Micronutrients as therapy in critical illness.

PURPOSE OF REVIEW: Recent large-scale randomized controlled trials (RCTs) challenged current beliefs about the potential role of micronutrients to attenuate the inflammatory response and improve clinical outcomes of critically ill patients. The purpose of this narrative review is to provide an overview and critical discussion about most recent clinical trials, which evaluated the clinical significance of a vitamin C, vitamin D, or selenium administration in critically ill patients. RECENT FINDINGS: None of the most recent large-scale RCTs could demonstrate any clinical benefits for a micronutrient administration in ICU patients, whereas a recent RCT indicated harmful effects, if high dose vitamin C was administered in septic patients. Following meta-analyses could not confirm harmful effects for high dose vitamin C in general critically ill patients and indicated benefits in the subgroup of general ICU patients with higher mortality risk. For vitamin D, the most recent large-scale RCT could not demonstrate clinical benefits for critically ill patients, whereas another large-scale RCT is still ongoing. The aggregated and meta-analyzed evidence highlighted a potential role for intravenous vitamin D administration, which encourages further research. In high-risk cardiac surgery patients, a perioperative application of high-dose selenium was unable to improve patients' outcome. The observed increase of selenium levels in the patients' blood did not translate into an increase of antioxidative or anti-inflammatory enzymes, which illuminates the urgent need for more research to identify potential confounding factors. SUMMARY: Current data received from most recent large-scale RCTs could not demonstrate clinically meaningful effects of an intervention with either vitamin C, vitamin D, or selenium in critically ill patients. More attention is needed to carefully identify potential confounding factors and to better evaluate the role of timing, duration, and combined strategies.

[Guidelines for clinical application of micronutrients in Chinese adult patients (2024 edition)].

Micronutrients, including trace elements and vitamins, are essential nutrients in human metabolism. The majority of patients who need nutritional therapy have different levels of micronutrient deficiency for various reasons, which can lead to disease progression and affect clinical outcomes. In order to further standardize the application of micronutrients in medical nutrition therapy, nearly 100 experts in related fields were organized by the Chinese Society of Parenteral and Enteral Nutrition (CSPEN) to elaborate on the role and dosage of micronutrients based on the existing evidence-based medical evidence in common clinical conditions such as severe illness, surgery, burns, inflammatory bowel disease, short bowel disease, malignant tumors, chronic liver and kidney disease, elderly comorbidity, weight loss and chronic infection. Finally, 13 questions and 30 recommendations were put forward to provide reference for clinical standard application of parenteral and enteral nutrition in adult patients.

The Effect of Micronutrients on Obese Phenotype of Adult Mice Is Dependent on the Experimental Environment.

The environment of the test laboratory affects the reproducibility of treatment effects on physiological phenotypes of rodents and may be attributed to the plasticity of the epigenome due to nutrient-gene-environment interactions. Here, we explored the reproducibility of adding a multi-vitamin-mineral (MVM) mix to a nutrient-balanced high-fat (HF) diet on obesity, insulin resistance (IR), and gene expression in the tissues of adult male mice. Experiments of the same design were conducted in three independent animal facilities. Adult C57BL/6J male mice were fed an HF diet for 6 weeks (diet induced-obesity model) and then continued for 9-12 weeks on the HF diet with or without 5-fold additions of vitamins A, B1, B6, B12, Zn, and 2-fold Se. The addition of the MVM affected body weight, fat mass, gene expression, and markers of IR in all three locations (p < 0.05). However, the direction of the main effects was influenced by the interaction with the experimental location and its associated environmental conditions known to affect the epigenome. In conclusion, MVM supplementation influenced phenotypes and expression of genes related to adipose function in obese adult male mice, but the experimental location and its associated conditions were significant interacting factors. Preclinical studies investigating the relationship between diet and metabolic outcomes should acknowledge the plasticity of the epigenome and implement measures to reproduce studies in different locations.

Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease.

Alzheimer's disease (AD) is a major global health problem today and is the most common form of dementia. AD is characterized by the formation of ß-amyloid (Aß) plaques and neurofibrillary clusters, leading to decreased brain acetylcholine levels in the brain. Another mechanism underlying the pathogenesis of AD is the abnormal phosphorylation of tau protein that accumulates at the level of neurofibrillary aggregates, and the areas most affected by this pathological process are usually the cholinergic neurons in cortical, subcortical, and hippocampal areas. These effects result in decreased cognitive function, brain atrophy, and neuronal death. Malnutrition and weight loss are the most frequent manifestations of AD, and these are also associated with greater cognitive decline. Several studies have confirmed that a balanced low-calorie diet and proper nutritional intake may be considered important factors in counteracting or slowing the progression of AD, whereas a high-fat or hypercholesterolemic diet predisposes to an increased risk of developing AD. Especially, fruits, vegetables, antioxidants, vitamins, polyunsaturated fatty acids, and micronutrients supplementation exert positive effects on aging-related changes in the brain due to their antioxidant, anti-inflammatory, and radical scavenging properties. The purpose of this review is to summarize some possible nutritional factors that may contribute to the progression or prevention of AD, understand the role that nutrition plays in the formation of Aß plaques typical of this neurodegenerative disease, to identify some potential therapeutic strategies that may involve some natural compounds, in delaying the progression of the disease.

The effect of macronutrient and micronutrient supplements on COVID-19: an umbrella review.

BACKGROUND AND AIMS: A healthy diet play an important role in the prevention and even treatment of various diseases. Proper nutrition plays an important role in boosting of immune system. These include the consumption of macronutrients such as proteins, lipids, carbohydrates, and also micronutrients including vitamins. Here, we aimed to systematically review the effects of macronutrients and micronutrients on the prevention and treatment of COVID-19. METHODS: We searched the databases of PubMed, Scopus, Embase, and Web of Science on December 23, 2023. The records were downloaded into an EndNote file, the duplicates were removed, and the studies underwent a two-phase screening process based on their title/abstracts and full texts. The included articles were screened and underwent inclusion and exclusion criteria. We included the English systematic reviews and meta-analyses that concurred with the aim of our study. The selected articles were assessed by Cochrane's Risk of Bias in Systematic Reviews for the quality check. The data of the eligible studies were extracted in a pre-designed word table and were used for the qualitative synthesis. RESULTS: A total of 28 reviews were included in this study. Most studies have shown that micronutrients are effective in morbidity and mortality controlling in viral respiratory infections such as COVID-19 but some studies have shown that micronutrients are sometimes not effective in controlling severity. On the other hand, calcifediol was by far the most successful agent in reducing intensive care needs and mortality between studies. CONCLUSION: Individuals without malnutrition had a reduced risk of SARS-CoV-2 infection and severe disease. The administration of Vitamin D is effective in reducing the morbidity and mortality of COVID-19 patients. Patients with vitamin D deficiency were more prone to experience severe infection, and they were at higher risk of morbidities and mortality. Other micronutrients such as Vitamin A, Vitamin B, and Zinc also showed some benefits in patients with COVID-19. Vitamin C showed no efficacy in COVID-19 management even in intravenous form or in high doses.

Nutrition in chronic inflammatory conditions: Bypassing the mucosal block for micronutrients.

Nutritional Immunity is one of the most ancient innate immune responses, during which the body can restrict nutrients availability to pathogens and restricts their uptake by the gut mucosa (mucosal block). Though this can be a beneficial strategy during infection, it also is associated with non-communicable diseases-where the pathogen is missing; leading to increased morbidity and mortality as micronutritional uptake and distribution in the body is hindered. Here, we discuss the acute immune response in respect to nutrients, the opposing nutritional demands of regulatory and inflammatory cells and particularly focus on some nutrients linked with inflammation such as iron, vitamins A, Bs, C, and other antioxidants. We propose that while the absorption of certain micronutrients is hindered during inflammation, the dietary lymph path remains available. As such, several clinical trials investigated the role of the lymphatic system during protein absorption, following a ketogenic diet and an increased intake of antioxidants, vitamins, and minerals, in reducing inflammation and ameliorating disease.

Parenteral support and micronutrient deficiencies in children with short bowel syndrome: A comprehensive retrospective study.

BACKGROUND & AIMS: Short bowel syndrome (SBS) is the leading cause of chronic intestinal failure. The duration of parenteral support (PS) and the long-term micronutrient needs in children with SBS vary, based on their clinical and anatomical characteristics. Our study aimed to review the clinical course and identify high risk patient groups for prolonged PS and long-term micronutrient supplementation. METHODS: A retrospective review was conducted on electronic medical records of children with SBS and chronic intestinal failure who were enrolled in the multidisciplinary intestinal rehabilitation program at Manchester Children's Hospital, UK. Children were included in the review if they required PN for more than 60 days out of 74 consecutive days and had at least 3 years of follow-up. Statistical analysis was performed using IBM SPSS Statistics 24.0. RESULTS: 40 children with SBS achieved enteral autonomy (EA) and 14 remained dependent on PS after 36 months of follow up. Necrotizing enterocolitis was the most common cause for intestinal resection (38.9%) followed by gastroschisis (22.2%), malrotation with volvulus (20.4%), segmental volvulus (9.3%) and long segment Hirschsprung disease (1.9%). Those who achieved EA had significantly longer intestinal length 27.5% (15.0-39.3) than those who remained on PS 6.0% (1.5-12.5) (p < 0.001). Type I SBS was only found in the PS cohort. Median PN dependence was 10.82 months [IQR 5.73-20.78]. Congenital diagnosis was associated with longer PN dependence (21.0 ± 20.0) than acquired (8.7 ± 7.8 months), (p = 0.02). The need for micronutrient supplementation was assessed after the transition to EA; 87.5% children had at least one micronutrient depletion, most commonly Vitamin D (64.1%), followed by iron (48.7%), Vitamin B12 (34.2%), and vitamin E (28.6%). Iron deficiency and vitamin A depletion were correlated with longer PS after multivariate analysis (OR: 1.103, 1.006-1.210, p = 0.037 and OR: 1.048, 0.998-1.102, p = 0.062 respectively). CONCLUSION: In our cohort, small bowel length was the main predictor for EA. Children on longer PS, had more often a congenital cause of resection and were at risk for micronutrient deficiencies in EA.

Micronutrient Deficiency in Inherited Metabolic Disorders Requiring Diet Regimen: A Brief Critical Review.

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.

Review of intervention products for use in the prevention and control of anemia.

Anemia remains a major public health problem, especially in low- and middle-income countries. The World Health Organization recommends several interventions to prevent and manage anemia in vulnerable population groups, including young children, menstruating adolescent girls and women, and pregnant and postpartum women. Daily iron supplementation reduces the risk of anemia in infants, children, and pregnant women, and intermittent iron supplementation reduces anemia risk in menstruating girls and women. Micronutrient powders reduce the risk of anemia in children. Fortifying wheat flour with iron reduces the risk of anemia in the overall population, whereas the effect of fortifying maize flour and rice is still uncertain. Regarding non-nutrition-related interventions, malaria treatment and deworming have been reported to decrease anemia prevalence. Promising interventions to prevent anemia include vitamin A supplementation, multiple micronutrient supplementation for pregnant women, small-quantity lipid-based supplements, and fortification of salt with iodine and iron. Future research could address the efficacy and safety of different iron supplementation formulations, identify the most bioavailable form of iron for fortification, examine adherence to supplementation regimens and fortification standards, and investigate the effectiveness of integrating micronutrient, helminth, and malaria control programs.

Dr. Johnstone et al. Reply to Dr. Elmrayed.

We thank Dr. Elmrayed and colleagues1 for highlighting clinical cautions in using broad-spectrum micronutrients to treat attention-deficit/hyperactivity disorder (ADHD) in children, in particular manganese (Mn) levels. We appreciate the opportunity to provide additional information and rationale for the vitamin and mineral doses contained in the studied formula.

Micronutrient intake to protect against osteoporosis during and after critical illness.

PURPOSE OF REVIEW: Improved survival from critical illness has enhanced the focus on ways to augment functional outcomes following discharge from the Intensive Care Unit. An area that is gaining increased attention is the effect of critical illness on bone health and fragility fractures following the episode. This review discusses the micronutrients that may play a role in bone metabolism and the potential benefits of their supplementation to prevent osteoporosis. These include calcium, phosphorous, magnesium, vitamin D, vitamin C, vitamin K, and certain trace elements. FINDINGS: Although there is sound physiological basis for the involvement of these micronutrients in bone health and fracture prevention, there are few clinically relevant publications in this area with calcium and vitamin D being the best studied to date. SUMMARY: In the absence of high-quality evidence in critically ill populations, attention to measurement and supplementation of these micronutrients as per current guidelines outlining micronutrient requirements in enteral and parenteral nutrition might mitigate bone loss and its sequelae in the recovery phase from critical illness.

Recovery from (treatment-resistant) depression after lifestyle changes and micronutrient precision supplementation: a preliminary field study in patients.

BACKGROUND AND PURPOSE: The incidence of depression is increasing, despite continued advances in psychological and pharmacological interventions. New treatment approaches are urgently needed. Here we assess the effects on depression of individualized micronutrient supplementation, in concert with a standard set of lifestyle changes. METHODS: We conducted a small field-study with 17 participants in Austria. Patients with depression (n = 11) and healthy volunteers (n = 6) underwent laboratory serum analysis and filled out the DASS-21 and a questionnaire about their medical history and condition. The list of parameters to be tested in the serum analysis was derived from an expert heuristic compilation of factors known to influence depression, narrowed down to a workable list to be tested in this initial study. On the basis of the results, the participants (n = 17) received individualized recommendations for micronutrient supplementation, in collaboration with their treating physician. Participants followed the individual supplementation regime for two months, along with a standard set of lifestyle changes. After two months the laboratory serum analyses, the DASS-21, and the questionnaire were repeated. RESULTS: All patients with micronutrient deficiencies were in the patient group; none of the healthy volunteers showed any micronutrient deficiencies. After two months of precision supplementation and lifestyle changes, all but one patient had recovered from their depression or had considerably improved. The one patient who didn't recover was the only one with a known trigger of their depression (trauma). Of 11 patients with depression, the trigger was unknown for the other ten. CONCLUSIONS: These results have promising implications for further research, treatment, drug development, and public health. We propose that systematic screening of patients with symptoms of depression be developed for future research, medical care, and practice. Psychiatry and psychotherapy may see improved results once they no longer have to push against the underlying constraints of existing micronutrient deficiencies.

Glycine: The Smallest Anti-Inflammatory Micronutrient.

Glycine is a non-essential amino acid with many functions and effects. Glycine can bind to specific receptors and transporters that are expressed in many types of cells throughout an organism to exert its effects. There have been many studies focused on the anti-inflammatory effects of glycine, including its abilities to decrease pro-inflammatory cytokines and the concentration of free fatty acids, to improve the insulin response, and to mediate other changes. However, the mechanism through which glycine acts is not clear. In this review, we emphasize that glycine exerts its anti-inflammatory effects throughout the modulation of the expression of nuclear factor kappa B (NF-κB) in many cells. Although glycine is a non-essential amino acid, we highlight how dietary glycine supplementation is important in avoiding the development of chronic inflammation.

Efficacy and safety of a vitamin-mineral intervention for symptoms of anxiety and depression in adults: A randomised placebo-controlled trial "NoMAD".

BACKGROUND: Anxiety and depression are increasingly burdening society. We investigated whether micronutrients (vitamins and minerals), improve anxiety and depression symptoms in an adult community setting. METHODS: Participants (n = 150) describing functionally-impairing symptoms of anxiety/depression randomly received micronutrients or placebo for 10 weeks. Primary outcome measures were Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder Scale-7 (GAD-7), and Clinical Global Impression-Improvement scale (CGII). They were monitored online with regular phone contact with a clinical psychologist. RESULTS: Linear mixed-effects modelling showed significant improvements in both groups, with the micronutrient group improving significantly more quickly on both the PHQ-9 (t = -2.17, p = 0.03) and the GAD-7 (t = -2.23, p = 0.03). Subsequent models with covariates showed that participant characteristics moderated time-by-group interactions; micronutrients provided fastest improvement relative to placebo for younger participants, those from lower socioeconomic groups and those who had previously tried psychiatric medication. On the CGII, there were no group differences at end-point ((F1,148) = 1.36, p = 0.25, d = 0.19, 95 % CI [-0.13 to 0.51]), with 49 % of the micronutrient and 44 % of the placebo groups being identified responders. Participants on micronutrients had significantly increased bowel motions compared with placebo. There was no increased suicidal ideation, no serious adverse events and the blind was adequately maintained. Drop out was low at 8.7 %. LIMITATIONS: The improvement under placebo and lack of formal diagnoses limit generalizability. CONCLUSIONS: Despite limited clinician contact, all participants improved significantly, though improvements were faster with micronutrients. Participants in some subgroups demonstrated a lower response to placebo, identifying where micronutrients may offer greatest potential as an intervention.

An update on essential micronutrients in critical illness.

PURPOSE OF REVIEW: Numerous micronutrients are involved in antioxidant and immune defence, while their blood concentrations are frequently low in critically ill patients: this has fuelled many supplementation trials. Numerous observational, randomized studies have been published, which are presented herein. RECENT FINDINGS: Micronutrient concentrations must be analysed considering the context of the inflammatory response in critical illness. Low levels do not always indicate a deficiency without objective micronutrients losses with biological fluids. Nevertheless, higher needs and deficiencies are frequent for some micronutrients, such as thiamine, vitamins C and D, selenium, zinc and iron, and have been acknowledged with identifying patients at risk, such as those requiring continuous renal replacement therapy (CRRT). The most important trials and progress in understanding have occurred with vitamin D (25(OH)D), iron and carnitine. Vitamin D blood levels less than 12 ng/ml are associated with poor clinical outcomes: supplementation in deficient ICU patients generates favourable metabolic changes and decreases mortality. Single high-dose 25(OH)D should not be delivered anymore, as boluses induce a negative feedback mechanism causing inhibition of this vitamin. Iron-deficient anaemia is frequent and can be treated safely with high-dose intravenous iron under the guidance of hepcidin to confirm deficiency diagnosis. SUMMARY: The needs in critical illness are higher than those of healthy individuals and must be covered to support immunity. Monitoring selected micronutrients is justified in patients requiring more prolonged ICU therapy. Actual results point towards combinations of essential micronutrients at doses below upper tolerable levels. Finally, the time of high-dose micronutrient monotherapy is probably over.

Adjunctive therapeutic effects of micronutrient supplementation in inflammatory bowel disease.

Growing evidence suggests that micronutrient status may have some impact on the course of inflammatory bowel disease (IBD). However, micronutrient deficiencies are easily overlooked during the treatment of IBD patients. There have been many studies on micronutrient supplementation, in which several clinical trials have been conducted targeting vitamin D and iron, but the current research is still preliminary for other vitamins and minerals. This review provides an overview of the adjunctive therapeutic effects of micronutrient supplementation in IBD, to summarize the available evidence, draw the attention of clinicians to micronutrient monitoring and supplementation in patients with IBD, and also provide some perspectives for future research directions.

Macronutrient and micronutrient requirements and therapeutic effects in critically ill patients with SARS-CoV-2: A narrative review.

BACKGROUND: COVID-19 can lead to critical illness and induce hypermetabolism, protein catabolism, and inflammation. These pathological processes may alter energy and protein requirements, and certain micronutrients may attenuate the associated detriments. This narrative review summarizes the macronutrient and micronutrient requirements and therapeutic effects in critically ill patients with SARS-CoV-2. METHODS: We searched four databases for randomized controlled trials (RCTs) and studies that measured macronutrient and micronutrient requirements, published from February 2020 to September 2022. RESULTS: Ten articles reported on energy and protein requirements, and five articles reported the therapeutic effects of ω-3 (n = 1), group B vitamins (n = 1), and vitamin C (n = 3). Patients' resting energy expenditure gradually increased with time, measuring approximately 20 kcal/kg body weight (BW), 25 kcal/kg BW, and 30 kcal/kg BW for the first, second, and third week onwards, respectively. Patients remained in negative nitrogen balances in the first week, and a protein intake of ≥1.5 g/kg BW may be necessary to achieve nitrogen equilibrium. Preliminary evidence suggests that ω-3 fatty acids may protect against renal and respiratory impairments. The therapeutic effects of group B vitamins and vitamin C cannot be ascertained, although intravenous vitamin C appears promising in reducing mortality and inflammation. CONCLUSION: There are no RCTs to guide the optimal dose of energy and protein in critically ill patients with SARS-CoV-2. Additional larger-scale, well-designed RCTs are needed to elucidate the therapeutic effects of ω-3, group B vitamins, and vitamin C.

Role of Antioxidant Vitamins and Other Micronutrients on Regulations of Specific Genes and Signaling Pathways in the Prevention and Treatment of Cancer.

Cancer is an escalating global issue, with 19.3 million new cases and 9.9 million deaths in 2020. Therefore, effective approaches to prevent cancer are urgently required. Diet plays a significant role in determining cancer risk. Nutrients and food bioactives influence specific signaling pathways in the body. Recently, there have been significant advances in cancer prevention research through nutrigenomics or with the effects of dietary components on the genome. Google Scholar, PubMed, and Scopus databases were used to search for peer-reviewed articles between 2017 and 2023. Criteria used were vitamins, minerals, tumors, cancer, genes, inflammation, signaling pathways, and nutrigenomics. Among the total of 1857 articles available, the highest relevant 90 articles that specifically discussed signaling pathways and genes on cancer cell lines and human cancer patients were selected and reviewed. Food sources are rich in antioxidant micronutrients, which are effective in activating or regulating signaling pathways involved in pathogenesis and cancer therapy by activating enzymes such as mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and phosphatidylinositol 3-kinase (PI3K). The micronutrients are involved in the regulation of ß-catenin (WNT/ß-catenin) including mutations in Kras and epidermal growth factor receptor (EGFR) alongside inhibition of the NF-kB pathway. The most common mechanism of cancer prevention by these micronutrients is their antioxidative, anti-inflammation, and anti-apoptosis effects. This review discusses how nutrigenomics is essential and beneficial for developing cancer prevention and treatment approaches.

Effectiveness of Nutritional Therapies in Male Factor Infertility Treatment: A Systematic Review and Network Meta-analysis.

BACKGROUND: Nutritional therapies are effective alternative treatments for male infertility or subfertility. These are cost-effective and easily implementable, unlike other advanced invasive treatments. Even moderate improvements in sperm quality could improve spontaneous pregnancy. OBJECTIVE: We aimed to compare the effectiveness of all nutritional therapies in male infertility/subfertility treatment and ranked their efficacy based on type and etiology. We intend to aid clinicians with an evidence-based approach to affordable and safer initial infertility treatment for those who mainly do not wish to have other advanced invasive treatments or could not afford or have access to them. METHODS: We included 69 studies with 94 individual study arms identified from bibliographic databases and registries. We included studies in adult men with proven infertility or subfertility that investigated nutritional or dietary supplement therapies compared with control or placebo and at least reported on a sperm parameter. We undertook a network meta-analysis and performed a pairwise meta-analysis on all sperm parameter outcomes and meta-regression. No language or date restriction was imposed. A systematic article search was concluded on August 29, 2022. RESULTS: Our network meta-analysis is the first to compare all dietary interventions in a single analysis, sub-grouped by intervention type and type of infertility. L-Carnitine with micronutrients, antioxidants, and several traditional herbal supplements showed statistically and clinically significant improvement in sperm quality. Meta-regression identified that improvement in the sperm count, motility and morphology translated into increased pregnancy rates (p < 0.001; p < 0.001; p < 0.002, respectively). In particular, L-carnitine with micronutrient therapy (risk ratio [RR]: 3.60, 95% CI 1.86, 6.98, p = 0.0002), followed by zinc (RR 5.39, 95% CI 1.26, 23.04, p = 0.02), significantly improved pregnancy rates. Men with oligozoospermia (RR 4.89), followed by oligoasthenozoospermia (RR 4.20) and asthenoteratozoospermia (RR 3.53), showed a significant increase in pregnancy rates. CONCLUSION: We ranked nutritional therapies for their ability to improve sperm quality in men with infertility. Nutritional therapies, particularly L-carnitine alone or combined with micronutrients, significantly improved sperm parameters and pregnancy rates even under severe conditions. We believe these affordable solutions may be valuable for people without access to or who do not wish to undergo more invasive and costly fertility treatments.