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January 2017

Florassist GI

Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances.

The human microbiome is overly exposed to antibiotics, due, not only to their medical use, but also to their utilization in farm animals and crops. Microbiome composition can be rapidly altered by exposure to antibiotics, with potential immediate effects on health, for instance through the selection of resistant opportunistic pathogens that can cause acute disease. Microbiome alterations induced by antibiotics can also indirectly affect health in the long-term. The mutualistic microbes in the human body interact with many physiological processes, and participate in the regulation of immune and metabolic homeostasis. Therefore, antibiotic exposure can alter many basic physiological equilibria, promoting long-term disease. In addition, excessive antibiotic use fosters bacterial resistance, and the overly exposed human microbiome has become a significant reservoir of resistance genes, contributing to the increasing difficulty in controlling bacterial infections. Here, the complex relationships between antibiotics and the human microbiome are reviewed, with focus on the intestinal microbiota, addressing (1) the effects of antibiotic use on the composition and function of the gut microbiota, (2) the impact of antibiotic-induced microbiota alterations on immunity, metabolism, and health, and (3) the role of the gut microbiota as a reservoir of antibiotic resistances.

Front Microbiol. 2016 Jan 12;6:1543

Dysbiosis of the gut microbiota in disease.

There is growing evidence that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extra-intestinal disorders. Intestinal disorders include inflammatory bowel disease, irritable bowel syndrome (IBS), and coeliac disease, while extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity.

Microb Ecol Health Dis. 2015 Feb 2;26:26191.

Role of stress, depression, and aging in cognitive decline and Alzheimer’s disease.

Late-onset Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the most common cause of progressive cognitive dysfunction and dementia. Despite considerable progress in elucidating the molecular pathology of this disease, we are not yet close to unraveling its etiopathogenesis. A battery of neurotoxic modifiers may underpin neurocognitive pathology via deleterious heterogeneous pathologic impact in brain regions, including the hippocampus. Three important neurotoxic factors being addressed here include aging, stress, and depression. Unraveling “upstream pathologies” due to these disparate neurotoxic entities, vis-à-vis cognitive impairment involving hippocampal dysfunction, is of paramount importance. Persistent systemic inflammation triggers and sustains neuroinflammation. The latter targets several brain regions including the hippocampus causing upregulation of amyloid beta and neurofibrillary tangles, synaptic and neuronal degeneration, gray matter volume atrophy, and progressive cognitive decline. However, what is the fundamental source of this peripheral inflammation in aging, stress, and depression? This chapter highlights and delineates the inflammatory involvement-i.e., from its inception from gut to systemic inflammation to neuroinflammation. It highlights an upregulated cascade in which gut-microbiota-related dysbiosis generates lipopolysaccharides (LPS), which enhances inflammation and gut’s leakiness, and through a Web of interactions, it induces stress and depression. This may increase neuronal dysfunction and apoptosis, promote learning and memory impairment, and enhance vulnerability to cognitive decline.

Curr Top Behav Neurosci. 2014;18:265-96

Exploring gut microbes in human health and disease: Pushing the envelope.

Humans have coevolved with their microbes over thousands of years, but this relationship, is now being dramatically affected by shifts in the collective human microbiome resulting from changes in the environment and societal norms. Resulting perturbations of intestinal host-microbe interactions can lead to miscues and altered host responses that increase the risk of pathogenic processes and promote “western” disorders such as inflammatory bowel diseases, cancers, obesity, diabetes, autism, and asthma. Given the current challenges and limitations in gene therapy, approaches that can reshape the gut microbiome represent a reasonable strategy for restoring the balance between host and microbes. In this review and commentary, we highlight recent progress in our understanding of the intestinal microbiome in the context of health and diseases, focusing on mechanistic concepts that underlie the complex relationships between host and microbes. Despite these gains, many challenges lie ahead that make it difficult to close the gap between the basic sciences and clinical application. We will discuss the potential therapeutic strategies that can be used to manipulate the gut microbiota, recognizing that the promise of pharmabiotics (“bugs to drugs”) is unlikely to be completely fulfilled without a greater understanding of enteric microbiota and its impact on mammalian physiology. By leveraging the knowledge gained through these studies, we will be prepared to enter the era of personalized medicine where clinical inventions can be custom-tailored to individual patients to achieve better outcomes.

Genes Dis. 2014 Dec;1(2):132-139

The interaction between gut microbiota and age-related changes in immune function and inflammation.

Intestinal microbiota and gut immune systems interact each other, maintaining a condition of homeostasis in the context of the intestinal habitat. However, both systems undergo modifications in elderly, thus accounting for a low grade inflammatory status which, in turn, may evolve toward more severe pathological conditions such as inflammatory bowel disease and colon rectal cancer. In addition, in western societies dietary habits may negatively influence the microbiota composition, also altering gut immune response which is per se impaired in elderly. In order to prevent the outcome of aged-related disease, supplementation of nutraceuticals able to correct abnormalities of both immune system and microbiota has become more frequent than in the past. In this respect, a better identification of components of the aged microbiota as well as a deeper analysis of gut mucosal immunity function should be pursued.

Immun Ageing. 2013 Aug 5;10(1):31

Intestinal bacteria and ageing.

Advancements in science and medicine, as well as improved living standards, have led to a steady increase in life expectancy, and subsequently a rise in the elderly population. The intestinal microbiota is important for maintenance of host health, providing energy, nutrients and protection against invading organisms. Although the colonic microbiota is relatively stable throughout adult life, age-related changes in the gastrointestinal (GI) tract, as well as changes in diet and host immune system reactivity, inevitably affect population composition. Recent studies indicate shifts in the composition of the intestinal microbiota, which may lead to detrimental effects for the elderly host. Increased numbers of facultative anaerobes, in conjunction with a decrease in beneficial organisms such as the anaerobic lactobacilli and bifidobacteria, amongst other anaerobes, have been reported. These changes, along with a general reduction in species diversity in most bacterial groups, and changes to diet and digestive physiology such as intestinal transit time, may result in increased putrefaction in the colon and a greater susceptibility to disease. Therapeutic strategies to counteract these changes have been suggested in ageing people. These include dietary supplements containing prebiotics, probiotics and a combination of both of these, synbiotics. Limited feeding trials show promising results with these supplements, although further longer-term investigations are required to substantiate their use in elderly healthcare fields.

J Appl Microbiol. 2007 May;102(5):1178-86

Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles.

BACKGROUND: The normal intestinal microflora plays an important role in host metabolism and provides a natural defence mechanism against invading pathogens. Although the microbiota in adults has been extensively studied, little is known of the changes that occur in the microflora with aging. These may have important consequences in elderly people, many of whom are receiving antibiotic therapy and who are most susceptible to intestinal dysbiosis. AIMS: To characterise the major groups of faecal bacteria in subjects of different ages using a combination of cultural, molecular, and chemotaxonomic approaches. METHODS: Comparative microbiological studies were made on four different subject groups: children (16 months to seven years, n=10), adults (21-34 years, n=7), healthy elderly subjects (67-88 years, n=5), and geriatric patients (68-73 years, n=4) diagnosed with Clostridium difficile diarrhoea. Selected faecal bacteria were investigated using viable counting procedures, 16S ribosomal RNA (rRNA) abundance measurements, and the occurrence of specific signature fatty acids in whole community fatty acid methyl ester profiles. RESULTS: The principal microbiological difference between adults and children was the occurrence of higher numbers of enterobacteria in the latter group, as determined by viable counts (p<0.05) and 16S rRNA (p<0.01) measurements. Moreover, a greater proportion of children’s faecal rRNA was hybridised by the three probes (bifidobacteria, enterobacteria, bacteroides-porphyromonas-prevotella) used in the study, indicating a less developed gut microbiota. Species diversity was also markedly lower in the Clostridium difficile associated diarrhoea group, which was characterised by high numbers of facultative anaerobes and low levels of bifidobacteria and bacteroides. Although it was a considerably less sensitive diagnostic tool, cellular fatty acid analysis correlated with viable bacterial counts and 16S rRNA measurements in a number of bacteria, including bacteroides. CONCLUSIONS: Polyphasic analysis of faecal bacteria showed that significant structural changes occur in the microbiota with aging, and this was especially evident with respect to putatively protective bifidobacteria. Reductions in these organisms in the large bowel may be related to increased disease risk in elderly people.

Gut. 2001 Feb;48(2):198-205

The gut microbiome and the brain.

The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.

J Med Food. 2014 Dec;17(12):1261-72