Causal Inference in Microbiome Medicine: Principles and Applications.

Microorganisms that colonize the mammalian skin and cavity play critical roles in various physiological functions of the host. Numerous studies have revealed strong associations between the microbiota and multiple diseases. However, association does not mean causation. To clarify the mechanisms underlying microbiota-mediated diseases, research is moving from associative analyses to causation studies. In this article, we first introduce the principles of the computational methods for causal inference, and then discuss the applications of these methods in microbiome medicine. Furthermore, we examine the reliability of theoretically inferred causality by the interventionist framework. Finally, we show the potential of confirmed causality in microbiota-targeted therapy, especially in personalized dietary intervention. We conclude that a comprehensive understanding of the causal relationships between diets, microbiota, host targets, and diseases is critical to future microbiome medicine.

A metabolomics footprint approach to understanding the benefits of synbiotics in functional foods and dietary therapeutics for health, communicable and non-communicable diseases.

Gut microbiota have been shown to affect various cellular and host response elements such as immunological, neurological, energy, storage, etc. In recent years, this has led to rapid expansion in dietary products containing probiotics, prebiotics and combination thereof in synbiotics. While benefits of consuming functional foods derived from probiotics strains have been demonstrated for various metabolites, a detailed analysis of the biochemical footprints and their benefits remain under-studied. Herein, using a combination of NMR metabolomics, microbial techniques and cell-culture assays, we have characterized metabolite profiles of probiotic viz. Lactobacillus delbruekii ATCC 9649, Lactobacillus casei ATCC 335, Lactobacillus plantarum NRC 716 and Bacillus coagulans ATCC 12425 cultures in fermented milk. We identified predominance of sugars, small chain fatty acids, organic acids and branched chain amino acids from natural abundance 13C NMR studies. Additionally, we identified myriad metabolites and their respective pathways using 1H NMR spectroscopy. Based on our findings, synbiotic fermented dairy products were customized with co-cultures and complemented with pro- and pre- biotics. Furthermore, we demonstrate epithelial cell interaction and anti-microbial activity of L. plantarum based ferment against a range of bacterial pathogens highlighting possible biochemical mechanisms for anti-microbial activity, quorum sensing, gut colonization and other beneficial factors that may be crucial. Furthermore, we propose plausible explanation against non-communicable diseases such as tumor-inhibitory, anti-proliferative and pro-apoptotic effects which has direct implications for dietary therapeutics.

The impact of dietary fiber and probiotics in infectious diseases.

Although antibiotics are commonly used to treat infectious diseases, emergence of antibiotic resistant strains highlights the necessity for developing novel alternative approaches. Meanwhile, clinically, antibiotics can destroy the gut microbes balance, which is not conducive to the recovery of infectious disorders. As a result, recent studies have begun to explore potential prevention and treatment methods for infectious diseases, starting with more readily available dietary fiber and probiotics. Moreover, researches have shown the personalized nature of host responses to dietary fiber intervention, with outcomes being dependent on individual pre-treatment gut microbes. In this review, we will focus on the roles of dietary fiber and probiotics on infectious diseases, how probiotics and dietary fiber work on infectious diseases and then explore their mechanisms, so as to guide clinical consideration of new therapies for infectious diseases.

Diet-microbiome-disease: Investigating diet's influence on infectious disease resistance through alteration of the gut microbiome.

Abiotic and biotic factors can affect host resistance to parasites. Host diet and host gut microbiomes are two increasingly recognized factors influencing disease resistance. In particular, recent studies demonstrate that (1) particular diets can reduce parasitism; (2) diets can alter the gut microbiome; and (3) the gut microbiome can decrease parasitism. These three separate relationships suggest the existence of indirect links through which diets reduce parasitism through an alteration of the gut microbiome. However, such links are rarely considered and even more rarely experimentally validated. This is surprising because there is increasing discussion of the therapeutic potential of diets and gut microbiomes to control infectious disease. To elucidate these potential indirect links, we review and examine studies on a wide range of animal systems commonly used in diet, microbiome, and disease research. We also examine the relative benefits and disadvantages of particular systems for the study of these indirect links and conclude that mice and insects are currently the best animal systems to test for the effect of diet-altered protective gut microbiomes on infectious disease. Focusing on these systems, we provide experimental guidelines and highlight challenges that must be overcome. Although previous studies have recommended these systems for microbiome research, here we specifically recommend these systems because of their proven relationships between diet and parasitism, between diet and the microbiome, and between the microbiome and parasite resistance. Thus, they provide a sound foundation to explore the three-way interaction between diet, the microbiome, and infectious disease.

La combinación de ejercicio y nutrición en la prevención y tratamiento de enfermedades crónicas no transmisibles / Combining exercise and nutrition for the prevention and treatment of non-communicable chronic diseases

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Triclosan and triclocarban exposure, infectious disease symptoms and antibiotic prescription in infants-A community-based randomized intervention.

BACKGROUND: Triclosan and triclocarban (TCs) are broad-spectrum antimicrobials that, until recently, were found in a wide variety of household and personal wash products. Popular with consumers, TCs have not been shown to protect against infectious diseases. OBJECTIVES: To determine whether use of TC-containing wash products reduces incidence of infection in children less than one year of age. METHODS: Starting in 2011, we nested a randomized intervention of wash products with and without TCs within a multiethnic birth cohort. Maternal reports of infectious disease symptoms and antibiotic use were collected weekly by automated survey; household visits occurred every four months. Antibiotic prescriptions were identified by medical chart review. Urinary triclosan levels were measured in a participant subset. Differences by intervention group in reported infectious disease (primary outcome) and antibiotic use (secondary outcome) were assessed using mixed effects logistic regression and Fisher's Exact tests, respectively. RESULTS: Infectious illness occurred in 6% of weeks, with upper respiratory illness the predominant syndrome. Among 60 (45%) TC-exposed and 73 (55%) non-TC-exposed babies, infectious disease reports did not differ in frequency between groups (likelihood ratio test: p = 0.88). Medical visits with antibiotic prescriptions were less common in the TC group than in the non-TC group (7.8% vs. 16.6%, respectively; p = 0.02). CONCLUSIONS: Although randomization to TC-containing wash products was not associated with decreased infectious disease reports by mothers, TCs were associated with decreased antibiotic prescriptions, suggesting a benefit against bacterial infection. The recent removal of TCs from consumer wash products makes further elucidation of benefits and risks impracticable.

Hospital and homecare malnutrition and nutritional therapy in Brazil. Strategies for alleviating it: a position paper / Desnutrición y terapia nutricional en hospitales y en domicilios en Brasil. Estrategias para aliviarlo: posicionamiento

Introduction: Malnutrition in hospitalized patients is not evaluated frequently. However, it is a critical issue given that it has been related to a high rate of infectious complications and increased mortality rates. There is a high prevalence of patients with nutritional impairment in the home environment, which favors their clinical worsening, the increase of re-hospitalizations and, consequently, the increase in public health expenditures. Objective: Nutrition experts have thoroughly discussed and written this positioning paper on hospital and homecare malnutrition to describe the prevalence of malnutrition in Brazil. Best practice recommendations for nutrition therapy of patients in hospital and homecare, in particular the use of oral nutritional supplements (ONS), to those who are at risk of malnutrition or malnourished were evaluated, and the impact on clinical and economic data were assessed. In addition, they emphasize that investments in oral nutritional supplementation are also important in the homecare environment (home or nursing homes). Materials and methods: Selected scientific articles on disease-related malnutrition, especially those carried out in Brazil, were assessed. Data on prevalence, clinical outcomes, and economic burdens were reviewed. Results and conclusion: Several studies have shown the importance of in-hospital nutritional assessment for early detection of malnutrition and early intervention with nutrition therapy, in particular with oral nutritional therapy. Unfortunately, hospital malnutrition remains high in Brazil, with severe consequences for patients. The implementation of universal nutritional screening and diagnosis as well as the therapeutic approach of malnutrition, particularly with the use, when possible, of oral nutrition supplements as the first step to address this condition is still low, and demands the investment in educational resources to change practices. Routine use of nutritional therapy in hospital and homecare settings improves clinical outcomes, is cost effective, and would be expected to help reduce healthcare costs (AU)

Introducción: la desnutrición en pacientes hospitalizados no se evalúa con frecuencia. Sin embargo, es un problema crítico dado que se ha relacionado con una alta tasa de complicaciones infecciosas y con el incremento de la mortalidad. Se observa una alta prevalencia de pacientes desnutridos en el entorno domiciliario, lo que favorece su deterioro clínico, el aumento de las rehospitalizaciones y, como consecuencia, el aumento del gasto sanitario público. Objetivo: expertos en nutrición realizaron una revisión detallada de los estudios para redactar un posicionamiento sobre la situación en Brasil respecto a la prevalencia de la desnutrición hospitalaria y domiciliaria. Se identificaron las mejores prácticas recomendadas para la terapia nutricional de los pacientes hospitalarios y en domicilio en riesgo de desnutrición o desnutridos y se evaluó la utilidad de los suplementos nutricionales orales (SNO) a través de datos clínicos y económicos. Adicionalmente, se evidenció que las inversiones en suplementos nutricionales orales son también importantes en el entorno domiciliario (domicilio o residencia). Materiales y métodos: se evaluaron artículos científicos seleccionados, especialmente los realizados en Brasil, sobre la desnutrición relacionada con enfermedades. Se revisaron los datos sobre la prevalencia, los resultados clínicos y las cargas económicas. Resultados y conclusión: varios estudios han demostrado la importancia de la evaluación nutricional en el hospital para la detección precoz de la desnutrición y la intervención temprana con terapia nutricional oral, siempre que sea posible, como estrategia inicial para abordar el problema. Desafortunadamente, la desnutrición hospitalaria continúa siendo elevada en Brasil, con consecuencias graves para los pacientes. La identificación del estado nutricional deficiente a través del cribado y el inicio de la terapia nutricional, particularmente con el uso, cuando es posible, de suplementos nutricionales orales, como primera etapa para combatir la desnutrición no está aún establecida y requiere una inversión en recursos educativos para cambiar las prácticas actuales. El uso rutinario de la terapia nutricional en el entorno hospitalario y domiciliario mejora los resultados clínicos y tiene un impacto positivo en la disminución de los costes asociados y, de esta forma, se espera que contribuya a la reducción de los costes de atención sanitaria (AU)

Nutritional Considerations for Healthy Aging and Reduction in Age-Related Chronic Disease.

A projected doubling in the global population of people aged ≥60 y by the year 2050 has major health and economic implications, especially in developing regions. Burdens of unhealthy aging associated with chronic noncommunicable and other age-related diseases may be largely preventable with lifestyle modification, including diet. However, as adults age they become at risk of "nutritional frailty," which can compromise their ability to meet nutritional requirements at a time when specific nutrient needs may be high. This review highlights the role of nutrition science in promoting healthy aging and in improving the prognosis in cases of age-related diseases. It serves to identify key knowledge gaps and implementation challenges to support adequate nutrition for healthy aging, including applicability of metrics used in body-composition and diet adequacy for older adults and mechanisms to reduce nutritional frailty and to promote diet resilience. This review also discusses management recommendations for several leading chronic conditions common in aging populations, including cognitive decline and dementia, sarcopenia, and compromised immunity to infectious disease. The role of health systems in incorporating nutrition care routinely for those aged ≥60 y and living independently and current actions to address nutritional status before hospitalization and the development of disease are discussed.

Safety and efficacy of outpatient parenteral antibiotic therapy in an academic infectious disease clinic.

WHAT IS KNOWN AND OBJECTIVE: Outpatient parenteral therapy (OPAT) has become a safe and effective modality for patients requiring intravenous or prolonged antimicrobial therapy since the 1970s. It is being increasingly utilized in various settings; however, studies evaluating the safety and efficacy of clinic-based OPAT are limited. Since 2012, patients being considered for OPAT have required an infectious disease (ID) consultation at our institution. Candidates receiving once-daily antimicrobials who were ineligible for home infusion or nursing home placement as determined by their insurance companies and those who preferred the clinic over nursing home or home infusion were referred to the ID clinic. This study assessed the safety and outcome of patients receiving OPAT in an academic inner-city ID clinic in Detroit, Michigan. METHODS: This was a retrospective cross-sectional study of electronic medical records of patients, identified through clinic records, who received at least 2 days of OPAT from December 2012 to December 2015. Demographics, types of infections, antimicrobial regimen used, adverse events and outcome were evaluated. RESULTS: A total of 122 cases were identified during the study period. Mean age was 62 years with 55% male; 102 (84%) of 122 patients had peripherally inserted central catheter (PICC). Fifty-five per cent of patients participated in the clinic-based OPAT programme for insurance reasons, and 43% preferred the clinic over nursing home or home infusion. The most common infections were bone and joint (36%), followed by skin and soft tissue (18%) and urinary tract infections (12%). Ertapenem (44%) and daptomycin (41%) alone or in combination were used most frequently with 40% of patients receiving at least 4 weeks of treatment. Thirteen patients (11%) experienced one or more adverse drug events on daptomycin and/or ertapenem; of these, nine (69%) patients were receiving daptomycin monotherapy. Gastrointestinal symptoms (29%), cramping and myalgias (29%) and asymptomatic creatine phosphokinase (CPK) elevation (24%) were the most common adverse events. Three (3%) of 102 patients had PICC-related complications. Fourteen (88%) of 16 patients with adverse events or PICC-related complications required changing or stopping antibiotics; two (2%) had infection-related readmission. Conversely, 113 (93%) of 122 patients who completed treatment were considered cured and none had treatment failure at the end of 30 days of treatment. No patients died as a result of treatment or infection-related complications. WHAT IS NEW AND CONCLUSION: Outpatient parenteral therapy in our academic ID clinic was a safe and effective alternative to home infusion or skilled nursing facilities for patients requiring long-term antibiotics with few adverse events and complications.

The Benefits of Breast Feeding.

Human milk is considered as the gold standard for infant feeding. Breastfeeding advantages extend beyond the properties of human milk itself. A complex of nutritional, environmental, socioeconomic, psychological as well as genetic interactions establish a massive list of benefits of breastfeeding to the health outcomes of the breastfed infant and to the breastfeeding mother. For this reason, exclusive breastfeeding is recommended for about 6 months and should be continued as long as mutually desired by mother and child. The evidence in the literature on the effect of breastfeeding on health outcomes is based on observational studies due to the fact that it is unethical and practically impossible to randomize children to be breastfed or not. As such, multiple confounders cloud the evidence and one must base conclusions on the accumulating evidence when not contradictory and on the only intervention study, PROBIT (Promotion of Breastfeeding Intervention Trial). This review highlights some of the health outcomes related to breastfeeding such as the prevention of infections, the effect of breastfeeding on neurodevelopmental outcome, obesity, allergy and celiac disease. Available evidence as well as some of the contradictory results is discussed.

Use of probiotics in pediatric infectious diseases.

We summarize current evidence and recommendations for the use of probiotics in childhood infectious diseases. Probiotics may be of benefit in treating acute infectious diarrhea and reducing antibiotic-associated diarrhea. Potential benefits of probiotic on prevention of traveler's diarrhea,Clostridium difficile-associated diarrhea, side effects of triple therapy in Helicobacter pylori eradication, necrotizing enterocolitis, acute diarrhea, acute respiratory infections and recurrent urinary tract infections remain unclear. More studies are needed to investigate optimal strain, dosage, bioavailability of drops and tablets, duration of treatment and safety. Probiotics and recombinant probiotic strain represent a promising source of molecules for the development of novel anti-infectious therapy.

[Vitamin D and infectious diseases]. / Vitamine D et infections.

Vitamin D plays a role in the synthesis of antibacterial peptids and in autophagy. Several studies have shown that low levels of vitamin D are associated with the susceptibility and the severity of acute infections on one hand, and with an unfavorable outcome of some chronic infections (such as HIV infection). Vitamin D supplementation improves response to treatment of some viral (such as chronic hepatitis C infection) or bacterial infections (such as pulmonar tuberculosis). Vitamin D supplementation demonstrated no benefit in reducing the incidence of pulmonary infections. The target level of vitamin D to be reached after supplementation is not known yet.

An overview of the modulatory effects of oleic acid in health and disease.

Evidences in the last years have showed the effects of oleic acid (OA) in human health and disease. Olive oil, rich in oleic acid, is supposed to present modulatory effects in a wide physiological functions, while some studies also suggest a beneficial effect on cancer, autoimmune and inflammatory diseases, besides its ability to facilitate wound healing. Although the OA role in immune responses are still controversial, the administration of olive oil containing diets may improve the immune response associated to a more successful elimination of pathogens such as bacteria and fungi, by interfering in many components of this system such as macrophages, lymphocytes and neutrophils. Then, novel putative therapies for inflammatory and infectious diseases could be developed based on the characteristics presented by unsaturated fatty acids like OA. Finally, the purpose of this work was to review some of the modulatory effects of OA on inflammatory diseases and health, aiming at high lightening its potential role on the future establishment of novel therapeutic approaches for infections, inflammatory, immune, cardiovascular diseases or skin repair based on this fatty acid mainly found in the Mediterranean diet.

Influencia del entorno ambiental y tipo de régimen dietético en la incidencia, duración e intensidad de los procesos infecciosos del lactante / The role of environmental factors and type of dietary regimen on morbidity in young infants

Objetivo. Estudiar las enfermedades infecciosas y su relación con el entorno ambiental en lactantes, desde su nacimiento hasta los 4 meses de edad. Material y Métodos. Han intervenido más de 600 pediatras. Se incluyó a niños de hasta 20 días que fueron reevaluados cuando tenían 4 meses, para estudiar las complicaciones infecciosas aparecidas. Análisis estadístico mediante regresión logística. Resultados. Se incluyeron 3.428 niños a término. Las infecciones oftálmicas fueron las más frecuentes (5,5 por ciento). Las bronquitis y neumonías las más graves (61 por ciento moderadas-graves) y de mayor duración (6,5 ñ 3 días). La polución, entorno fumador y convivencia con hermanos constituyen factores de riesgo. A los 4 meses, la administración de una fórmula sin nucleótidos se añadió a los factores de riesgo previos. Conclusiones. El entorno ambiental es importante en la incidencia de enfermedades infecciosas en el lactante. El riesgo aumenta por: asistencia a guarderías, polución y ambiente fumador. La alimentación con leche materna y una fórmula con nucleótidos son favorables para el desarrollo inmunológico de los lactantes. (AU)