7. Popular Restrictive Dietary Patterns with Insufficient Evidence in IBD
7.1. Ketogenic Diet
A ketogenic diet (KD) is characterised by severe carbohydrate restriction and sufficient fat intake to induce nutritional ketosis. Its composition varies considerably; some versions rely heavily on meat, dairy fat, coconut oil, and processed low-carbohydrate products, whereas others use olive oil, nuts, seeds, avocado, fish, and low-carbohydrate vegetables. A KD should therefore not be automatically equated with a carnivore diet or high saturated fat intake.
Ketone bodies can modulate cellular metabolism and selected inflammatory pathways, creating a theoretical rationale for benefit. Conversely, severe carbohydrate restriction may reduce fibre, resistant starch, fruits, legumes, and whole grains, potentially lowering microbial substrate diversity. The net effect likely depends on food quality, fat composition, duration, and the baseline microbiome. The available reviews of ketogenic diets are insufficient to establish their safety or efficacy in IBD [76].
Direct human evidence for the KD in IBD remains inadequate. Associations between the overall inflammatory potential of habitual diet and either disease activity [21] or incident IBD [77] do not test a ketogenic intervention, and mechanistic studies of long-chain fatty acids cannot be generalised to every ketogenic formulation [63,78]. Potential concerns include reduced fibre and micronutrient intake, hyperlipidaemia, constipation, loss of dietary diversity, and difficulty maintaining adequate energy intake during active disease [76,78]. Accordingly, a KD cannot currently be recommended as routine anti-inflammatory therapy for IBD; future trials would need to define diet composition precisely and distinguish well-formulated ketogenic diets from high-saturated-fat or carnivore patterns.
7.2. Intentional Carnivore Diet
The intentional carnivore diet consists almost exclusively of meat, eggs, animal fats, and sometimes dairy products, with near-complete exclusion of plant foods. This should be distinguished from a predominantly animal-based diet resulting from restricting or eliminating plant foods such as vegetables, fruits, legumes, or other foods perceived to worsen gastrointestinal symptoms. In such cases, dietary restriction may be driven by symptom management rather than by the intentional adoption of a carnivore diet. It differs conceptually from a high-meat dietary pattern identified through epidemiological analysis. This dietary pattern provides virtually no dietary fibre. It eliminates most plant-derived polyphenols, while potentially providing high amounts of saturated fat, haem iron and processed meat depending on food choices. These features raise concerns about microbial diversity, bowel function, cardiometabolic risk, and micronutrient adequacy [19,79].
Animal-protein-rich diets have been associated with microbial profiles enriched in taxa and pathways linked to endotoxin production, and an animal-protein-rich diet exacerbated experimental colitis compared with a plant-protein-rich diet [25,80]. These observations support caution but do not constitute direct evidence that an intentional carnivore diet worsens IBD in humans. Conversely, a case series of 10 self-selected patients reported improved IBD-related quality of life while following a carnivore-ketogenic diet [81]. The absence of a control group, reliance on self-report, heterogeneous disease status, and lack of systematic endoscopic assessment make the results highly uncertain.
The available evidence is insufficient to classify the intentional carnivore diet as either a proven pro-inflammatory exposure or an effective treatment. Its extreme restriction, absence of prospective controlled efficacy data, and uncertain long-term nutritional and cardiometabolic safety argue against routine use. Clinicians should address patient interest non-judgementally, emphasising nutritional assessment, objective disease monitoring, and the risk of substituting an unproven dietary approach for effective medical therapy.
Ketogenic and carnivore diets may also have adverse effects on the lipid profile, particularly when these diets are high in saturated fat. This may be clinically relevant in patients receiving corticosteroids, which can independently contribute to adverse metabolic and cardiovascular risk profiles.
The reasons patients choose ketogenic or carnivore diets are likely multifactorial. Some patients encounter claims in non-scientific or non-professional sources suggesting that these diets have anti-inflammatory effects. Others may experience subjective symptom improvement after reducing fermentable or fibre-rich foods, although this should not be interpreted as evidence of reduced intestinal inflammation. Interest in restrictive diets may also arise when patients perceive conventional treatment as insufficient and seek alternative approaches

ABSTRACT

Ferroptosis is a programmed cell death characterized by excessive, iron-dependent accumulation of membrane lipid peroxides due to insufficient glutathione-dependent antioxidant defense. It is influenced by the metabolism of amino acids, lipids, and iron, and occurs in conditions of decreased glutathione peroxidase 4 (GPX4) activity. The increased polyunsaturated fatty acid (PUFA) content in membrane phospholipids is associated with cellular hypersusceptibility to ferroptosis. In contrast, incorporation of monounsaturated fatty acids may protect cells against ferroptotic cell death. Cellular sensitivity to ferroptosis is additionally influenced by glutamine catabolism and the xc–system-mediated import of cystine, which modulate glutathione production, and by elevated iron levels, which lead to the buildup of reactive oxygen species (ROS) that attack membrane-localized PUFAs. This review focuses on recent findings of perturbed metabolic processes in cancer that create a high iron demand and an altered lipid composition, thereby predisposing cells to ferroptosis. We analyze the therapeutic potential of pharmacological agents that can selectively trigger ferroptosis in tumor cells.

Abstract
The study of diet and nutrition is often filled with numerous myths and misconceptions. A Google Scholar search of “diets health” yields over 4 million results. This review examines frequently asked questions about diets and dietary habits. These questions include the following: 1) Is a caloric surplus necessary for building skeletal muscle? 2) Is it possible to lose body mass or fat mass without caloric restriction? 3) Is intermittent fasting better than chronic caloric restriction for weight loss? 4) Are there sex differences in the response to fasting? 5) Can diet alone fulfill the macro and micronutrient needs of exercise-trained individuals? 6) Is there an ideal dietary macronutrient ratio? 7) Are most of the benefits of diets in overweight/obese individuals due primarily to the weight loss itself? 8) Do DNA-based diets induce greater fat mass loss? 9) Does eating late at night result in a gain in fat mass? 10) Are there data (i.e. observational, randomized controlled trials, etc.) on the carnivore diet? 11) Is there a diet that is best for healthy aging and longevity? 12) Is there such a thing as “superfoods?” 13) Can one consume adequate protein on a vegan diet? 14) Do high-protein diets harm the kidneys? 15) Does a greater meal frequency lead to greater weight loss? 16) Are carbohydrates more “fattening” than dietary fats? To answer these questions, we conducted an evidence-based scientific evaluation of the literature on these topics regarding the diet category.

Abstract

Polyunsaturated fatty acids (PUFAs) are essential nutrients supporting numerous cellular processes in normal and neoplastic cells, yet PUFA-containing phospholipids predispose cells to ferroptosis. How cancer cells from various lineages or genetic backgrounds proliferate in the presence of PUFA remains poorly understood. Here, by systematically profiling various fatty acids using a barcoded and pooled cancer cell line library, we show that a subset of cell lines is sensitive to PUFA treatment at concentrations comparable to physiological levels. We demonstrate that PUFA treatment alone is sufficient to induce ferroptosis in these cell lines that are also vulnerable to GPX4 inhibition. By correlating patterns of PUFA sensitivity with cancer cell line features including basal mRNA transcript levels, we show that PUFA sensitivity is positively associated with fatty acid binding protein 1 (FABP1) expression. Additionally, by profiling a diverse collection of fatty acids and analogs, we find that ferroptosis in cancer cells can be effectively induced by conjugated linolenic acids, in addition to PUFAs containing 1,4-pentadiene groups. Genome-wide CRISPR modifier screens in the PUFA-sensitive ES2 cells reveal a pro-ferroptosis pathway defined by enzymes that convert PUFAs to membrane-associated phospholipids, and an anti-ferroptosis pathway that segregates PUFAs by delivering them to lipid droplets. Together, we present the first comprehensive data set of PUFA-induced ferroptosis sensitivity in a collection of 554 cell lines from 19 primary lineages and suggest a potential therapeutic avenue to induce tumor cell ferroptosis using dietary metabolites.

Abstract

Ketogenic dietary therapies (KDTs) have been used for a century in drug-resistant epilepsy, and β-hydroxybutyrate (BHB), the major ketone body, is recognized as a signaling metabolite. This review examines how KDTs and BHB modulate mitochondrial function and evaluates evidence supporting these mechanisms. BHB is oxidized through D-β-hydroxybutyrate dehydrogenase 1 and succinyl-CoA:3-oxoacid-CoA transferase and alters redox balance and oxidative phosphorylation. It also inhibits class I histone deacetylases, serves as the substrate for lysine β-hydroxybutyrylation, activates hydroxycarboxylic acid receptor 2, and blocks the NLR family pyrin domain-containing 3 inflammasome. These pathways influence redox defense, organelle quality, and inflammation. However, ketogenic feeding suppresses mitochondrial one-carbon metabolism and some signaling effects occur only at BHB concentrations exceeding those typically achieved through dietary ketosis. Clinical benefits are best established in drug-resistant epilepsy and appear genotype-dependent in primary mitochondrial disease, with potential benefit in mitochondrial DNA (mtDNA) variant carriers but possible harm in DNA polymerase gamma-related disease and mtDNA deletion myopathy. Outside neurology, human evidence includes a hemodynamic response to infused 3-hydroxybutyrate in heart failure, sustained glycemic improvement in non-randomized diabetes cohorts, and small trials in psychiatric and oncological populations. Most clinical studies have not directly measured mitochondrial outcomes. Proposed mitochondrial mechanisms of KDTs and BHB remain plausible but are not established explanations for clinical benefit. Genotype-stratified trials, ketone exposure assessment, and direct measurement of mitochondrial variables in patients are needed.

Abstract

The study of diet and nutrition is often filled with numerous myths and misconceptions. A Google Scholar search of “diets health” yields over 4 million results. This review examines frequently asked questions about diets and dietary habits. These questions include the following: 1) Is a caloric surplus necessary for building skeletal muscle? 2) Is it possible to lose body mass or fat mass without caloric restriction? 3) Is intermittent fasting better than chronic caloric restriction for weight loss? 4) Are there sex differences in the response to fasting? 5) Can diet alone fulfill the macro and micronutrient needs of exercise-trained individuals? 6) Is there an ideal dietary macronutrient ratio? 7) Are most of the benefits of diets in overweight/obese individuals due primarily to the weight loss itself? 8) Do DNA-based diets induce greater fat mass loss? 9) Does eating late at night result in a gain in fat mass? 10) Are there data (i.e. observational, randomized controlled trials, etc.) on the carnivore diet? 11) Is there a diet that is best for healthy aging and longevity? 12) Is there such a thing as “superfoods?” 13) Can one consume adequate protein on a vegan diet? 14) Do high-protein diets harm the kidneys? 15) Does a greater meal frequency lead to greater weight loss? 16) Are carbohydrates more “fattening” than dietary fats? To answer these questions, we conducted an evidence-based scientific evaluation of the literature on these topics regarding the diet category.

Abstract
Ketone bodies are a major source of cerebral energy during fasting and the ketogenic diet, but whether they can sustain brain tissue metabolism when glucose is absent remains uncertain. This question is difficult to resolve in vivo because circulating glucose is maintained, even during starvation, through endogenous production. We therefore used an ex vivo brain preparation to examine the metabolic capacity of tissue following incubation with β-hydroxybutyrate (BHB) as the only exogenous fuel, isolating brain tissue from its primary endogenous glucose sources. Mitochondrial respiration was monitored following 4-hour incubation in glucose-free, BHB-rich artificial cerebrospinal fluid, and tissue resilience was tested by inducing spreading depolarization, a severe energetic challenge that requires rapid restoration of ionic and metabolic homeostasis. Following acute reliance on exogenous BHB, in addition to endogenous energy reserves, mitochondrial electron transfer system function persisted, with lower O2 flux than following incubation with exogenous glucose. BHB-supported tissue maintained sufficient energetic capacity to generate and recover from repeated spreading depolarizations. In contrast, tissue relying solely on endogenous energy reserves failed to undergo repeated spreading depolarizations, suggesting that exogenous BHB provided the needed short-term energetic support beyond that available from endogenous substrates in the complete absence of exogenous glucose. The results broaden our understanding of cerebral fuel flexibility and provide evidence that BHB can support highly energetic neural function in the absence of exogenous glucose.

Announcement post: https://x.com/benbikmanphd/status/2111117683425239429?s=46&t=82xAluz7o0-3UpKQSlT57Q

Abstract

Background & aims

Ketogenic diets are increasingly used for weight management and metabolic health; however, evidence regarding short-term changes in specific plasma trace elements during ketogenic dietary interventions remains limited. Therefore, this study aimed to examine changes in plasma concentrations of iron, zinc, and copper, along with body composition and metabolic parameters, following a four-week ketogenic dietary intervention among healthy adults.

Methods

This single-arm interventional study was carried out at the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan, between October 2021 and December 2023. A total of 46 healthy adults aged between 25 and 45 years were enrolled and placed on an ad libitum ketogenic diet for a duration of four weeks. Adherence to the dietary intervention was evaluated through measurement of blood ketone levels. Anthropometric measurements, dietary energy intake, and fasting blood samples were obtained at baseline and after completion of the intervention. Plasma concentrations of iron, zinc, and copper were analyzed, and statistical comparisons were performed using paired sample t-tests.

Results

A total of 46 participants completed the study, with a mean age of 30.20 ± 5.67 years and a mean BMI of 26.28 ± 2.62 kg/m². Nutritional ketosis was successfully achieved, as demonstrated by blood ketone concentrations exceeding 0.5 mmol/L. Following the four-week intervention, significant reductions were observed in body weight (− 3.9 ± 0.9 kg, p < 0.001), daily energy intake, and fasting blood glucose levels. Plasma zinc concentrations showed a significant increase (p = 0.016), whereas plasma iron levels decreased significantly (p = 0.008). In contrast, no statistically significant change was identified in plasma copper levels.

Conclusion

A four-week ketogenic diet was associated with reductions in body weight, body fat, and muscle mass, as well as changes in plasma concentrations of iron and zinc, while plasma copper concentrations remained unchanged. These findings suggest that short-term ketogenic dietary interventions may be associated with changes in selected plasma trace element concentrations and body composition in healthy adults. Further controlled studies with larger sample sizes and longer follow-up are needed to confirm these findings.

Trial registration

ISRCTN Registry, ISRCTN13729125. Registered on 28 September 2025. Retrospectively registered.

Nisa, Meher Un, Sadia Fatima, Syed Hamid Habib, Syed Rashid Habib, Khawaja Nizamuddin, Saima Shaheen, Miraj Ahmad, and Munaza Khattak. "Effect of a four-week ketogenic diet on plasma iron, zinc, copper, and body composition in healthy adults." BMC Nutrition (2026).

https://link.springer.com/article/10.1186/s40795-026-01500-3

ABSTRACT

Objective

Intermuscular adipose tissue (IMAT) is associated with impaired skeletal muscle (SM) quality and declining mobility in older adults with obesity. This secondary analysis examined the effects of a very low-carbohydrate diet (VLCD) versus a low-fat diet (LFD) on changes in IMAT, muscle strength, and physical function in older adults with obesity.

Methods

Adults (age ≥ 60 years) with obesity were randomized to a weight-maintaining VLCD (< 10% energy from carbohydrates) or LFD (55% energy from carbohydrates) for 8 weeks. Thigh SM and IMAT were measured by MRI. Physical function was assessed via hand grip strength, isometric knee extension, reach score, and six-minute walk tests. Multiple linear regressions examined whether changes in IMAT were associated with changes in physical function outcomes.

Results

The VLCD group showed a significantly greater decrease in IMAT (−24.4% vs. −1.0%, p < 0.01). Across all participants, greater decreases in IMAT were associated with greater improvements in hand grip strength (r² = 0.95, p < 0.01), isometric knee extension (r² = 0.88, p < 0.05), and reach score (r² = 0.75, p < 0.05), after adjusting for changes in thigh SM volume and body weight.

Conclusions

Dietary interventions that reduce IMAT, such as a VLCD, may help preserve physical function and muscle strength in older adults with obesity.

Trial Registration

ClinicalTrials.gov identifier: NCT02760641

Study Importance

• What is already known?
  • ○ Older adults with obesity have greater amounts of intermuscular adipose tissue, which is associated with impaired muscle strength, declining mobility, and greater risk of metabolic dysfunction.
  • ○ We previously reported that following an 8-week diet intervention, older adults with obesity experienced significantly greater loss in IMAT in response to a very low-carbohydrate diet compared to a low-fat diet.
• What does this study add?
  • ○ Participants in the very low-carbohydrate diet group lost more IMAT and showed improvement in muscle function and strength compared to the low-fat diet group.
  • ○ Greater loss of thigh IMAT is significantly correlated with greater improvement in hand grip strength, isometric knee extension strength, and reach score, independent of changes in thigh skeletal muscle volume.
• How might these results change the direction of research or the focus of clinical practice?
  • ○ A low-carbohydrate diet may be a helpful tool to preserve physical function and muscle strength in older adults with obesity.
  • ○ More research with a larger sample size is needed to determine how a VLCD influences IMAT, skeletal muscle, and physical function in older adults with obesity.

Abstract

Purpose

Obesity-associated dysfunction of visceral white adipose tissue (vWAT) is characterized by impaired glucose handling, altered adipokine secretion, and redox imbalance, contributing to metabolic deterioration. Palmitoleic acid (16:1n-7), a monounsaturated fatty acid, has been implicated in regulation of glucose and lipid metabolism in rodent and cellular models; however, its effects on human adipocytes under metabolically compromised conditions remain incompletely understood. Here, we investigated the effects of in vitro treatment with 16:1n-7 on glucose uptake and metabolism, adipokine secretion, and oxidative stress in isolated adipocytes and vWAT obtained from women with obesity and prediabetes.

Methods

vWAT explants were treated in vitro with palmitoleic acid (16:1n-7) or palmitic acid (16:0) at 200 µM for 48 h. Glucose and lipid metabolism, adipokine secretion, and oxidative stress were evaluated.

Results

16:1n-7 increased basal and insulin-stimulated glucose uptake in association with upregulation of GLUT1 and GLUT4 expression and increased AMPKα protein content. In parallel, 16:1n-7 promoted coordinated changes in metabolic gene expression favoring glucose utilization and glyceroneogenesis rather than de novo lipogenesis, without changes in lipolytic activity, accompanied by increased citrate synthase and PPARG expression. Endocrine function was also modulated, as 16:1n-7 reduced resistin secretion without impairing adiponectin levels. Moreover, although lipid peroxidation remained unchanged, 16:1n-7 reduced protein oxidation and reactive oxygen species production, together with increased IDH2 and reduced NOS2 expression, supporting selective attenuation of oxidative stress.

Conclusion

Palmitoleic acid enhances glucose uptake through coordinated regulation of GLUT1 and GLUT4 and contributes to improved metabolic function in human adipocytes and redox homeostasis in vWAT obtained from women with obesity and prediabetes. These findings identify 16:1n-7 as a bioactive lipid that modulates human adipose tissue function under metabolically compromised conditions, underscoring its role in the nutritional regulation of glucose metabolism and redox homeostasis.

Editor’s summary

Regulation of lipid metabolism in mitochondria of adipocytes requires integration of information about time of day from the circadian clock, environmental temperature, and nutrient availability. Karavaeva et al. found an important role for the transporter protein SLC25A34 in such control of lipid metabolism and thermogenesis in brown adipocytes from mice and humans (see the Perspective by van der Laan). Inputs from the circadian clock, cold temperatures, and diet all regulated the expression of SLC25A34, allowing control of lipogenesis and mitochondrial biogenesis, lipid oxidation, and thermogenesis. Such regulation may offer insights into inflammation associated with obesity and metabolic diseases. —L. Bryan Ray

Structured Abstract

INTRODUCTION

Brown and beige thermogenic adipocytes (fat cells) have uniquely high energy expenditure capacity. This activity is critical for defending body temperature in small mammals and is linked to cardiometabolic health in humans. Energy expenditure from thermogenic fat cycles daily on a rhythm set by the circadian clock, rising after waking and dropping during sleep. At any point, however, this activity can be suddenly induced by exposure to cold temperature or by ingestion of a calorie-dense, high-fat meal. How thermogenic fat can seamlessly achieve both rhythmic continuity and acute responsiveness is a fundamental question of energy homeostasis that has remained unknown.

RATIONALE

We set out to understand how diverse cues from the body’s clock, environmental temperature, and diet are molecularly integrated in adipocytes to facilitate both anticipatory and adaptive regulation. By combining unbiased analysis of DNA-binding patterns, gene expression, and protein levels in thermogenic fat from mice that were subject to different circadian, environmental, and dietary perturbations, we identified the orphan mitochondrial metabolite transporter SLC25A34 as the convergence point of all three physiological paradigms.

RESULTS

Similar to fat’s thermogenic activity, the expression of Slc25a34 mRNA exhibited a daily rhythm, which was mediated by the nuclear receptors REV-ERBα and REV-ERBβ. REV-ERBs are transcriptional repressors in the circadian clock that recruit histone deacetylase 3 to the Slc25a34 promoter during sleep to shut off transcription. When animals wake and REV-ERB circadian repression is lifted, the peroxisome proliferator–activated receptors α and γ (PPARα and PPARγ) are able to bind the Slc25a34 promoter and restore expression. However, at any time, when animals are suddenly confronted with an unanticipated need for adipocyte energy expenditure such as exposure to cold temperatures or eating a lipid-rich meal, REV-ERB repression is rapidly overridden and PPARs are activated by lipolytic signals to boost SLC25A34 levels. When the energy demand is met, the REV-ERB–mediated rhythmicity of Slc25a34 is reestablished.

Our biochemical and metabolic data support a functional model in which SLC25A34 transports oxaloacetate into mitochondria. In doing so, SLC25A34 helps to maintain high tricarboxylic acid (TCA) cycle activity, which is required for powering energy expenditure in thermogenic adipocytes. The need for SLC25A34 during times of high energetic demand arises because thermogenic adipocytes not only oxidize fatty acids in the mitochondria but also simultaneously synthesize lipids in the cytosol, a process collectively known as lipid cycling. Lipid synthesis requires continuous production of acetyl–coenzyme A (acetyl-CoA) in the cytosol, and the two major pathways responsible for this acetyl-CoA pool also generate oxaloacetate as a by-product, which then needs to be transported back into the mitochondria. Increased cytosolic acetyl-CoA additionally promotes the transcription of genes linked to mitochondrial respiration. Thus, SLC25A34 supports both sides of this self-reinforcing cycle in which lipids are continually broken down and resynthesized.

CONCLUSION

These findings identify SLC25A34 as a molecular node that integrates circadian, temperature, and dietary cues and reveal how thermogenic fat activity can sustain a daily rhythm while remaining acutely responsive to sudden energy demands. This mechanism may offer a new entry point for therapeutically enhancing energy expenditure in metabolic disease.

Abstract

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator–activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl–coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.