention, carcinogenesis, and anti-cancer therapy. A large number of studies have indicated that microbial dysbiosis contributes to cancer susceptibility via multiple pathways. Further studies have suggested that the microbiota and their associated metabolites are not only closely related to carcinogenesis by inducing inflammation and immune dysregulation, which lead to genetic instability, but also interfere with the pharmacodynamics of anticancer agents. In this article, we mainly reviewed the influence of gut microbiota on cancers in the gastrointestinal (GI) tract (including esophageal, gastric, colorectal, liver, and pancreatic cancers) and the regulation of microbiota by diet, prebiotics, probiotics, synbiotics, antibiotics, or the Traditional Chinese Medicine. We also proposed some new strategies in the prevention and treatment of GI cancers that could be explored in the future. We hope that this review could provide a comprehensive overview of the studies on the interactions between the gut microbiota and GI cancers, which are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, diagnosis, and treatment.