Background. Hemoglobinopathies, among which thalassemic syndromes  and sickle cell disease (SCD), are the most widespread monogenic diseases worldwide. Hemoglobinopathies are endemic and spread-out all-over Italy, as result of internal and external migration flows. Nowadays, the increase therapeutic options associated to the general aging of patients with hemoglobinopathies related to the improvement in clinical management, contribute to the abnormalities in kidney function going from blood and urine test alterations to chronic kidney disease and end stage renal disease. Methods. Here, we carried out a revision of the literature as panel of recognized experts in hemoglobinopathies with the consultancy and the revision of two nephrologists on kidney alteration and kidney disease in patients with TDT, NTDT and SCD. This is part of the action of the Italian society for the study of thalassemia and hemoglobinopties (SITE). The purpose of this “good practice (GP)” is to provide recommendations for follow-up and therapy for the management of kidney alterations in patients with TDT, NTDT and SCD. The literature review covers the period 1.1.2016 to 31.12.2022. In consideration of the rarity of these diseases, the analysis was extended from 5 to 7 years. Moreover, in the absence of relevant scientific papers in the identified time frame, we referred to pivotal or population studies, when available. Finally, in the absence of evidence-based data from prospective and randomized trials, the authors had to refer to expert opinion (expert consensus) for many topics. Results. We generated question and answer boxes to offer a friendly consultation, using color code strategy and focused answers. Conclusions. The present GP will help in improving the clinical management, and the quality of care of patients with hemoglobinopathies.  Hemoglobinopathies, among which are thalassemia syndromes and sickle cell disease (SCD), are the most widespread monogenic diseases worldwide ,2,3. ItaThe introduction of different medical treatment strategies such as oral iron chelating agents in thalassemia, screening for hepatitis C in blood transfusion units, and specific antiviral therapy, as well as the wide use of hydroxyurea in drepanocytosis associated with screening for vascular cerebropathy and antibiotic prophylaxis at a pediatric age, improved the average survival in adults and children ,6,7,8, bAlterations of renal function are described early in SCD subjects, presenting with age-dependent non-selective proteinuria, reported in approximately 50% of patients between 36 and 45 years ,11,12. TRenal damage is caused by the occlusion of glomerular and peritubular capillaries during a sickle cell crisis, resulting in the loss of nephrons with initial hypertrophy of the surviving glomeruli, tubulo-interstitial alterations of the ischemic type with functional impairment , and an increase in proteinuria up to the nephrotic value (proteinuria > 3.5 g/24 h). Other observed histological pictures are membrano-proliferative glomerulonephritis and thrombotic microangiopathy. Variants of APOL1, HMOX1, HBA1, and HBA2 have a role in the onset and progression of SCD-associated nephropathy  and non-transfusion-dependent (NTDT) thalassemias, and sickle cell disease. In the present document, we consider HbH disease as part of the NTDT group ,26. The The purpose of this “good practice” article is to briefly describe the various aspects of kidney disease in hemoglobinopathies and to provide recommendations for follow-up and therapy for the management of patients with TDT, NTDT, and SCD.The literature review covers the period from 1.1.2016 to 31.12.2022; in consideration of the rarity of the pathologies, it was extended from 5 to 7 years. Moreover, in the absence of relevant scientific papers from the identified time frame, we referred to pivotal or population studies, when available. Finally, in the absence of evidence-based data from prospective and randomized trials, the panel of authors had to refer to expert opinion (expert consensus) for many topics .grade IA: strong recommendation based on strong evidence certainties and meta-analyses;grade IB: strong recommendation based on strong evidence certainties;grade IIA: strong recommendation based on moderate evidence certainties;grade IIB: strong recommendation based on moderate–weak evidence certainties;grade IIC: strong recommendation based on weak evidence certainties;grade IIIA: conditional recommendation based on strong evidence certainties;grade IIIB: conditional recommendation based on moderate evidence certainties;grade IIIC: conditional recommendation based on weak evidence certainties;grade IV: conditional recommendation based on expert indication.The grading used in the present good practice is as follows:In consideration of the rarity of hemoglobinopathies, SITE undertook a project aimed at integrating, with a systematic method, the lack of scientific papers to reach an adequate degree of consensus on recommendations for the clinical “management” of renal complications in this patient setting.The Management Committee of SITE selected and brought together a multidisciplinary and multiprofessional group made up of experts in hemoglobinopathies and experts in nephropathies and organ transplantation, flanked by experts with methodological and organizational expertise, in order to create recommendations based on the integration of available scientific evidence together with expert opinion, with the aim of supporting clinicians in the decision-making process, thus improving the appropriateness of the therapies.The members making up the scientific panel come from the following areas of expertise: 5 clinicians, who are experts on hemoglobinopathies; 1 nephropathy specialist expert in the management of patients with hemoglobinopathies; and 1 specialist expert in transplants belonging to the National Transplant Center.In 2021, the Management Committee of SITE identified the members of the multidisciplinary panel, entrusting the coordination of the panel to two experts in hemoglobinopathies.The panel of experts first divided the clinical problem into specific areas of interest and, for each area, identified specific scenarios and formulated the corresponding clinical questions . The panIn order to increase the readability of the document, the panel labeled the study populations with three different color codes: gray for hemoglobinopathies, blue for thalassemia, and green for SCD.-https://www.societaitalianatrapiantidiorgano.com/linee-guida/) (accessed on 25 October 2022);S.I.T.O. guidelines (-https://kdigo.org/guidelines/)  (accessed on 2 July 2022)SITE good practice , National Institute for Clinical Excellence (NICE), Pubmed, and Cochrane); the keywords used (both as MeSH terms and as non-MeSH terms) for the literature search are thalassemia, sickle, hemoglobinopathies, diagnosis, kidney, renal function, iron chelation–thalassemia, non-transfusion-dependent thalassemia, kidney transplantation, dialysis, cystatin, and deferasirox.The search was completed manually and by questioning the panel experts about any “missing papers”.A critical evaluation of evidence in terms of quality, up-to-dateness, and debated topics was carried out by the panel, who deemed it necessary to integrate what was selected from clinical studies focused on specific evidence for hemoglobinopathies.The literature search identified a total of 149 titles and abstracts. After a first evaluation—carried out based on abstracts—and a second one—carried out based on full texts—a total of 149 reference documents were considered to be relevant .After completing the literature review evaluation, the authors answered the questions, specifying the evidence used to support the answer.The authors presented and discussed what was prepared during eight plenary meetings held virtually between March 2021 and December 2022.Following the presentation of the answers, an informal process took place to reach consensus on the strength and direction of the recommendations.For the evaluation of the evidence relating to clinical efficacy, the Evidence-Based Medicine (EBM) approach, which establishes a linear link between the quality of the evidence and the strength of the recommendation, was used and adopted for this purpose, dividing evidence based on the study design evaluation and on evidence levels.For a transparent and systematic evaluation of the literature, the panel considered it appropriate to use a set of instruments to support the decision-making process in relation to the formulated clinical questions , as outlTherefore, the evidence is divided intostrong and meta-analyses—systematic reviews and meta-analyses;strong—clinical studies with a randomized control group (RTC);moderate—clinical studies with a control group;moderate weak—cohort studies, case control studies, and observational studies;weak—case reports, case studies, and expert opinion.Evidence levels are divided intoAdata derived from several systematic reviews and meta-analyses;Bdata derived from only one systematic review and meta-analysis or from various clinical studies with a randomized control group (RTC);Cdata derived from observational, retrospective clinical studies or expert opinion.grade IA: strong recommendation based on strong evidence certainties and meta-analyses;grade IB: strong recommendation based on strong evidence certainties;grade IIA: strong recommendation based on moderate evidence certainties;grade IIB: strong recommendation based on moderate–weak evidence certainties;grade IIC: strong recommendation based on weak evidence certainties;grade IIIA: conditional recommendation based on strong evidence certainties;grade IIIB: conditional recommendation based on moderate evidence certainties;grade IIIC: conditional recommendation based on weak evidence certainties;grade IV: conditional recommendation based on expert indication.The following list shows the grading used by the panel in this Good Practice:The indications by the panel of authors were formulated based on common clinical experience, even in the absence of evidence or in the absence of sufficient supporting evidence, on issues deemed relevant to clinical practice.The recommendations were written in clear and unambiguous language. Where necessary, notes were added including information on limitations and conditions of applicability, as well as details on target populations, interventions, settings, and outcomes.In order to improve wording, solve ambiguities, remove futile or potentially dangerous statements, and suggest comments and criticalities, an editing process was performed.The final version of the document was forwarded, for external review, to independent experts and representatives of patient associations in order to receive their comments and proposals for modification or supplementation.The comments received by revisers were considered by the authors’ panel, who replied to comments and decided which changes should be made to the text based on such comments.GP guidelines shall be updated every three years, starting from the date of publication. The methodology followed in the update will be the same as used in the present version.The literature search shall begin from the date the present search was carried out.Once the GP document is deemed suitable for publication, it will be published on the SITE website; it will also be presented at the main conferences on hemoglobinopathies and will be translated and submitted for publication to an international peer-reviewed journal.


This comprehensive review examines critical aspects of evidence-based human kinetics, focusing on bridging the gap between scientific evidence and practical implementation. To bridge this gap, the development of tailored education and training programs is essential, providing practitioners with the expertise and skills to effectively apply evidence-based programs and interventions. The effectiveness of these programs in improving physical fitness across all age groups has been widely demonstrated. In addition, integrating artificial intelligence and the principles of slow science into evidence-based practice promises to identify gaps in knowledge and stimulate further research in human kinetics. The purpose of this review is to provide researchers and practitioners with comprehensive information on the application of scientific principles in human kinetics. By highlighting the importance of evidence-based practice, this review is intended to promote the adoption of effective interventions to optimize physical health and enhance performance. The importance of evidence-based practice (EBP) in advancing public health has been extensively documented in the literature ,2. EBP oEBP has become a crucial decision-making process in various fields, including human kinetics . The EBPThe three-part model of EBP assumes that clinical decision making is based on research evidence, clinical expertise, and client values . While tOverall, EBP is a decision-making process that practitioners go through in five steps . The firHow do practitioners evaluate scientific findings for practical use? Systematic reviews that meticulously summarize research findings to answer specific questions are considered the heart of EBP . ScientiMurad and colleagues  argue thAs mentioned earlier, the main goal of EBP is to provide the most effective interventions based on the best available evidence. Human kinetics serves as a prime example of the practical application of this approach, as sport science research often focuses on the translation of findings into practice. EBP in sport can be defined as the integration of technical expertise, athlete values, and the most reliable evidence to support decision making in the athlete training process . In receDespite considerable progress, there is still a large gap between scientific knowledge and its practical implementation in human kinetics. This calls for the exploration of potential solutions to ensure the effective implementation of research findings and recommendations in real-world sport contexts. The purpose of this comprehensive review is, therefore, to examine several key aspects of EBP in human kinetics, highlight the existing gap between science and practice, and identify potential opportunities for EBP to improve outcomes in the field. Our goal is to enable researchers and practitioners to critically evaluate the application of EBP in human kinetics by presenting comprehensive information.This article presents a qualitative synthesis in the form of a narrative literature review. A literature search strategy was developed using the following electronic databases: PubMed, Web of Science, ScienceDirect, and Scopus. The selection of these databases was based on preliminary and exploratory research that indicated they contained significant and relevant work. Searches were conducted using keywords associated with the following groups of search terms: (a) evidence-based practice ); (b) sport science . The different search terms within each group were combined using the Boolean operator “OR”. The search terms from both groups were then combined with the Boolean operator “AND”. In addition, the reference lists of retrieved articles were analyzed to identify additional studies that met the defined eligibility criteria. In a further step, the studies were also searched via Google Scholar. An integrative perspective was adopted, including studies of all types to capture the context, processes, and important elements related to the topic under discussion. Therefore, publications that met the following criteria were eligible for this synthesis: books and peer-reviewed articles published in English between 1990 and 2023. Articles published in conference proceedings, abstracts, and unpublished manuscripts were not considered. Duplicate and unlinked articles were excluded before the full-text reading phase.Incorporating EBP into human kinetics has the potential to improve performance, minimize errors, facilitate informed and data-driven decisions, prioritize empirical evidence over faith-based perspectives, and foster collaboration between practitioners and clients . HoweverCollaboration between researchers and practitioners is critical to bridging the gap between research and practice. Unfortunately, this cooperation is often insufficient and leads to discrepancy between research results and their practical applications. One study found that high-performing coaches prefer informal conversations with their colleagues to acquire scientific knowledge, highlighting the need for more structured and formal collaboration . In addiAnother barrier to implementing evidence-based human kinetics is the lack of access to research findings, which are often published in academic journals that require a subscription, making them inaccessible to practitioners ,29,30. TThe application of EBP in human kinetics can be challenging for practitioners, who may lack the necessary scientific terminology to accurately communicate research findings. Consequently, research findings may be misinterpreted, misapplied, or overlooked. In addition, practitioners’ attitudes and beliefs may hinder the adoption of EBP, as some people lack confidence in research findings and instead rely solely on their intuition and personal experience, which may prove impractical and time consuming ,29. PracFor those seeking a collaborative approach, Bishop  has deveOther models focusing on multidisciplinary approaches to performance optimization have been proposed in recent years ,37 and iExpertise is one of the three components of EBP, along with client values/preferences and best available research ,7,8. HowEducation plays a key role in developing the necessary expertise for EBP. Although EBP has long been used in clinical practice, education and training in EBP is often inadequate . IntegraSome authors, such as Straus and colleagues , acknowlA variety of teaching methods are used in college courses and training programs to promote the use of EBP among professionals. These methods may include didactic lectures, interactive workshops, online courses, and clinical practices. Didactic lectures and seminars are commonly used in EBP courses to provide students with a comprehensive understanding of EBP principles and the skills necessary to apply them in clinical practice. These lectures typically cover basic aspects of EBP, such as formulating clinical questions, conducting evidence searches, and assessing the quality of evidence . AlthougIncorporating interactive workshops into EBP education and training can be an effective method for developing EBP skills because they use small group activities, case studies, and role-playing to enhance EBP skills. A randomized controlled trial has shown that interactive EBP workshops are more effective than didactic lectures in improving EBP-related knowledge, skills, and attitudes . In thishttps://www.cebm.net/ (accessed on 26 January 2023)) has developed several online EBP learning modules. These online courses/modules are often accessible via in-service learning and have quality criteria to ensure that students and practitioners apply the material in practice [Online courses and modules are also popular because they offer learners convenience and flexibility. They use a combination of didactic lectures, interactive activities, and self-directed learning to teach EBP skills. For example, the Center for Evidence-Based Medicine in Oxford (practice . Howeverpractice .Incorporating information technology (IT) is another effective approach to EBP education. This involves the use of technology, such as mobile devices, in the classroom or clinical setting to teach EBP search tactics, critical evaluation of clinical guidelines, and task-oriented information for clinical practice ,52. HoweIn addition, integrating EBP education with clinical practice has proven to be a popular approach to EBP teaching because it provides learners with practical opportunities to apply their EBP skills in the real world . ClinicaOn the other hand, informal gatherings such as journal clubs provide professionals with a platform to discuss current research findings and their practical implications. These clubs can promote critical thinking skills and the application of research findings to practice ,58. AlthFinally, the use of librarians is a valuable method of teaching EBP. These librarians can help students develop search strategies and understand EBP concepts before they enter clinical practice. They can teach students how to navigate databases, evaluate sources, and synthesize evidence, providing them with important information skills for their future practice. Involving academic librarians in EBP education can be an effective approach to teaching the five steps of EBP described in the Sicily Statement. The first three steps can be taught in a classroom setting, while the last two steps can be applied in a clinical setting, allowing students to apply what they learn in real-life situations .Research courses and workshops are common methods for teaching EBP ,54. ThesIn this regard, questionnaires are a valuable tool to better understand EBP because they provide a consistent and structured method to collect information about practitioners’ beliefs, attitudes, and behaviors. They offer several benefits, including identifying EBP barriers, addressing knowledge gaps, and promoting practitioner adoption of EBP. Questionnaires can be used to develop tailored interventions that address knowledge, attitudes, and barriers to EBP, thereby increasing effectiveness and the likelihood of behavior change. In addition, questionnaires can be used to track progress, assess long-term impact, and identify areas for improvement . FinallyIn summary, to improve the integration of research and practice in human kinetics, further research is needed that focuses on fostering collaboration between researchers and practitioners. This collaboration can be facilitated through qualitative research methods that can help understand practitioners’ goals and develop co-created objects of study . GainingAI is a new and promising approach to EBP. It involves computer systems that are able to learn and reason similarly to humans, enabling them to perform cognitive tasks that normally depend on human cognitive abilities, such as problem solving, decision making, and perception ,72. By iThe amount of information available online is increasing exponentially every year. However, analyzing the voluminous data from clinical trials can be challenging with traditional data processing systems. With the continuous increase in information, the use of machine learning (ML) has become crucial for automated knowledge extraction . ML is dML algorithms have the potential to streamline data collection from multiple studies and enable semi-automated synthesis of results, including systematic reviews and meta-analyses. Several AI-based technologies such as RobotReviewer ,77, ASReThe use of AI is not limited to automated literature searches and synthesis of evidence. It can also be used to analyze electronic records and other datasets to uncover patterns and relationships that are not apparent using traditional analytical methods. This can lead to new insights and the development of tailored and effective solutions . By leveAI has the potential to revolutionize EBP by enabling professionals to access and analyze large amounts of data more efficiently, leading to better outcomes and cost reductions. Still, the application of AI in EBP comes with certain challenges and limitations. For example, if AI algorithms are not properly trained or validated, they may introduce bias or provide unreliable results, and ethical concerns have been raised about the use of AI in healthcare . The notThe concept of slow science offers an alternative approach to the traditional model of science. It emphasizes a careful, reflective, and collaborative method that values attention and slowness as crucial elements of scientific practice . AlthougThe combination of slow science and AI has the potential to revolutionize EBP by combining careful analysis with cutting-edge technology. AI can analyze massive amounts of data quickly, while slow science offers a more reflective and analytical approach to research, taking the time to consider the implications of the results. This approach can lead to the identification of new research topics, the refinement of current ideas, and the development of innovative EBP-based interventions ,85. TherIn summary, slow science and AI can work harmoniously to improve EBP by providing a thorough yet efficient approach to data analysis and research. In their recent study, Marshall and colleagues  highlighThe integration of AI and slow science holds the potential for significant advances in evidence-based human kinetics. ML techniques, supported by improved computational power and access to new data sources, can provide valuable insights for training, performance improvement, and injury prevention in human kinetics, both on and off the field . WearablWhile AI has the potential to automate repetitive tasks and provide support, human interpretation, synthesis, and creativity remain necessary for meaningful contributions and theory development . PractitEvidence-based programs are comprehensive interventions designed to help clients with complex problems . These pIn recent decades, the use of research-based programs that rely on credible scientific evidence to improve health outcomes has gained prominence . These phttp://www.vivifrail.com/ (accessed on 6 February 2023) is an example of such a program. It is an individualized and multi-part exercise program for the elderly that includes exercises to improve various aspects of physical fitness, nutritional counseling, and cognitive training to promote a healthy lifestyle [As people age and look for ways to maintain their health and independence, evidence-based physical activity programs become increasingly valuable. These programs are developed based on sound scientific research and are designed to improve strength, balance, flexibility, and cardiovascular health. Vivifrail  is one such program that has gained popularity. HIIT alternates periods of high intensity with periods of active or passive recovery . StudiesIn summary, evidence-based human kinetics programs play a critical role in improving athletic performance and promoting overall health and well-being, as shown in Evidence-based human kinetics is a key component in promoting optimal health and performance outcomes for diverse groups. Despite a growing body of research on successful fitness programs and therapies, a large gap remains between evidence and practice. To close this gap, education and training programs must be developed to provide practitioners with the expertise and skills they need to effectively deliver evidence-based programs and interventions.Collaboration between sport and health sciences also plays a critical role in pursuing a comprehensive and integrated approach to human well-being. By bridging the gap between these disciplines, we can improve our understanding of the intricate relationships between physical activity, performance, and health. This interdisciplinary approach sets the stage for EBP to maximize human potential, prevent disease, and promote overall wellness. The partnership between sport science and health science transcends the boundaries of their respective disciplines. By fostering collaboration and sharing knowledge, we can leverage the synergies between these fields and drive advances in both sport performance and public health. Together, we have the power to promote a culture of lifelong physical activity, improve athletic performance, and enhance the overall health and well-being of individuals and communities.In addition, evidence-based programs have been shown to improve health outcomes, such as cardiovascular health, body composition, and muscle strength. However, for these programs to be successful, a detailed understanding of relevant research and practical concerns, such as individual differences in health status and preferences, is required. In addition, integrating AI and slow science into EBP has the potential to increase the effectiveness of interventions by identifying knowledge gaps and opportunities for additional research, thereby expanding the human kinetics database. This appears to be a potential avenue when combined with slow science.Following this comprehensive review, see In summary, evidence-based human kinetics provides a solid framework for understanding the positive effects of exercise and physical activity on health and performance. We can continue to improve our understanding of human kinetics and help people optimize their physical health and performance by promoting evidence-based sport science and advancing the dissemination of accurate and reliable information. Education, the use of evidence-based programs, and the incorporation of AI into practice are all viable ways to advance the discipline and improve outcomes for people around the world.


Bifidobacterium supplementation and symptomatic control in patients with IBS. The research was conducted using the National Guideline Clearinghouse, National Electronic Library for Health of the British NHS, Canadian Medical Association Practice Guidelines InfoBase, Cochrane Library, Database of Abstracts of Reviews of Effectiveness, Bandolier, Evidence-Based Medicine Online, and PubMed. Articles published between March 2017 and March 2022 in humans and written in Portuguese, Spanish, and English using the terms IBS and Bifidobacterium were included. To stratify the level of evidence (LOE), the Strength of Recommendation Taxonomy (SORT), from the American Academy of Family Physicians, was used. Thirty-seven articles were found corresponding to the search terms, and a total of seven articles were selected. Three clinical trials and a simple review have demonstrated improvement in symptoms, although further studies are needed. The guideline and the systematic review did not demonstrate superiority in symptomatic relief when compared to other species of probiotics. The meta-analysis did not show the efficacy of the isolated use of Bifidobacterium. The evidence of an association between supplementation with Bifidobacterium and symptomatic control in patients with IBS is not clear. Some studies seem to demonstrate benefits in improving symptoms (SORT C).Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, with a global prevalence of around 11%. Family doctors should be aware of the diagnosis and treatment of this pathology. The benefit of using probiotics is questionable. The purpose of this review is to establish the evidence of the association between  Irritable bowel syndrome (IBS) is a group of symptoms that occur together including abdominal pain and alterations in bowel habits, without any organic disease ,2. The RBifidobacterium and symptomatic control among patients with IBS.Family physicians are usually the first point of contact and the ones who make a positive diagnosis of IBS after excluding the alarm signs that warrant referral ,9. EstabMethodsBifidobacterium,” in the following databases: National Guideline Clearinghouse, National Electronic Library for Health of the British NHS, Canadian Medical Association Practice Guidelines InfoBase, Cochrane Library, Database of Abstracts of Reviews of Effectiveness, Bandolier, Evidence-Based Medicine Online, and PubMed.Research was conducted on clinical trials, guidelines, meta-analyses, systematic reviews, and narrative reviews, using the Medical Subject Heading (MeSH) terms “irritable bowel syndrome” and “Bifidobacterium; comparison, placebo/no treatment with Bifidobacterium; outcome, the effect of Bifidobacterium supplementation and symptomatic control among patients with IBS (PICO).We included articles published between March 2017 and March 2022 in humans and written in Portuguese, English, and Spanish languages that met the following eligibility criteria: population, adult individuals with IBS; intervention, treatment with Duplicate articles, articles that did not meet the PICO criteria, and articles with non-inclusive typologies for this study were excluded. The selection of articles based on title and abstract was independently performed by the three authors Figure . ArticleResultsIn the following table Table , we analBifidobacterium infantis 35624 in patients with irritable bowel syndrome: a meta-analysis” [B. infantis was compared with placebo, selected five studies, three of which were exclusively on B. infantile 666, and concluded that treatment with only B. infantis 666 did not affect the symptoms, and its effectiveness was not confirmed. LOE was A, which is strong research-based evidence .The meta-analysis “Efficacy of Bifidobacterium on Reducing Symptomatic Abdominal Pain in Patients with Irritable Bowel Syndrome: A Systematic Review” [Bifidobacterium depending on the species, dosage, and formulation. LOE was B, which is moderate evidence .The systematic review included in the study “The Effect of  Review”  comparedThe guideline included in the review “British Society of Gastroenterology guidelines on the management of irritable bowel syndrome”  concludeBifidobacteria and Their Health-Promoting Effects” [B. animalis HN019 has shown to improve gastrointestinal function, while B. animalis DN171010 reduced IBS symptoms. Bifidobacterium infantis has demonstrated the ability to reduce pro-inflammatory cytokines, not only at the gastrointestinal level but also systemically. Further studies with robust scientific evidence are needed to support the beneficial effects of this particular group of gut bacteria. LOE was C, which is limited research-based evidence .The narrative review “Effects”  concludeBifidobacterium and symptomatic control in patients with IBS is not clear. Some studies seem to demonstrate benefits in improving symptoms (SORT C).The evidence of an association between supplementation with Bifidobacterium appears to be useful in treating IBS symptoms and has not been associated with significant adverse effects. Still, it is not possible to recommend any specific probiotic; however, there is some benefit in treating general symptoms and abdominal pain. It is necessary to evaluate the anti-inflammatory effect of Bifidobacterium strains in patients with IBS. This review was useful in stratifying the available evidence, which is currently still limited and heterogeneous, hence the need for more studies.Despite the heterogeneity of the results found, supplementation with


Heart failure (HF) is the terminal manifestation of various cardiovascular diseases. Recently, accumulating evidence has demonstrated that gut microbiota are involved in the development of various cardiovascular diseases. Gut microbiota and their metabolites might play a pivotal role in the development of HF. However, previous studies have rarely described the complex role of gut microbiota and their metabolites in HF. In this review, we mainly discussed bile acids (BAs), the metabolites of gut microbiota. We explained the mechanisms by which BAs are involved in the pathogenesis of HF. We also discussed the use of gut microbiota and BAs for treating HF in Chinese medicine, highlighting the advantages of Chinese medicine in treating HF. Mortality and morbidity associated with HF remain high, and despite new drugs and treatment strategies in recent years, HF remains a leading cause of death worldwide.–5 The current treatment and research mainly focus on angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins. It is of great significance to clarify the pathogenesis of HF and further explore new therapeutic targets to reduce the economic burden of HF and improve patients quality of life.Heart failure (HF) is the final manifestation of various cardiovascular diseases, such as valvular heart disease, cardiomyopathy, myocarditis, and myocardial infarction. HF is characterized by impaired ejection function or ventricular filling due to abnormal structural and functional alterations. Due to reduced cardiac output and altered systemic circulation in HF, there is inadequate gut perfusion, which causes mucosal ischemia, intestinal edema, and impaired function of the gut barrier. In addition to increased gut permeability and altering the gut dysbiosis, the compromised gut barrier may allow microbial penetration into the systemic circulation and aggravate the chronic inflammation in patients with HF.Many studies have shown that gut microbiota are directly or indirectly involved in the development of various cardiovascular diseases. but not on the relationship between microbial metabolites and HF. Bile acids (BAs) are produced by cholesterol decomposition in the liver. Recent studies have found that BAs production is affected by the composition and function of intestinal flora, and abnormal metabolism of BAs can cause a severe inflammatory response and endothelial dysfunction, thereby increasing the risk of HF. Therefore, in this review, we discussed how gut microbiota and their metabolites, BAs, participate in HF. Herein, we reviewed the underlying mechanisms and summarized the current approaches and progress of Chinese medicine.The "Gut hypothesis" focuses on gut bacterial translocation, enhanced inflammatory response, and oxidative stress,–10 As a "metabolite filter", its function is strongly associated with daily activities. Therefore, gut microbiota must be in dynamic equilibrium to protect the mucosal barrier, prevent pathogen colonization, and maintain human health. If the gut microbiome is unbalanced, pathogenic microorganisms may outnumber nonpathogenic microorganisms, which may affect the progression and pathogenesis of various chronic diseases, particularly HF.The gut is the biggest microeco system in humans, gut microbiota are form a complex biological community made of up to 100 trillion microorganisms.HF and gut microbiota have been linked by many studies. The imbalance of gut microbiota refers to abnormal intestinal microecology, which mainly manifests with altered quantity, proportion, and localization of species. Localization metastasis refers to the translocation of intestinal flora and their products such as endotoxin. HF development and progression can damage the intestinal mucosa, leading to gut dysbiosis and systemic inflammatory response. By inducing the inflammatory response and unfavorable reactions such as cachexia in the late stages of HF, the dysfunctional microbiota further exacerbate HF. Decreased abundance of protective bacteria like bifidobacteria and lactic acid bacteria, and increased abundance of pathogenic bacteria such as campylobacter, shigella, salmonella, yersinia, and candida have been detected in the feces of patients with HF. The composition of gut microbiota in patients with HF significantly differs from that in normal subjects, although it is very similar among different subgroups of HF. A study indicated that patients with HF have a higher abundance of Synergistetes, Enterococcus and Lactobacillus and a lower abundance of Butyricicoccus, Sutterella, Lachnospira, and Ruminiclostridium. Additionally, it was unfolded that some pathogenic bacteria, including Shigella, Campylobacter, and Candida, are associated with the severity of HF, which can serve as prognostic markers in HF. It has also been shown that microbial dysbiosis can lead to immune dysregulation, chronic inflammation, and deterioration of HF with decreased ejection fraction. Figure Patients with HF have gut dysbiosis, characterized by altered gut microbial composition and decreased diversity of gut microbiota.Gut microbiota and BAs have bidirectional interactions. BAs can alter the composition and function of gut microbiota; in return, gut microbiota modulate BAs metabolism. BAs also regulate innate immune system and bacterial defense, thereby influencing the composition of gut microbiota. Gut microbiota can also regulate BAs synthesis and their signaling pathways through BAs hydrolase. When BAs are released into the gastrointestinal tract, the gut microbiota can further metabolize BAs. This process includes debinding, oxidation, differential isomerization, 7-dehydroxylation, rebinding, and other reactions.When the combined BAs are released into the intestine, hydrolysis of BAs by intestinal flora is the first step of their metabolism. Bacterial bile salt hydrolas is responsible for hydrolysis. Several species of bacteria, such as Lactobacillus, Clostridium, Enterococcus, and Bifidobacterium, can produce BA hydrolase.In addition to hydrolytically binding BAs, 7-dehydroxylation of BAs is one of the most important pathways of metabolic transformation. Clostridium and eubacteria are responsible for 7-dehydroxylation through a series of catalytic reactions, which involves a cascade of enzymatic activities mediated by the Bai gene cluster. The Bai gene cluster consists of 8 genes, with 7 enzyme-encoding genes and 1 transporter protein-encoding gene. After dehydroxylation, cholic acid (CA) is converted into deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) is converted into lithocholic acid (LCA).Differential isomerization of BAs promotes the enrichment of secondary BA species. Differential isomerism of BAs consists of 2 steps and can occur on the hydroxyl groups at the 3, 7, and 12 positions. BAs can be isomerized in 2 steps on the hydroxyl group at positions 3, 7, and 12. In the position 7 of CDCA, the hydroxy group at position 7 of CDCA is oxidized and dehydrogenby position-specific hydroxysteroid dehydrogenase to form 7-oxoLCA, which is the oxidation step. Then, another position-specific hydroxysteroid dehydrogenase is reduced to form ursodeoxycholic acid. Two steps are combined to convert the 7-αOH of CDCA to 7-βOH, in which the difference-direction isomerization is completed. Microorganisms such as Bacteroides, Eubacterium, Clostridium, and Ruminococcus can oxidize and isomerize BAs. Figure In addition to the aforementioned pathways, recombination is a transformation method found in recent years. Similar to hepatocytes, intestinal flora can rebind free BAs. Instead of traditional taurine and glycine, Enterocloster bolteae can bind phenylalanine, leucine, and tyrosine to the carboxyl position of C24. These new BAs are called "microbe-conjugated bile acids"(MCBA), suggesting that gut microbiota uses additional mechanisms to prepare BAs for excavation. Emerging evidence indicates that BAs can possibly control cardiovascular function. BAs interact with farnesoid (FXR) and pregnane/steroid and xenobiotic receptors, 2 nuclear receptors, in the heart and systemic circulation. BAs can reduce heart rate by controlling calcium channel conductance in sino-atrial and ventricular cardiomyocytes. They also control vascular tonicity through both endothelium-dependent and independent mechanisms.BAs are synthesized by gut microbiota. They are crucial for regulating lipid and energy metabolism, nutrient absorption, and preserving gut homeostasis. It indicates that BAs metabolism, rather than BAs level, is involved in chronic HF. On the other hand, it was recently discovered that high levels of total serum BAs can contribute to liver-associated cardiac dysfunction in the mice model, possibly through impaired oxidation of cardiac fatty acids. These findings suggest that the BAs pool, rather than specific BAs, is involved in HF.In individuals with HF, decreased cardiac output reduces hepatic arterial blood flow and liver congestion, which can affect liver function and BAs excretion, compromise gut and hepatic circulation, and increase BAs levels. Recently, Mayerhofer and colleagues showed that the secondary-to-primary BAs ratio is elevated in patients with HF.According to their structural differences, BAs can be divided into 2 groups: free BAs, such as CA, DCA, CDCA, and LCA; and conjugated BAs, such as Glycocholic acid, Glycodeoxycholic acid, and taurocholic acid. Taurocholic acid and Glycocholic acid are produced by the combination of taurine or glycine and BAs. Primary BAs, such as CA and CDCA, are directly produced from cholesterol in hepatocytes. DCA and LCA are secondary BAs produced by dehydroxylation. Primary BAs are processed by gut microorganisms.Primary BAs can be produced through 2 pathways: the classical pathway and the alternative pathway. The majority of BAs are synthesized via the classical pathway. Cholesterol-7α-hydroxylase (CYP7A1) is the first enzyme in the classical pathway, and then steroid-12α-hydroxylase (CYP8B1) mediates 12α-hydroxylation. Thereafter, cholesterol-27-hydroxylase (CYP27A1) catalyzes 27α-hydroxylation. Then, side chain breakage and other steps occur to finally generate CA and CDCA. A small proportion of BAs are produced through the alternative pathway, in which CYP27A1 catalyzes cholesterol production, and cholesterol oxysterol 7α-hydroxylase (CYP7B1) generates CDCA as a primary BA.After being synthesized in the liver, BAs are stored in the gallbladder. Eating stimulates BAs secretion into the intestine, and 95% of BAs are reabsorbed, whereas the remaining is expelled with feces. Through active and passive transport mechanisms, the conjugated and free BAs are reabsorbed, respectively. The portal vein carries the reabsorbed BAs, including primary and secondary BAs and conjugated and free BAs, into the liver. The liver converts free BAs into conjugated BAs, which are then released with bile into the intestinal lumen, "Enterohepatic circulation of BAs" is the name of this process. Reusing the scarce BAs and fostering the digestion and absorption of lipids are the physiological purposes of the enterohepatic circulation of BAs. Figure On average, the human liver only contains 3 to 5 grams of BAs. The liver has to generate 16 to 32 grams of lipids every day to maintain lipid digestion and absorption. Inadequate production of BAs can be compensated by the enterohepatic circulation of BAs. It maximizes the emulsification of the restricted BAs pool and supports regular digestion and absorption of lipids. The enterohepatic circulation can be repeated 2 to 4 times after each meal. BAs cannot be recycled when the enterohepatic circulation is impaired; for instance, in cases of partial ileectomy or diarrhea. Impairment of enterohepatic circulation increases saturated biliary cholesterol levels, thereby enhancing the risk of cholesterol stones. On the other hand, it influences the digestion and absorption of lipids.BAs have hydrophobic methyl, hydrocarbon nuclei, and hydrophilic hydroxyl and carboxyl groups. The spatial coordination of hydroxyl and carboxyl groups all exist at the same time. Therefore, BAs primary structure contains hydrophilic and hydrophobic groups, providing interfaceal activity. BAs can lower the surface tension between oil and water and enhance lipid emulsification. They can help the absorption and digestion of medications, dietary fat, cholesterol, and fat-soluble vitamins.Cholesterol cannot be dissolved in water. Cholesterol easily precipitates in the gallbladder due to oversaturation. However, bile contains BA salts and lecithin, which help micelle formation and prevent gallstone formation.BAs also function as signaling molecules. They activate the nuclear receptor FXR and the cell surface receptor G-protein coupled receptor 5 (TGR5). BAs regulate homeostatic pathways, glucose, triglyceride, and cholesterol energy metabolism, inflammation, tumorigenesis, and cell proliferation. In order to prevent excessive BAs production under physiological or pathological situations, it is crucial to maintain the proper balance between BAs species and quantities.,30 such as IL-1, interleukin-8, interleukin-6, and TNF-α.Inflammation and HF are connected. Patients with HF have higher levels of inflammatory mediators. Inflammation significantly affects the incidence, progression, and prognosis of HF. Numerous experimental studies have demonstrated that proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6, interleukin-8, and tumor necrosis factor-α (TNF-α) have higher levels in individuals with HF. Patients with HF have progressive congestion that is linked to the increased levels of inflammatory mediators,Recently, it has been revealed that gut microbiota is important for both maintaining health and causing diseases. By triggering the inflammatory pathways, gut dysbiosis helps the development of HF. Therefore, the potential association between gut dysbiosis and HF is worth investigating. Modest concentrations of CDCA can interact with FXR to attenuate inflammation in vascular smooth muscle and prevent coronary atherosclerosis. BAs can also prevent cardiac remodeling and hypertrophy by inhibiting nuclear factor-κB (NFκ-B), a transcription factor for several inflammatory mediators.FXR is a nuclear hormone receptor known to play a key role in the metabolism of BAs. It is strongly activated by CDCA followed by DCA, CA, and LCA. The tissue-specific expression of FXR alters the mechanistic roles they play in maintaining BA homeostasis.–38 By controlling redox pathway, BAs can protect the myocardium, both TCA and TCDCA have been shown to increase the expression of peroxisome proliferator-activated receptor gamma, Ras-related C3 botulinum toxin substrate 1, NADPH oxidase 4, p21CIP, and endothelial nitric oxide synthase. Additionally, TGR5 overexpression reduced oxidative stress and inflammation by activating the AKT pathway in the cardiac myoblast cell line. LCA inhibited high glucose-induced cardiac hypertrophy in H9c2 cells, in addition, TGR5 activation enhanced myocardial survival.Evidence from clinical and experimental studies has shown that HF increases systemic and myocardial oxidative stress.Mitochondria are surrounded by 2 membranes to provide energy for normal cellular function. As it consumes too much energy, the heart must constantly produce ATP to support muscle contraction and relaxation. In normal myocardial mitochondria, fatty acids are used as the principal fuel for β-oxidation, which produces about 70% of myocardial ATP. Fatty acids can even provide up to virtually 100% of the total myocardial energy. With the development of HF, myocardial fuel gradually shifts from fatty acids to glucose. Therefore, improving mitochondrial function is pivotal for treating HF.In addition, mitochondria-mediated cardiomyocyte apoptosis plays a significant role in the development of HF. Impaired mitochondrial structure and function can lead to cell apoptosis, myocardial metabolic remodeling, and chronic HF.Previous studies have increasingly shown that end-stage HF is the result of mitochondrial dysfunction. Additionally, recent studies have shown that mitochondrial dysfunction has a role in oxidative stress and cardiomyocyte death, forming a vicious cycle in the failing heart. Some scientists reported that gut microbiota may indirectly upregulate SIRT1 and FXR via BAs to control mitochondrial function.In addition, secondary BAs can affect the function of the intestinal barrier, inflammation, and mitochondrial biosynthesis.Cardiomyocyte apoptosis plays a key role in the development of early HF. Extensive cardiomyocyte apoptosis can deteriorate myocardial function in HF. Inadequate blood supply and increased oxygen consumption accelerate cardiomyocyte death and exacerbate ventricular remodeling in HF. Therefore, improved cardiac energy metabolism can decrease cardiomyocyte death. Consistently, cardiomyocyte apoptosis has been linked to HF in a mice model. The experimental studies uncovered that UDCA can treat prenatal cardiomyocyte dysfunction.The plasma level of BAs can affect the cardiovascular system in both directions. High levels of BAs can stimulate FXR nuclear receptor and activate mitochondrial death signal and apoptosis.FXR is a member of a nuclear receptor superfamily that is crucial for controlling inflammatory response, oxidative stress, and glucose and lipid metabolism. Recently, it has been demonstrated that FXR is expressed in adult cardiomyocytes, myocardial tissue, and vascular wall. Numerous investigations have indicated the function of FXR in the cardiovascular system. FXR controls BAs production, cholesterol metabolism, inflammation, oxidative stress, cell death, and vascular remodeling. By triggering the AMPK signaling pathway, FXR ameliorates ET-1-mediated cardiomyocyte injury. All of these findings indicate that the FXR receptor may play a role in the development and progression of HF by influencing lipid and glucose metabolism, oxidative stress, inflammation, cell death, and vascular remodeling.Pu et al showed that FXR is expressed in cardiac cells and its activation significantly induces apoptosis through mitochondrial death signaling. They showed that FXR signaling is implicated in several cardiac diseases. They further confirmed their findings in an animal model of myocardial ischemia/reperfusion injury. The most potent ligand of FXR is CDCA, followed by CA, DCA, and LCA. UDCA does not activate FXR. It rather inhibits FXR activation. These findings suggest that after FXR activation, BAs can contribute to the development of HF by modulating several signaling pathways.FXR is a nuclear receptor that is activated by BAs. After activation, FXR controls important genes that are involved in the production, transportation, and reabsorption of BAs, and in the metabolism of carbohydrates and lipids. Numerous targets of the VDR are related to cardiac diseases. Previous findings suggest that changes in the vitamin D axis are linked to cardiac diseases. In several animal models, it has been demonstrated that vitamin D prevents ventricular hypertrophy and cardiac dysfunction.The vitamin D receptor (VDR) is a nuclear receptor for steroid hormones with a significant impact on gene transcription. VDR is a gene regulator that may be particularly relevant to cardiovascular disease and HF. Previous studies revealed that VDR is a more sensitive BA receptor than FXR and pregnane X receptor (PXR), particularly for LCA and its main metabolite 3-keto-LCA55. It was also uncovered that VDR may be activated by CA, a secondary BA stones.ANP and BNP are biomarkers of HF since they are components of the RAS counter-regulatory mechanism. Chen and colleagues showed that isoproterenol-induced ventricular hypertrophy activates VDR expression and hBNP promoter, suggesting a direct relationship between VDR and hBNP promotor.PXR is a nuclear receptor activated by various chemical stimuli, including gut microbial metabolites. It plays a crucial role in controlling the inflammatory response and maintaining the function of intestinal epithelium under both normal and inflammatory conditions. Vascular endothelium and smooth muscle cells both express PXR.2O2. PXR activation in endothelial cells controls toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors to maintain immune/inflammatory balance. PXR activation can directly upregulate TLR2, TLR4, TLR9, nucleotide-binding oligomerization domain-containing protein 1, and nucleotide-binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP3), thereby leading to caspase-1 and IL-1 shear maturation.In vascular endothelial cells, PXR can increase the activity of phase I and phase II oxidases, transporters, and enzymes associated with oxidative stress. It can also mitigate endothelial dysfunction caused by H PXR may play a role in the incidence and progression of HF based on its function in immune response, oxidative stress, and inflammation.Activated PXR can control gene expression and contribute to the treatment of cholestatic liver disease.,60 TGR5 is a G-protein-coupled receptor (GPCR) that is expressed in various tissues, including adipose tissue, muscular tissue, immune cells, spinal cord, and enteric nervous system. TGR5 inhibits atheroma formation and myocardial inflammation. In bovine aortic endothelial cells, activated TGR5 promoted nitric oxide production and inhibited NF-κB activity, thereby suppressing monocyte adhesion and preventing the development of atherosclerosis.In 2003, TGR5 was discovered by Kawamata using the human spleen cDNA library for GPCR after being first reported by Japanese researchers in 2002. Figure BAs, especially TGR5 agonists, increased myocardial response to inotropes, and hemodynamic stress in mice. TGR5 may be a potential therapeutic target for HF since it plays a significant role in myocardial adaptation.TCM has a long history of treating HF with extensive experience. TCM has a thorough understanding of the location, etiology, pathophysiology, and process of HF. It uses decoction, Chinese herbal compounds, Chinese herbal formulas, Chinese patent medicine, acupuncture, and other treatment methods to treat diseases, with fewer side effects, and acceptable efficacy. It also has a holistic approach and emphasizes syndrome differentiation and treatment as the treatment idea. TCM successfully alleviates immune response and improves objective measures such as left ventricular ejection fraction and N-terminal pro-brain natriuretic peptide. Several herbal medications can treat diseases by altering gut microbial composition and its metabolites. These medications are frequently used in the management of HF. TCM-based modulation of gut microbiota has received much attention for preventing HF. Additionally, TCM has been shown to control BAs production and BA transporter gene expression and regulate pathways related to BA transportation.TCM can protect the intestinal mucosal barrier, restore gut microbial diversity, and enhance immune function by regulating the number and proportion of intestinal microflora, inflammatory factors, signaling pathways, and genes. There are many similarities between intestinal microecology and Chinese medicine theory, such as the holistic concept and the theory of the “heart is connected with the small intestine.” These similarities provide a theoretical basis to prevent and treat diseases by regulating intestinal microecology, suggesting that the cross-talk between gut microbiota and the heart may become a new therapeutic target for HF. In recent years, 130 different components of TCM have been screened for PXR activation. Several compounds with potential CYP3A4 induction and inhibition ability have been identified, including artemisinin, glycyrrhizic acid, and tanshinone IIA. Wu et al found that quercetin can affect primary BA biosynthesis by regulating gut microbiota, thereby reducing TC, TG, HDL, LDL, TNF-α, and IL levels and improving vascular damage.The active components of traditional Chinese medications can trigger the necessary signal pathways. Due to their function as FXR and TGR5 agonists, coptis alkaloids, the active component of traditional Chinese medications, have lipid-lowering properties. Si-Miao-Yong-An Tang considerably increased the production of taurocholic acid, and glycine CA, and significantly lowered cholesterol levels in a mice model of hyperlipidemia. Simiaoyong decoction may cause a significant decrease in cholesterol level by promoting the conversion of cholesterol into BAs. Chaihu Shugansan dramatically increased TUDCA production in rats with slight liver damage. Xiexin Decoction decreased intimal damage in a mice model of atherosclerosis. It also improved gut dysbiosis, promoted BA synthesis, increased BA pool, and reduced proinflammatory factors and lipid levels. Yinchenzhufutang effectively improved abnormal BAs homeostasis, BAs transporter, inflammatory cell infiltration and other pathological damage.Numerous studies have demonstrated that TCM can affect the composition and function of gut flora, and improve BAs production. Xiaoqinglongtang regulated gut microbial composition, ameliorated myocardial fibrosis, cardiac hypertrophy, and inflammatory cell infiltration, and decelerated HF progression in hypertensive rats. Figure Qishen Granule is frequently used to treat and alleviate myocardial ischemia and HF. Qishen Granule can regulate the production of UDCA, glycodeoxycholic acid, and other BAs in the rat model of HF.Gut microbiota and HF have interwoven relationships. Gut microbiota produces BAs, a bile metabolite that is crucial for lipid absorption, regulation of energy metabolism, and preserving intestinal homeostasis. BAs may regulate cardiovascular function by modulating cardiac inflammation, cardiomyocyte apoptosis, oxidative stress, mitochondrial dysfunction, and other processes via receptors, such as FXR, VDR, PXR, TGR5, and muscarinic receptor, and channels, such as BK channel.TCM offers extensive experience in treating HF by focusing on gut microbiota. TCM has paid more attention to gut flora and BA in cardiovascular diseases. Chinese herbal medicine like Coptis chinensis, Artemisia annua, Glycyrrhiza uralensis, Salvia miltiorrhiza, Bupleurum chinense, Chaihu Shugan Powder, Simiao Yong'an Decoction, Xiexin Decoction, Chinese patent medicine Qishen granules, and herbal cake separated moxibustion reduce cardiomyocyte apoptosis and oxidative stress by improving gut dysbiosis. These findings indicate that TCM can treat HF by controlling gut flora and BAs. How TCM controls gut flora and uses BA to treat HF, remains to be known. Although FXR, VDR, PXR, TGR5, and muscarinic receptors are expressed in the cardiovascular system, there is only indirect evidence that BAs interact with these receptors to improve HF. It is therefore necessary to examine the mechanism of Chinese medicine in treating HF by focusing on gut microbiota and BAs.Conceptualization: Min Shi, Zhihua Guo.Formal analysis: Min Shi, Jiaming Wei.Funding acquisition: Ya Li, Zhihua Guo.Supervision: Zhihua Guo.Validation: Ya Li, Zhihua Guo.Writing – original draft: Min Shi, Hui Yuan.Writing – review & editing: Min Shi, Zhihua Guo.


The adsorption of acetonitrile results in the formation of hydrogen-bonded complexes, which exhibit a deprotonation state that follows a similar trend to the deprotonation induced by acetone. This allows for a semi-quantitative comparison of the acidity strengths of BAS within and between the different aluminosilicate frameworks.Understanding the adsorption behavior of base probes in aluminosilicates and its relationship to the intrinsic acidity of Brønsted acid sites (BAS) is essential for the catalytic applications of these materials. In this study, we investigated the adsorption properties of base probe molecules with varying proton affinities  within six different aluminosilicate frameworks . An important objective was to propose a robust criterion for evaluating the intrinsic BAS acidity . Based on the bond order conservation principle, the changes in the covalent bond between the aluminum and oxygen carrying the proton provide a good description of the BAS deprotonation state. The ammonia and formamide adsorption cause BAS deprotonation and cannot be used to assess intrinsic BAS acidity. The transition from ion-pair formation, specifically conjugated acid/base interaction, in formamide to strong hydrogen bonding in acetone occurs within a narrow range of base proton affinities (812–822 kJ mol The acid sites are formed upon replacing tetrahedral silicon atom in zeolite lattice with trivalent aluminum and thus introducing a negative charge that needs to be counterbalanced with a cation. Proton compensation results in the formation of Brønsted acid sites (BAS), whereas the presence of metallic cations as compensating species leads to Lewis acid sites (LAS). Also, another source of Lewis acidity is the presence of extra-framework aluminum species (EFAL) that cannot be entirely eliminated during the aluminosilicate synthesis3. Understanding the properties and behavior of BAS is essential for optimizing the performance of these heterogeneous catalysts, as the Brønsted acidity is of particular interest due to the wide range of catalytic applications.Aluminosilicate zeolites are an important class of heterogenous catalysts due to the presence of catalytically active acid sites7. These efforts led to several key findings; (i) the IR fingerprint of the bridging hydroxyl band at approximately 3600 cm−1 was found to be an inadequate indicator of zeolite acidity strength, in contrast to analogous relationships observed in other acids; (ii) an increase of aluminum content in zeolite framework results in a decrease of zeolite acidity, with the Si/Al ratio limit being topology-dependent; (iii) the proton affinity (PA) of probe base molecules was found to correlate with T–O bond lengths that participate in hydroxyl bond due to the bond order conservation principle; (iv) probe base molecules that deprotonate BAS characterize acid site concentration, rather than the corresponding BAS acidity strength; (v) base probe molecules that form hydrogen bonding with BAS can be used to distinguish acidity strength among the BAS; (vi) acid–base reactions in aluminosilicate materials do not necessarily correlate with the established acidity ranking based on probe adsorption analysis. Figure During the mid-1990s, significant progress was made in the development of the basic theoretical premises regarding the Brønsted acidity of aluminosilicatesEDPE)  across various aluminosilicate frameworks. However, calculating the accurate value of EDPE is, in principle, quite challenging, especially upon comparing different aluminosilicate zeolites. In addition, EDPE appears to be uncorrelated with other acidity descriptors, such as T–O–T angles. Furthermore, efforts to establish a correlation between EDPE and ammonia adsorption enthalpies have been unsuccessful, largely due to the formation of hydrogen bonds and dispersion stabilization  of NH4+ species within zeolite cavities that render the relation to intrinsic acidity strength hardly tractable. As a result, it was suggested that EDPE is an incomplete acidity descriptor without decomposition into covalent and ionic parts and the corresponding analysis of the formed transition state for particular reaction process. In contrast, it was reported that EDPE correlates reasonably well with the adsorption enthalpy of ammonia for the same structural topology but different metal substitutions and similarly for Keggin polyoxometalates.The theoretical concept of deprotonation energy (PE) Fig. A enables30. Hydrogen-bonded complexes or ionic pairs are formed in dependence on the proton affinity (PA) of the base probe and temperature. Note that the low dielectric constants of zeolites mean that the strength of the probe bases scales more closely with its gas phase values rather than its aqueous counterparts (cf. ammonia and pyridine). The interaction of BAS with weak bases such as carbon monoxide or acetonitrile leads to a significant red shift in BAS νOH frequency. It has been observed that there is a good correlation between the magnitude of νOH shift and the corresponding adsorption enthalpy for several aluminosilicate materials32. This suggests that the νOH shift could potentially serve as an acidity descriptor. However, this observation was found to be not universally applicable due to the spatial constraints at the BAS, which in turn influence the base orientation and magnitude of the νOH shift. Similar considerations apply to the frequency shifts on the probe itself 26. For strong base probes, the interaction with BAS results in the formation of an ionic pair that can be quantified using experimental techniques such as temperature-programmed desorption (TPD), infrared spectroscopy, and thermogravimetry. However, due to the strong stabilization of the protonated base in the confined space of the aluminosilicate framework, it is difficult to separate the energy requirements of the proton transfer from the overall stabilization energy. As a result, small strong bases like ammonia are useful for sampling the concentration of acid sites, while larger bases like pyridine are better for probing the accessibility of acid sites, but neither samples the intrinsic acidity of the BAS. Additionally, a scaling relation based on the adsorption enthalpies of probe base adsorbates with increasing proton affinity (PA) has been considered as an acidity descriptor. However, while a good correlation between adsorption enthalpies and transition state energies has been observed for certain zeolite topologies, introducing a different topology can clearly break the observed trends.The adsorption of probe base molecules in zeolites is one of the most used techniques to access aluminosilicate’s acidity and properties Fig. B20–30. H36. A certain advantage of ssMAS NMR spectroscopy is the possibility to obtain both qualitative and quantitative data on acid centers. For this purpose, a number of nuclei are used, such as 1H, 2D, 13C, 15N, 17O, 31P, etc. The type of hydroxyls on the surface of solids can be distinguished using the chemical shift of 1H nuclei 37, the accessibility, concentration and reactivity of acid centers can be studied using H/D exchange reactions whose course is monitored using NMR spectroscopy 40. Adsorption of suitable probe molecules , trimethylphosphine oxide (TMPO), etc.) is often used for determining the acid site strength43. TMP was found to be insensitive to the strength of the Brønsted acid sites 44, while TMPO showed a correlation between the 31P chemical shift and the acidic strength of the solid 45. Zheng et al. found a linear correlation between δ31P chemical shift of TMPO adsorbed and the proton affinity calculated by DFT43, and similar correlations were also found for adsorbed pyridine and acetone47.Besides the standard FT-IR techniques, the solid state magic angle spinning nuclear magnetic resonance (ssMAS NMR) spectroscopy is an extensively used advanced spectroscopy for the study and characterization of acidic sites in solid materials60. A significant observation is that the concentration of Brønsted acidic sites (BAS) is positively correlated with reaction rates. In many processes, there exists a direct relationship between the equilibrium adsorption constant  and acidity strength. Therefore, an aluminosilicate with a lower concentration of highly acidic BAS can exhibit the same activity as a material with a higher concentration of weakly acidic BAS. The optimal test reactions aim to minimize the yield of side products and the effects of diffusion. However, challenges, such as those encountered during the adsorption of probe base adsorptive, persist. One can argue that the complexity increases due to the necessity to form a transition state structure, where the topology of the aluminosilicate can play a significant role .The performance of aluminosilicate in a particular reaction or industrial process is of utmost importance Fig. C48–60. AB (HB)–Al, with structural variations mainly in T–OB bond lengths, T–OB–T angle, and proton confinement. Theoretical evaluations are likely to provide a better understanding of BAS properties than experimental measurements, which usually give average values over all available BAS in the material. This study focuses on the structural response of six aluminosilicate frameworks  to the increasing proton affinity of probe base adsorbates. The probes range from weaker basicity (acetonitrile and acetone) to stronger base (ammonia), with formamide also investigated to improve understanding of framework response in the narrow range of ionic pair formation (812–854 kJ mol−1).Assessing the acidity scaling of aluminosilicate BAS remains challenging due to the similarity in the structural motif Si–OFAU, CHA, IFR, MOR, FER, and TON  that were balanced with protons. The structures were optimized with a proton on each symmetrically inequivalent oxygen atoms as defined in a previous study14. Note that numbering of T positions and corresponding oxygen labeling follows the IZA notation, except for TON material, where lowering of the symmetry leads to two inequivalent O6 oxygens denoted as O6a and O6b61. The structures of investigated zeolites were taken from the database of DFT optimized zeolite frameworks62. To reduce interactions between neighboring BAS, 1 × 1 × k supercells were used for IFR, MOR, FER (k = 2), and TON (k = 3). The modified SLC polarizable force-field in GULP was used for simulated annealing of the structures from 600 K, providing a good starting point for ab initio optimization65. DFT optimization was performed using the PBE66 functional with periodic boundary conditions and PAW pseudopotentials as implemented in the VASP computational package69. The plane-wave basis energy cutoff was set at 400 eV, and the first Brillouin zone was sampled with the Γ-point, as the investigated zeolites have sufficiently large unit cells. SCF energies and gradients were converged to 10–7 eV and 10–3 eV/Å, respectively. All the results are summarized in Table The following aluminosilicate zeolites were investigated TON Fig. . The BASTo obtain structures as close to the global minimum as possible, up to 10 different starting positions and orientations were used for optimizing the probe base molecules in the vicinity of the BAS. Note that the initial orientations of probe molecules were constrained so that the atom with lone electron pair  was directed at BAS. The adsorption energy, 62. Especially, upon considering the structural response of the aluminosilicate driven mostly by electrostatic interactions that can be slightly overestimated at the DFT level25. Thus, Grimme’s D2 dispersion correction was added a posteriori at the supersystem geometry 70. Note that the mean dispersion contribution to the adsorption energy is 16% (ammonia), 28% (formamide), 40% (acetone), and 32% (acetonitrile). All regression characteristics are performed iteratively with a reweighted least squares approach to reduce the effect of outliers71.While the importance of dispersion interactions in describing the energetics of adsorption is well known, using dispersion correction to account for structural features of zeolites can be problematicB–Si angle, see 19. Thus, while it would be advantageous to circumvent the intricate behavior of the framework in response to adsorption or the challenges linked to the accessibility of BAS, this study primarily focuses on evaluating acidity via the adsorption of basic probe molecules. The most straightforward descriptor of acidity is the adsorption heat, which provides an exact measure of the BAS response. However, the adsorption heat also includes terms that are completely unrelated to the proton transfer process (see below). If geometric parameters are considered as descriptors, the most natural one would be the OB–HB distance (corresponding to the shift in the BAS OH frequency) along with the Al–OB–Si angle . These descriptors may not be optimal in case of (i) “full” proton transfer to the probe molecule and (ii) low framework deformation energy in the vicinity of BAS . In this work, we propose the descriptor based on monitoring the change in Al-OB bond length upon adsorption, that is normalized by Al–OB change between BAS without an adsorbate  and the fully deprotonated state , is defined as follows:The attempts to extract information about the BAS acidity from properties of empty zeolite framework could not establish any relevant link between intrinsic BAS acidity, as determined by deprotonation energy, and proposed descriptors of BAS acid strength  is sufficient to remove the proton from the BAS, resulting in the formation of ionic pair with a mean OB–HB distance of 1.61 Å. The most stable adsorption complexes do not necessarily form at the lowest energy BAS for any given T position. One reason for this is that the most stable BAS cannot accommodate the NH3 molecule . Additionally, factors such as diffusion limitations for protonated ammonia can also impact the formation of the most thermodynamically stable NH3@BAS complexes. For instance, the most stable BAS at the MOR/Al1–O4 position forms a complex in the main channel with a relatively low adsorption energy of 142 kJ mol−1. The transition of ammonia to Al1–O2 , is not feasible as it would require passing through the MOR layer. On the other hand, there are many occurrences when the formation of ionic pairs at the most stable BAS does not preclude the formation of the thermodynamically most stable adsorption minimum at BAS of higher relative energy. Note that the higher energy BAS may become populated upon decreasing the Si/Al ratio72. As a result, the observed changes in ammonia adsorption heat upon changes in Si/Al ratio can be to some extent explained by changes in proton distribution and not necessarily significant change in intrinsic BAS acidity . For low Si/Al ratios, a repulsion between ammonia ions can further decrease the adsorption heats. In contrast, it has been shown that the interaction with the nearest neighbor Al atoms can play an important role, and thus a comparison/interpretation of theoretical and experimental values is difficult unless proton distributions along with ammonia loading are treated in the correct statistical fashion for medium to lower Si/Al ratios59.The adsorption energies and main geometric parameters of NH74. Ammonia forms either two hydrogen bonds with oxygen atoms connected to Al, with one of these bonds usually being shorter . The structures like in Fig. B–HB–N angles and lower adsorption energies . However, the level of correlation with OB–N bond length is dependent on the OB–HB–N angle.Regarding the structural features of NH3@BAS, two main geometry motifs were identified that are consistent with previously determined structurester Fig. a, or twoter Fig. b. These 4+ and the aluminosilicate framework, as well as the formation of hydrogen bonds with framework oxygens19. These factors strongly affect the calculated or experimentally measured values, even though they are not directly related to the intrinsic acid strength of the BAS, but rather depend on the framework topology and local framework density. The deprotonation energies do not correlate with any energetic or geometric descriptors of the most stable NH3@BAS adsorption complexes in accordance with observation for MFI19. This is not surprising considering the possibility that small differences in intrinsic acidity between the aluminosilicate’s T-positions are overshadowed by the intermolecular interactions of NH4+ cation with aluminosilicate. Examining the BAS response to NH3 adsorption, the most marked difference is observed in the behavior of the Al–OB–Si angle upon comparison with BAS without adsorbate and its corresponding anion. The deprotonation of BAS is accompanied by a substantial decrease in the Al–OB–Si angle, but for NH3@BAS complexes, the Al–OB–Si angle is changed only marginally (−0.2° ± 2.4°). In contrast, upon NH3 adsorption, the Al–OB and Si–OB bonds are shortened due to the weakened proton coordination with the framework. This observation also holds for other investigated probes, thus indirectly confirming that the proposed fdep descriptor can be used for BAS acidity scaling.Considering the ammonia adsorption, adsorption energy or enthalpy are typically regarded as primary indicators of BAS acidity. However, the relationship between acidity and adsorption heat is complex due to the dispersion interaction between NH−1 are summarized in Table S3. The lower proton affinity of formamide is reflected in the fact that, on average, the adsorption energy between formamide and aluminosilicate is lower than that of NH3@BAS by approximately 25 and 10 kJ mol−1 at the PBE and PBE-D2 levels of theory, respectively. It appears that the differences in PBE adsorption energies follow more closely the difference in proton affinities. The increase of dispersion interactions, as seen in the case of formamide, decreases the level of correlation between adsorption energy and proton affinity. A similar observation was made in the case of butylamine adsorption, where the significant contribution from dispersion interactions causes the dependence of adsorption enthalpy on proton affinity to deviate from the trend observed with smaller amine probes75.The results of formamide adsorption with its proton affinity of 822.2 kJ molB–O distance (~ 1.14 Å) is significantly shorter than the OB–HB bond length (~ 1.33 Å)]. The most stable formamide@BAS structures usually possess a second strong hydrogen bond, in which the amino group of formamide binds to another framework oxygen connected to Al  and HB–O–C (enforced by the presence of electron lone pairs on O) angles. These requirements lead to a solid correlation between deprotonation factor fdep .Formamide interacts with BAS preferentially through its carbonyl group rather than its amino group, yielding in most cases BAS deprotonation . The−1) and formamide proton affinities of about 10 kJ mol−1, but acetone adsorption exhibits rather strong hydrogen bonding than BAS deprotonation or proton-sharing arrangements. The acetonitrile (PA = 779.2 kJ mol−1) proton affinity is significantly lower, but it is still sufficient to form strong hydrogen-bonded complexes even on BAS with the intra-zeolitic hydrogen bonds. The comparison between adsorption geometries of carbonyl and nitrile groups shows that while both adsorbates have mean hydrogen bond angles well over 170°, the electron lone pairs on carbonyl oxygen require a narrow range of HB–O–C angles, unlike in the case of nitrile group, where larger deviations from the preferable linear arrangement are observed. The acetone/acetonitrile adsorption energies do not correlate with deprotonation energy models. Additionally, in the case of acetone, the fdep further correlates with OB–HB and other related bond distances similar to the formamide probe. In contrast, no such correlation is observed for the acetonitrile probe . The most likely explanation is the lower proton affinity of acetonitrile that introduces significantly smaller variation in OB–HB distance than probes of higher PA, and thus the role of local BAS environment plays a more important role. Upon closer examination of Fig. S5, it becomes evident that there is a reasonable correlation between the deprotonation factor (fdep) and the lengths of the OB–HB bonds for base probes that have a PA around the threshold for deprotonation, such as acetone and formamide. However, this correlation disappears for probes with a PA that is too low (acetonitrile) or for probes that induce the deprotonation of the BAS (ammonia). Hence, it can be inferred that the fdep descriptor demonstrates the anticipated behavior and appears to be more reliable than relying solely on the OB–HB bond lengths, even for base probes that deviate from the optimal proton affinity to a reasonable extent.The result of acetone and acetonitrile adsorption are summarized in Tables S4 and S5. There is only a small difference between acetone (PA = 812.0 kJ molfdep (descriptor of acidity) with OB–HB distances and adsorption energies for the thermodynamically most stable adsorption sites. The deprotonation factor visibly splits the data into groups according to the proton affinity of the base probe, which is consistent with the response in OB–HB bond length and adsorption energy. The inclusion of the dispersion correction diminishes the level of correlation for adsorption energies , as the dispersion contribution varies with the nature/size of the adsorbate. The trend observed in Fig. Eads–PA relationship, as the correlation between the adsorption energy and fdep for a given base probe (with constant PA) is practically nonexistent. Note that Fig. fdep and the OB–HB bond lengths for base probes with PA close to the deprotonation threshold . However, it does not directly establish a scaling of individual BAS with their acidity strength. To establish such a scaling, the different base probes need to provide reasonably close BAS acidity ranking. Figure fdep descriptor for the most stable adsorption sites. The data in Fig. 6, who suggested that the most effective approach to evaluate zeolite acidity is to closely mimic the reactant by using an adsorbate that is as similar as possible. This partially alleviates the effects associated with adsorption that are unrelated to the intrinsic BAS acidity, such as BAS confinement/accessibility and interactions between the probe/adsorbate and the zeolite wall.Figure B–HB > HB–X) provide very different rankings from probes with lower proton affinity. This is a result of strong ion-pair interactions, including the formation of hydrogen bonds and dispersion stabilization. It can be concluded that in the case of probes with sufficient proton affinity to “fully deprotonate” the BAS, the information about intrinsic BAS acidity is lost . In contrast, there is a weak trend between deprotonation factors of acetone and acetonitrile. The dependence of deprotonation factors for acetone and acetonitrile is depicted in Fig. TON) demonstrate the difficulties in extracting information about intrinsic acidity from the corresponding deprotonation factors. As mentioned earlier, there is a noticeable difference in the adsorption behavior between acetonitrile and acetone. This disparity arises from the presence of electron lone pairs on the oxygen atom of the carbonyl group, which limits the accessibility of acetone to the BAS. The TON/Al4 BAS falls exactly into this category, where the HB–O–C angle of about ~ 152° is far from its optimal value of about ~ 120°. Furthermore, the site itself is located deeper within the TON layer , resulting in reduced accessibility of the BAS. This is evident from lower adsorption energies calculated for all the investigated probes. Contradictory to lower adsorption heats, the deprotonation factor of acetonitrile adsorption at TON/Al4 BAS does not significantly deviate from the average. The second class of the outliers in Fig. TON BAS; however, there is no clear indication in the data why this effect is taking place except for significantly longer OB–HB bond lengths observed upon acetone adsorption. The comparison of framework geometries reveals that acetone adsorption induces large changes in the 10-ring geometry, indicating that the effect occurs far from the BAS position , as observed in Fig. Moreover, Fig. er Fig. S, resultiFAU zeolites74.To summarize, base probes that do not cause deprotonation of the BAS but still possess a sufficiently high proton affinity to bring the proton on the BAS as close as possible to the deprotonation state allow for a semi-quantitative scaling of the BAS acidity between different T-positions within the aluminosilicate framework, as well as between frameworks of different topology. A closer inspection of Fig. FAU, CHA, IFR, MOR, FER, and TON) was investigated through the adsorption of base probe molecules  with varying proton affinities. The adsorption complexes displayed interesting characteristics pertaining to the intrinsic acidity of the different Brønsted acid sites (BAS). The transition from the strong hydrogen bonding in acetone to ion-pair formation  in formamide occurs within a very narrow range of base proton affinities (812–822 kJ mol−1). This range appears to be independent of the aluminosilicate material but can be influenced by the accessibility of the BAS or the mode of interaction with the base probe. The degree of BAS deprotonation was assessed through the changes in the Al–OB bond (with the framework oxygen carrying the proton) using the bond order conservation principle.Brønsted acidity in zeolites (fdep) for the most stable adsorption sites.Base probes leading to full deprotonation of BAS, such as ammonia and formamide, are unsuitable for assessing the intrinsic acidity of these sites, as information about the deprotonation threshold is lost after forming the corresponding ion pair. In contrast, base probes with a proton affinity sufficient to disrupt intra-zeolitic hydrogen bonds but below the deprotonation threshold (Brønsted hydrogen located close to the framework oxygen), such as acetonitrile and acetone, exhibit consistency among their acidity rankings. These rankings are determined by the acidity descriptor  small differences in intrinsic acidity among different BAS, as demonstrated by their deprotonation energies, (ii) geometrical constraints arising from the presence of lone pairs on the proton acceptor of the base probe molecule, and (iii) dispersion effects stemming from the framework flexibility, such as deformations of large rings containing BAS. All these issues contribute to the difficulties in extracting information about intrinsic acidity from the corresponding deprotonation factors. Nonetheless, the ranking of BAS obtained from the adsorption of acetonitrile is recommended as the most reliable.Supplementary Information.