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Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure

Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 382585, 5 pages http://dx.doi.org/10.1155/2015/382585 Review Article Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure 1 2 3 4 Evasio Pasini, Roberto Aquilani, Giovanni Corsetti, and Francesco S. Dioguardi “S. Maugeri Foundation” IRCCS, Medical Centre, Lumezzane, 25065 Brescia, Italy Department of Biologyand Biotechnology“L. Spallanzani”,UniversityofPavia,27100 Pavia, Italy Division of Human Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25124 Brescia, Italy Department of Internal Medicine, University of Milan, 20100 Milan, Italy Correspondence should be addressed to Giovanni Corsetti; giovanni.corsetti@unibs.it Received 15 May 2015; Accepted 10 September 2015 Academic Editor: Tamer Mohamed Copyright © 2015 Evasio Pasini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic heart failure is a complicated multifactorial disease with wide-spread social-economic consequences. In spite of the recent development of new drugs and therapeutic strategies, CHF-related mortality and morbidity remain high. Recent evidence suggests that changes in organs such as skeletal muscle and gut flora may play an important and independent role in CHF prognosis. This paper illustrates these phenomena, proposing how to identify them and presenting current therapies which treat organs all too oen ft underestimated but which have a fundamental role in worsening CHF. 1. Introduction composition alteration and/or gut microbiota activity could be an important step to improve CHF patient care. This would Chronic heart failure (CHF) is a very common and multi- avoid additional and independent clinical damage and allow factor syndrome. In spite of currently used therapies, it still traditional therapies to work more efficiently. has high mortality and mobility [1]. Malnutrition, in partic- ular with protein metabolism impairment and consequent 2. Malnutrition cachexia, has oeft n been found in CHF patients and correlates closely with mortality [2]. Furthermore, we recently demon- 2.1. A Definition. Malnutrition is a general term that encom- strated that CHF patients have important changes in both gut passes various forms of inadequate nutrition. It is mul- flora and intestinal permeability, which influence systemic tifactorial but is basically caused by the reduced balance inflammation and global metabolism by modifying nutrients between body nutrient intake and needs. Qualitative and absorption and production of molecules fundamental for cell quantitative malnutrition are oeft n present in CHF and life (authors’ unpublished data). These conditions are oeft n protein malnutrition, leading to the disarrangement of both ignored or underestimated by most clinicians, although they visceral and muscular proteins. eTh se conditions have been have been showntoincreasemorbidity,hospitalstay, and extensively studied in CHF [2, 4]. mortality risk independent of the primary cause of CHF. Protein malnutrition can be estimated in patients by mea- This paper illustrates the clinical problems related to suring visceral protein (e.g., serum albumin concentrations) malnutrition (basically, protein malnutrition) and gut flora and muscular wasting (e.g., arm muscle area). Indeed, serum modification in CHF patients. We also look at some possibly albumin level< 3.5 g/dL (without diseases interfering with easily repeatable methods to identify these pathological albumin metabolism, such as liver or renal insufficiency) conditions and to try to care for them. In the wait for and muscular sarcopenia (<5th percentile of normal upper- genetic therapies and stem cells for CHF [3], we believe arm muscle area) are important markers of poor protein that identifying and possibly curing protein malnutrition and nutritional status. This is because they can predict morbidity 2 BioMed Research International and mortality in CHF independent of the primary cause of from alternative metabolic pathways, and muscle AA are the disease [5, 6]. Recently, other simple nutritional assess- used to produce glucose essential to maintain the glucose- ment tools, such as the Geriatric Nutritional Risk Index dependent metabolism of fundamental structures such as the (GNRI), which considers serum albumin and body mass brain and erythrocytes. index (BMI), correlate with lower serum hemoglobin and Moreover, under these conditions, muscle glycogen systemic inflammation (higher C-reactive protein) and have reserves are depleted and free fatty acids (FFA) become the been seen to be useful aids in CHF. This index predicts principal fuel for the muscle. However, FFA use is a limiting functional dependency and mortality in CHF patients even factor for energy production [14]. In fact, accumulation of with a preserved ejection fraction [7]. FFA in the myocytes reduces energy production during exercise with consequent skeletal muscle fatigue [15]. Notably, 2.2. eTh Clinical Problem. Data show that protein visceral insulin also plays an important role in regulating adipose malnutrition impairment in patients with CHF is not always metabolism. Small increases in plasma insulin significantly as severe as muscle wasting. Very oen, ft visceral protein reduce lipolysis in adipose tissue. This insulin increase synthesis is also conserved. Indeed, skeletal muscle wasting reduces the availability of FFA for acetyl-CoA production, (measured by magnetic resonance spectroscopy) was found which is fundamental for maintaining cell energy produc- in 68% of CHF patients, while up to 24% of patients had tion. Consequently, cell energy production via the anaerobic serum albumin levels<3.5 g/dL [3]. This apparent discrep- metabolic pathway is maintained by acetate which is derived ancy can be explained by considering the metabolic role of predominantly from AA breakdown and oxidation. It is clear theamino acids(AA) of striatemuscles.Indeed,wecan that the availability of AA is a key factor in maintaining mammal cell metabolism. say that skeletal muscle is a pivotal organ, which maintains body metabolic performance by the continuous exchange of fuel with the liver. Under malnutrition, starvation, 2.4. Possible New Therapeutic Approaches. In the light of and/or catabolic circulating stimuli, striate muscle protein is thesefindings,wecan saythatthe alteration of protein degradedandAAarereleasedintotheblood.ThereleasedAA metabolism is clinically important. This could be due to are essential for maintaining global protein synthesis (includ- different conditions related to age and/or inflammatory ing albumin) and glucose plasma levels, through hepatic diseases, reduced qualitative/quantitative food intake, and/or gluconeogenesis and cell energetic metabolism. Indeed, AA malabsorption. We believe that combined pharmacological contain carbon, oxygen, hydrogen, and nitrogen. eTh y can and nutritional interventions, such as personalized therapy therefore be metabolized into carbohydrates (such as glucose) based on the specific needs of individual patients, can or directly into lipids in accordance with the thermodynamic maintain cell metabolism hence aiding traditional standard status of the cell. It must be pointed out that lipids cannot therapy in CHF patients. be transformed into carbohydrates by mammals. In addition, Data show that exogenous oral supplementation with a AA are fundamental intermediaries for the tricarboxylic special mixture of individual essential AA tailored for human acid cycle [8]. Clinically interesting, about 16% of patients needs (EAAm) could be a valid therapeutic strategy to use in with muscular wasting progress to cachexia. However, this patients with CHF, in combination with conventional therapy phenomenon is related to a dramatic increase in mortality as to prevent protein malnutrition with protein wasting for the 50% of cachectic patients die within 18 months [9, 10]. following reasons. Firstly, EAAm could resolve malnutrition related to 2.3. Why It Occurs. The genesis of visceral and muscular reducednutrientgut absorption duetoexocrineexhaustion proteins breakdown in CHF has not yet been completely of the pancreas caused by CHF. It is well known that the understood. eTh more accepted hypotheses indicate that pancreas is the major consuming organ of AA. Furthermore, the catabolic effects of inflammatory cytokines (e.g., tumor the pancreas plays a fundamental role in food digestion. How- necrosis factors and interleukins) and neuroendocrine hor- ever, digestion and food absorption need adequate synthesis mones (catecholamines, cortisol, and renin) are responsible and secretion of different enzymes. for this phenomenon [11, 12]. This process uses enormous quantities of AA and energy Indeed, the increase in plasma catabolic molecules in at all meals. In patients with CHF, the exocrine efficiency of patients with CHF has been well documented. Recently, the pancreas is progressively reduced. As we have seen, this impairment of anabolic hormones such as insulin with then causes a vicious circle, lower digestion of proteins, and insulin resistance (IR) has also been found in 58% of CHF lower availability of AA for digestive enzyme synthesis. patients [13]. In muscles, the lack of anabolic stimulation due This condition leads to impaired digestion with a conse- to IR and the increase of catabolic stimuli causes protein quent reduction of plasma patterns of AA which are insuf- degradation and AA release. es Th e AA are used in the liver to ficient to promote protein synthesis. Interestingly, single AA produce glucose by gluconeogenesis. In addition, IR inhibits are not digested. eTh y are rapidly absorbed and immediately mRNA synthesis of phosphoenol pyruvate carboxykinase availableinthe bloodfor proteinsynthesis [16]. (the key enzyme of the gluconeogenesis pathway) in the liver. Secondly, EAAm are positive signals for maintaining This contributes to reducing gluconeogenesis further via muscle protein stores and so reducing IR. Indeed, AA inhibit pyruvate originating from lactate. us, Th a vicious circle is changes to glucose transport as well as gluconeogenesis generated, where malnutrition does not supply exogenous mediated by IR. In addition, at high physiological concen- nutrients, the liver produces low quantities of carbohydrate trations, AA activate various important phases of protein BioMed Research International 3 synthesis [17, 18]. Data show that AA are signals for the present in the majority of CHF patients. Indeed, we found secretion of IGF-1 and -2 (insulin-like growth factor-1 and - the massive presence of Candida, Campylobacter, Shigella, 2) [19]. IGF-1 is the somatomedin responsible for the main Salmonella,and Yersinia in the stools of CHF patients. eTh activation of growth hormone (GH), an anabolic hormone massive presence of this pathogenic contaminating flora had which promotes protein synthesis and counteracts IR. important pathophysiological eeff cts on patients with CHF, Thirdly,EAAmmodulatethe eeff cts of insulinonadipo- because they significantly correlate with systemic inflamma- cytes enhancing glucose-induced desensitization of insulin- tion and intestinal functions including permeability (authors’ stimulated glucose transport and regulate the synthesis of unpublished data). FFA [20]. In particular this eect ff is mediated by glutamine. Finally, it has recently been demonstrated that EAAm, 3.2. eTh Consequence. Research shows that there are molec- including essential and branched ones as well as lysine, ular reasons for the link between dysbiosis and systemic can maintain protein synthesis, support energy needs, and catabolism. Indeed, pathogens produce lipopolysaccharide stimulate mitochondrial biogenesis [21]. es Th e eeff cts are due (LPS) and other fungal or bacterial toxins which cause locally to the capability of AA to activate AMP-activated protein produced cytokines with consequent intestinal epithelial kinase mammalian target of rapamycin (mTOR) and nitric inflammation, which increases gut membrane permeability. oxide synthase (NOS). es Th e are important enzymes which This intestinal endothelial dysfunction allows the translo- stimulate cell life and development (including stem and cation of fungal or bacterial toxins from the gut to the endothelial cells), regulating energy production/use, protein circulating blood. In turn, this increases both circulation synthesis, cell proliferation, antiapoptotic processes, and inflammatory molecules such as TNF-alfa and LPS. es Th e mitochondrial biogenesis [22, 23]. stimulate inflammatory cells to produce catabolic molecules In addition to EAAm, other molecules have been inves- capable of causing muscular wasting, sarcopenia, and finally tigated and are presently under investigation, as nutritional cachexia [28–30]. support for CHF patients in order to understand their role in Recently, researchers have identified the enzymatic activ- avoiding protein disarrangement. A recent multicenter phase ities of protein effectors injected into host cells by pathogens III clinical trial demonstrated that Amalirin (orally active such as Shigella, Salmonella,and Yersinia.Thisoccursthrough ghrelin receptor antagonist) can reverse muscle wasting in their type III secretion system, which modulates host innate cancer cachexia and has been proposed as a therapeutic agent immune responses. Specifically, bacterial acetyl-transferase for all stage of cachexia. The protein’s anabolism can also modifies AA residues of cellular MAPK and I-KK-beta be modulated by stimulation of selective androgen receptor modulating inflammatory cell response and activating intra- modulators (SARMs) in humans and by activating type II cellular apoptosis [31]. The consequent state of chronic receptor of Myostatin in both animal models and humans. inflammation has been well documented in CHF patients Another animal study showed that the anabolic/catabolic and it is thought to be responsible for functional organs transforming agent MT-102 reverses muscle wasting in rats dysfunction and clinical deterioration [28]. [24]. The anatomical and functional alteration of the ente- rocytes induced by contaminating flora also influences the 3. Gut Flora Dysbiosis intestinal nutrient absorption and gastrointestinal mobility causing malnutrition. This aspect is particularly important in eTh mammalian gastrointestinal tract contains about 100 CHF patients because it is well known that malnutrition, with trillion microorganisms called gut flora or microbiota. This consequent muscular wasting and cachexia, is very common. is ten times greater than the total number of human cells Various hypotheses can be formulated to explain the massive in the body. For this reason, it is also called “the forgotten presence of contaminating pathological microorganisms in organ.” Microbiota benefits the host by exerting many the gut flora. eTh more accredited hypotheses consider local crucial functions for host life. Indeed, microbiota regulates ischemia and indiscriminate antibiotic use as responsible the guts’ barrier function and motion, inu fl ences nutrient of pathogens overgrowth. Local ischemia is due to CHF- absorption, produces important metabolic intermediaries, mediated distribution of blood flow which underperfuses including vitamins, and modulates local and systemic gut endothelium. Ischemia causes intramucosal acidosis, inflammation through innate immunity. Consequently, gut hypercapnia, and oxygen-free radical production. Moreover, microbiota influences the metabolism of tissues outside the CHF patients have neuroendocrine activation with nore- intestine. u Th s, alterations of the composition and/or activity pinephrine increase. es Th e conditions are all known to be of microbiota, known as dysbiosis, as well as intestinal activators of bacterial virulence and can also influence patho- functions, influence the evolution of diseases independent logical bacteria overgrowth (authors’ unpublished data). The of the original cause of the disease. Recently, gut microbiota overuse of antibiotics in the food chain may contribute to dysbiosis has been proposed as an environmental factor selecting antibiotic resistant pathogens, which then colonizes capable of causing a catabolic state with consequent muscle the intestine. wasting [25–27]. 4. Therapies 3.1. The Evidence. Recently, we demonstrated that CHF patients had signicfi ant qualitative and quantitative impair- Currently, there are no specific therapies to cure microbiota ment of gut flora. Particularly, pathological species were dysbiosis available. However, encouraging data suggest that 4 BioMed Research International gut dysbiosis can be modified by several means such as nutri- [6] M. Liu, C.-P. Chan, B. P. Yan et al., “Albumin levels predict survival in patients with heart failure and preserved ejection tional supplementation with specific nutrients (prebiotics) fraction,” European Journal of Heart Failure,vol.14, no.1,pp. and/or live bacteria (probiotics) and/or local therapies with 39–44, 2012. fecal microbiota transplant or colon hydrotherapy [32]. [7] Y. Kinugasa, M. Kato, S. Sugihara et al., “Geriatric nutritional Fecal microbiota transplant (or stool transplant) is a pro- risk index predicts functional dependency and mortality in cess of transplanting fecal bacteria from healthy individuals patients with heart failure with preserved ejection fraction,” into recipients. FMT involves restoring the colonic microflora Circulation Journal, vol. 77, no. 3, pp. 705–711, 2013. by introducing healthy bacterial flora through the infusion [8] A. Lehninger, Biochemistry,Worth,New York,NY, USA, 1975. of stools. Colon hydrotherapy is a technique which reduces [9] S. D. Anker, J. W. Swan, M. Volterrani et al., “eTh influence of waste material in the colon by using tubes in order to insert muscle mass, strength, fatigability and blood flow on exercise water, with or without specicfi therapy, into the colon via the capacity in cachectic and non-cachectic patients with chronic rectum with special equipment [32]. heart failure,” European Heart Journal,vol.18, no.2,pp. 259– 269, 1997. [10] S. D. Anker and M. Rauchhaus, “Insights into the pathogenesis 5. Conclusive Remarks of chronic heart failure: immune activation and cachexia,” CHF is a complicated multifactor disease with important Current Opinion in Cardiology,vol.14, no.3,pp. 211–216, 1999. social-economic impact. In spite of the recent development of [11] M. Packer, “Neurohormonal interactions and adaptations in congestive heart failure,” Circulation,vol.77, no.4,pp. 721–730, new drugs and therapeutic strategies, CHF-related mortality and morbidity remain high. Recent evidence suggests that [12] S. Sasayama,A.Matsumori,and Y. Kihara,“Newinsightsinto changesinorganssuchasskeletalmuscleandgutfloraplayan the pathophysiological role for cytokines in heart failure,” Card- important and independent role in CHF prognosis. Specific iovascular Research,vol.42, no.3,pp. 557–564, 1999. therapies need to be identified in the future in order to [13] J. W. Swan, S. D. Anker, C. Walton et al., “Insulin resistance in maintain the metabolic and functional homeostasis of these chronic heart failure: relation to severity and etiology of heart organs so that we can cure CHF patients better. failure,” Journalofthe American CollegeofCardiology,vol.30, no. 2, pp. 527–532, 1997. Conflict of Interests [14] F. Brouns and G. J. van der Vusse, “Utilization of lipids during exercise in human subjects: metabolic and dietary constraints,” eTh authors declare that there is no conflict of interests British Journal of Nutrition, vol. 79, no. 2, pp. 117–128, 1998. regarding the publication of this paper. [15] J.A.Timmons, T. Gustafsson,C.J.Sundbergetal.,“Substrate availability limits human skeletal muscle oxidative ATP regen- eration at the onset of ischemic exercise,” JournalofClinical Acknowledgment Investigation,vol.101,no. 1, pp.79–85,1998. [16] F. S. Dioguardi, “Influence of the ingestion of branched chain The authors would like to thank Professor Robert Coates amino acids on plasma concentrations of ammonia and free (Centro Linguistico, Universita` Bocconi, Milan, Italy), medi- fatty acids,” JournalofStrengthand Conditioning Research,vol. cal writer, for his linguistic revision. 11, no. 4, pp. 242–245, 1997. [17] M. E. Patti, E. Brambilla, L. Luzi, E. J. Landaker, and C. R. Kahn, References “Bidirectional modulation of insulin action by amino acids,” Journal of Clinical Investigation,vol.101,no. 7, pp.1519–1529, [1] S. A. Hunt, W. T. Abrams, M. H. Chin et al., “ACC/AHA guide- line update for diagnosis and management of chronic heart [18] L. Mosoni, M.-L. Houlier, P. P. Mirand, G. Bayle, and J. Grizard, failure in adult-summary article. A report of the American Col- “Effect of amino acids alone or with insulin on muscle and liver lege of Cardiology/American Heart Association task force on protein synthesis in adult and old rats,” American Journal of practice guidelines,” Journalofthe American CollegeofCardio- Physiology: Endocrinology and Metabolism,vol.264,no. 4, pp. logy, vol. 46, pp. 1116–1143, 2005. E614–E620, 1993. [2]D.M.Mancini,G.Walter, N. Reicheketal.,“Contribution [19] M. Giordano, P. Castellino, and R. A. DeFronzo, “Differential of skeletal muscle atrophy to exercise intolerance and altered responsiveness of protein synthesis and degradation to amino muscle metabolism in heart failure,” Circulation,vol.85, no.4, acid availability in humans,” Diabetes,vol.45, no.4,pp. 393– pp.1364–1373,1992. 399, 1996. [3] S.Koudstaal,S.J.JansenofLorkeers, R. Gaetanietal.,“Concise [20] J. E. Hesketh, M. H. Vasconcelos, and G. 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VonHaehling, “eTh emerging role of the gut in chronic heart failure,” Current OpinioninClinicalNutrition andMetabolic Care, vol. 11, no. 5, pp. 632–639, 2008. [27] A. Sandek, I. Bjarnason, H.-D. Volk et al., “Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure,” International Journal of Cardiology,vol. 157, no. 1, pp. 80–85, 2012. [28] B. Levine, J. Kalman, L. Mayer, H. M. Fillit, and M. Packer, “Elevated circulating levels of tumor necrosis factor in severe chronic heart failure,” eTh New England Journal of Medicine ,vol. 323, no. 4, pp. 236–241, 1990. [29] A. Sandek,J.Bauditz,A.Swidsinskietal.,“Alteredintestinal function in patients with chronic heart failure,” Journal of the American College of Cardiology,vol.50, no.16, pp.1561–1569, [30] C. Opasich, C. Rapezzi, D. 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Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure

Pasini, Evasio; Aquilani, Roberto; Corsetti, Giovanni; Dioguardi, Francesco S.
BioMed Research International – Jan 1, 2015
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Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 382585, 5 pages http://dx.doi.org/10.1155/2015/382585 Review Article Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure 1 2 3 4 Evasio Pasini, Roberto Aquilani, Giovanni Corsetti, and Francesco S. Dioguardi “S. Maugeri Foundation” IRCCS, Medical Centre, Lumezzane, 25065 Brescia, Italy Department of Biologyand Biotechnology“L. Spallanzani”,UniversityofPavia,27100 Pavia, Italy Division of Human Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25124 Brescia, Italy Department of Internal Medicine, University of Milan, 20100 Milan, Italy Correspondence should be addressed to Giovanni Corsetti; giovanni.corsetti@unibs.it Received 15 May 2015; Accepted 10 September 2015 Academic Editor: Tamer Mohamed Copyright © 2015 Evasio Pasini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic heart failure is a complicated multifactorial disease with wide-spread social-economic consequences. In spite of the recent development of new drugs and therapeutic strategies, CHF-related mortality and morbidity remain high. Recent evidence suggests that changes in organs such as skeletal muscle and gut flora may play an important and independent role in CHF prognosis. This paper illustrates these phenomena, proposing how to identify them and presenting current therapies which treat organs all too oen ft underestimated but which have a fundamental role in worsening CHF. 1. Introduction composition alteration and/or gut microbiota activity could be an important step to improve CHF patient care. This would Chronic heart failure (CHF) is a very common and multi- avoid additional and independent clinical damage and allow factor syndrome. In spite of currently used therapies, it still traditional therapies to work more efficiently. has high mortality and mobility [1]. Malnutrition, in partic- ular with protein metabolism impairment and consequent 2. Malnutrition cachexia, has oeft n been found in CHF patients and correlates closely with mortality [2]. Furthermore, we recently demon- 2.1. A Definition. Malnutrition is a general term that encom- strated that CHF patients have important changes in both gut passes various forms of inadequate nutrition. It is mul- flora and intestinal permeability, which influence systemic tifactorial but is basically caused by the reduced balance inflammation and global metabolism by modifying nutrients between body nutrient intake and needs. Qualitative and absorption and production of molecules fundamental for cell quantitative malnutrition are oeft n present in CHF and life (authors’ unpublished data). These conditions are oeft n protein malnutrition, leading to the disarrangement of both ignored or underestimated by most clinicians, although they visceral and muscular proteins. eTh se conditions have been have been showntoincreasemorbidity,hospitalstay, and extensively studied in CHF [2, 4]. mortality risk independent of the primary cause of CHF. Protein malnutrition can be estimated in patients by mea- This paper illustrates the clinical problems related to suring visceral protein (e.g., serum albumin concentrations) malnutrition (basically, protein malnutrition) and gut flora and muscular wasting (e.g., arm muscle area). Indeed, serum modification in CHF patients. We also look at some possibly albumin level< 3.5 g/dL (without diseases interfering with easily repeatable methods to identify these pathological albumin metabolism, such as liver or renal insufficiency) conditions and to try to care for them. In the wait for and muscular sarcopenia (<5th percentile of normal upper- genetic therapies and stem cells for CHF [3], we believe arm muscle area) are important markers of poor protein that identifying and possibly curing protein malnutrition and nutritional status. This is because they can predict morbidity 2 BioMed Research International and mortality in CHF independent of the primary cause of from alternative metabolic pathways, and muscle AA are the disease [5, 6]. Recently, other simple nutritional assess- used to produce glucose essential to maintain the glucose- ment tools, such as the Geriatric Nutritional Risk Index dependent metabolism of fundamental structures such as the (GNRI), which considers serum albumin and body mass brain and erythrocytes. index (BMI), correlate with lower serum hemoglobin and Moreover, under these conditions, muscle glycogen systemic inflammation (higher C-reactive protein) and have reserves are depleted and free fatty acids (FFA) become the been seen to be useful aids in CHF. This index predicts principal fuel for the muscle. However, FFA use is a limiting functional dependency and mortality in CHF patients even factor for energy production [14]. In fact, accumulation of with a preserved ejection fraction [7]. FFA in the myocytes reduces energy production during exercise with consequent skeletal muscle fatigue [15]. Notably, 2.2. eTh Clinical Problem. Data show that protein visceral insulin also plays an important role in regulating adipose malnutrition impairment in patients with CHF is not always metabolism. Small increases in plasma insulin significantly as severe as muscle wasting. Very oen, ft visceral protein reduce lipolysis in adipose tissue. This insulin increase synthesis is also conserved. Indeed, skeletal muscle wasting reduces the availability of FFA for acetyl-CoA production, (measured by magnetic resonance spectroscopy) was found which is fundamental for maintaining cell energy produc- in 68% of CHF patients, while up to 24% of patients had tion. Consequently, cell energy production via the anaerobic serum albumin levels<3.5 g/dL [3]. This apparent discrep- metabolic pathway is maintained by acetate which is derived ancy can be explained by considering the metabolic role of predominantly from AA breakdown and oxidation. It is clear theamino acids(AA) of striatemuscles.Indeed,wecan that the availability of AA is a key factor in maintaining mammal cell metabolism. say that skeletal muscle is a pivotal organ, which maintains body metabolic performance by the continuous exchange of fuel with the liver. Under malnutrition, starvation, 2.4. Possible New Therapeutic Approaches. In the light of and/or catabolic circulating stimuli, striate muscle protein is thesefindings,wecan saythatthe alteration of protein degradedandAAarereleasedintotheblood.ThereleasedAA metabolism is clinically important. This could be due to are essential for maintaining global protein synthesis (includ- different conditions related to age and/or inflammatory ing albumin) and glucose plasma levels, through hepatic diseases, reduced qualitative/quantitative food intake, and/or gluconeogenesis and cell energetic metabolism. Indeed, AA malabsorption. We believe that combined pharmacological contain carbon, oxygen, hydrogen, and nitrogen. eTh y can and nutritional interventions, such as personalized therapy therefore be metabolized into carbohydrates (such as glucose) based on the specific needs of individual patients, can or directly into lipids in accordance with the thermodynamic maintain cell metabolism hence aiding traditional standard status of the cell. It must be pointed out that lipids cannot therapy in CHF patients. be transformed into carbohydrates by mammals. In addition, Data show that exogenous oral supplementation with a AA are fundamental intermediaries for the tricarboxylic special mixture of individual essential AA tailored for human acid cycle [8]. Clinically interesting, about 16% of patients needs (EAAm) could be a valid therapeutic strategy to use in with muscular wasting progress to cachexia. However, this patients with CHF, in combination with conventional therapy phenomenon is related to a dramatic increase in mortality as to prevent protein malnutrition with protein wasting for the 50% of cachectic patients die within 18 months [9, 10]. following reasons. Firstly, EAAm could resolve malnutrition related to 2.3. Why It Occurs. The genesis of visceral and muscular reducednutrientgut absorption duetoexocrineexhaustion proteins breakdown in CHF has not yet been completely of the pancreas caused by CHF. It is well known that the understood. eTh more accepted hypotheses indicate that pancreas is the major consuming organ of AA. Furthermore, the catabolic effects of inflammatory cytokines (e.g., tumor the pancreas plays a fundamental role in food digestion. How- necrosis factors and interleukins) and neuroendocrine hor- ever, digestion and food absorption need adequate synthesis mones (catecholamines, cortisol, and renin) are responsible and secretion of different enzymes. for this phenomenon [11, 12]. This process uses enormous quantities of AA and energy Indeed, the increase in plasma catabolic molecules in at all meals. In patients with CHF, the exocrine efficiency of patients with CHF has been well documented. Recently, the pancreas is progressively reduced. As we have seen, this impairment of anabolic hormones such as insulin with then causes a vicious circle, lower digestion of proteins, and insulin resistance (IR) has also been found in 58% of CHF lower availability of AA for digestive enzyme synthesis. patients [13]. In muscles, the lack of anabolic stimulation due This condition leads to impaired digestion with a conse- to IR and the increase of catabolic stimuli causes protein quent reduction of plasma patterns of AA which are insuf- degradation and AA release. es Th e AA are used in the liver to ficient to promote protein synthesis. Interestingly, single AA produce glucose by gluconeogenesis. In addition, IR inhibits are not digested. eTh y are rapidly absorbed and immediately mRNA synthesis of phosphoenol pyruvate carboxykinase availableinthe bloodfor proteinsynthesis [16]. (the key enzyme of the gluconeogenesis pathway) in the liver. Secondly, EAAm are positive signals for maintaining This contributes to reducing gluconeogenesis further via muscle protein stores and so reducing IR. Indeed, AA inhibit pyruvate originating from lactate. us, Th a vicious circle is changes to glucose transport as well as gluconeogenesis generated, where malnutrition does not supply exogenous mediated by IR. In addition, at high physiological concen- nutrients, the liver produces low quantities of carbohydrate trations, AA activate various important phases of protein BioMed Research International 3 synthesis [17, 18]. Data show that AA are signals for the present in the majority of CHF patients. Indeed, we found secretion of IGF-1 and -2 (insulin-like growth factor-1 and - the massive presence of Candida, Campylobacter, Shigella, 2) [19]. IGF-1 is the somatomedin responsible for the main Salmonella,and Yersinia in the stools of CHF patients. eTh activation of growth hormone (GH), an anabolic hormone massive presence of this pathogenic contaminating flora had which promotes protein synthesis and counteracts IR. important pathophysiological eeff cts on patients with CHF, Thirdly,EAAmmodulatethe eeff cts of insulinonadipo- because they significantly correlate with systemic inflamma- cytes enhancing glucose-induced desensitization of insulin- tion and intestinal functions including permeability (authors’ stimulated glucose transport and regulate the synthesis of unpublished data). FFA [20]. In particular this eect ff is mediated by glutamine. Finally, it has recently been demonstrated that EAAm, 3.2. eTh Consequence. Research shows that there are molec- including essential and branched ones as well as lysine, ular reasons for the link between dysbiosis and systemic can maintain protein synthesis, support energy needs, and catabolism. Indeed, pathogens produce lipopolysaccharide stimulate mitochondrial biogenesis [21]. es Th e eeff cts are due (LPS) and other fungal or bacterial toxins which cause locally to the capability of AA to activate AMP-activated protein produced cytokines with consequent intestinal epithelial kinase mammalian target of rapamycin (mTOR) and nitric inflammation, which increases gut membrane permeability. oxide synthase (NOS). es Th e are important enzymes which This intestinal endothelial dysfunction allows the translo- stimulate cell life and development (including stem and cation of fungal or bacterial toxins from the gut to the endothelial cells), regulating energy production/use, protein circulating blood. In turn, this increases both circulation synthesis, cell proliferation, antiapoptotic processes, and inflammatory molecules such as TNF-alfa and LPS. es Th e mitochondrial biogenesis [22, 23]. stimulate inflammatory cells to produce catabolic molecules In addition to EAAm, other molecules have been inves- capable of causing muscular wasting, sarcopenia, and finally tigated and are presently under investigation, as nutritional cachexia [28–30]. support for CHF patients in order to understand their role in Recently, researchers have identified the enzymatic activ- avoiding protein disarrangement. A recent multicenter phase ities of protein effectors injected into host cells by pathogens III clinical trial demonstrated that Amalirin (orally active such as Shigella, Salmonella,and Yersinia.Thisoccursthrough ghrelin receptor antagonist) can reverse muscle wasting in their type III secretion system, which modulates host innate cancer cachexia and has been proposed as a therapeutic agent immune responses. Specifically, bacterial acetyl-transferase for all stage of cachexia. The protein’s anabolism can also modifies AA residues of cellular MAPK and I-KK-beta be modulated by stimulation of selective androgen receptor modulating inflammatory cell response and activating intra- modulators (SARMs) in humans and by activating type II cellular apoptosis [31]. The consequent state of chronic receptor of Myostatin in both animal models and humans. inflammation has been well documented in CHF patients Another animal study showed that the anabolic/catabolic and it is thought to be responsible for functional organs transforming agent MT-102 reverses muscle wasting in rats dysfunction and clinical deterioration [28]. [24]. The anatomical and functional alteration of the ente- rocytes induced by contaminating flora also influences the 3. Gut Flora Dysbiosis intestinal nutrient absorption and gastrointestinal mobility causing malnutrition. This aspect is particularly important in eTh mammalian gastrointestinal tract contains about 100 CHF patients because it is well known that malnutrition, with trillion microorganisms called gut flora or microbiota. This consequent muscular wasting and cachexia, is very common. is ten times greater than the total number of human cells Various hypotheses can be formulated to explain the massive in the body. For this reason, it is also called “the forgotten presence of contaminating pathological microorganisms in organ.” Microbiota benefits the host by exerting many the gut flora. eTh more accredited hypotheses consider local crucial functions for host life. Indeed, microbiota regulates ischemia and indiscriminate antibiotic use as responsible the guts’ barrier function and motion, inu fl ences nutrient of pathogens overgrowth. Local ischemia is due to CHF- absorption, produces important metabolic intermediaries, mediated distribution of blood flow which underperfuses including vitamins, and modulates local and systemic gut endothelium. Ischemia causes intramucosal acidosis, inflammation through innate immunity. Consequently, gut hypercapnia, and oxygen-free radical production. Moreover, microbiota influences the metabolism of tissues outside the CHF patients have neuroendocrine activation with nore- intestine. u Th s, alterations of the composition and/or activity pinephrine increase. es Th e conditions are all known to be of microbiota, known as dysbiosis, as well as intestinal activators of bacterial virulence and can also influence patho- functions, influence the evolution of diseases independent logical bacteria overgrowth (authors’ unpublished data). The of the original cause of the disease. Recently, gut microbiota overuse of antibiotics in the food chain may contribute to dysbiosis has been proposed as an environmental factor selecting antibiotic resistant pathogens, which then colonizes capable of causing a catabolic state with consequent muscle the intestine. wasting [25–27]. 4. Therapies 3.1. The Evidence. Recently, we demonstrated that CHF patients had signicfi ant qualitative and quantitative impair- Currently, there are no specific therapies to cure microbiota ment of gut flora. Particularly, pathological species were dysbiosis available. However, encouraging data suggest that 4 BioMed Research International gut dysbiosis can be modified by several means such as nutri- [6] M. Liu, C.-P. Chan, B. P. Yan et al., “Albumin levels predict survival in patients with heart failure and preserved ejection tional supplementation with specific nutrients (prebiotics) fraction,” European Journal of Heart Failure,vol.14, no.1,pp. and/or live bacteria (probiotics) and/or local therapies with 39–44, 2012. fecal microbiota transplant or colon hydrotherapy [32]. [7] Y. Kinugasa, M. Kato, S. 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