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Carnivore Diet as Regenerative Immunotherapy for Inflammatory Bowel Disease: Literature Review, A Novel Hypothesis and Experimental Design

Submitted:

31 August 2024

Posted:

02 September 2024

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Abstract
The purpose of this paper is to evaluate the possible application of a therapeutic carnivore diet regimen in the treatment of chronic inflammatory bowel disease (IBD). Based on current research and anecdotal reports, we hypothesized that the diet might potentially exhibit both anti-inflammatory and microbiome-modulating properties salutary to the IBD patient population. Our hypothesis demands comprehensive clinical validation. Therefore, in this paper, we review theories on ketogenic and carnivore diets, discussing their immunomodulatory effects and propose an experimental study to test the feasibility, safety, and clinical efficacy of the carnivore diet for IBD treatment.
Keywords: 
carnivore diet
;  
ketogenic diet
;  
inflammatory bowel disease
;  
meat
Subject: 
Medicine and Pharmacology  -   Immunology and Allergy

Introduction

A carnivore diet consists of only animal-based  products: meat, fish, eggs, and animal fats. It has been anecdotally attributed  to a number of health benefits, including improved digestion, weight loss, and  reduced inflammation. Preliminary evidence and personal testimony show that it  may be effective in managing the symptoms of chronic IBDs. It is hypothesized  that the carnivorous diet might have regenerative immunotherapeutic effects  with the potential of inducing the resolution of IBD, having modes of action  shared with, but not being exclusive to, the ketogenic diets. Our goal is to  present best available evidence, formulate a hypothesis and provide an  experimental framework for its clinical validation.
Ketogenic Diet as Regenerative  Immunotherapy
The ketogenic diet (KD) is a high-fat, very  low-carbohydrate diet (VLCKD) that has been shown to induce a metabolic state  similar to that of fasting, which stimulates the synthesis of ketone bodies in  the liver. It has shown clinical efficacy in drug-resistant epilepsy  (Martin-McGill et al., 2020, Sourbron et al., 2020, and Kossoff et al., 2021)  and displays promising potential in the treatment of psychiatric (Needham et  al., 2023) and neurodegenerative diseases (Bohnen et al., 2023); it is now  being studied with respect to metabolic and inflammatory conditions (Toth et  al., 2016). Interestingly, KD regulates the immune response by virtue of  lowered pro-inflammatory cytokine levels, Th1/Th2 balance, and pathways like  the NLRP3 inflammasome (Srivastava et al., 2023). In an interesting manner, KD  promotes the growth of colonic short-chain fatty acid-producing bacteria with  an eventual effect on modulating gene expressions that regulate tissue  inflammation. Of particular importance is this finding in the context of  dysbiosis, which is highly prevalent in IBD patients (Kaur et al., 2021).  Ketone bodies were even able to directly regulate stem cell activity and  control gene expression post-transcriptionally leading to improved intestinal  regenerative capacity (Anderson et al., 2023, Cheng et al., 2019).
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Figure 1. Ketone bodies directly interact with gene expression and post-translational modifications on the level of intestinal stem cells. This strengthens the regenerative capacity of the intestinal wall. Adapted from Cheng et al., 2019. Graphics with kind permission from the MOJO Institute.
Figure 1. Ketone bodies directly interact with gene expression and post-translational modifications on the level of intestinal stem cells. This strengthens the regenerative capacity of the intestinal wall. Adapted from Cheng et al., 2019. Graphics with kind permission from the MOJO Institute.
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Carnivore Diet as a Regenerative Immunotherapy

The carnivore diet has recently gained recognition  as a potential paradigm-shifting therapeutic modality for complex chronic  diseases. Possibly, the effects are mediated by this diet being closest to the  evolutionary origins of our species, as homo sapiens were most likely an apex  predator with a carnivorous diet in higher, rather rigid trophic levels up to  the late pleistocene (Ben-Dor et al., 2021).
The carnivore diet expands on principles of the  VLCKD by excluding all plant-based foods and relying only on animal-derived  nutrients. Advocates claim that it enhances gut health by removing plant toxins  and anti-nutrients such as solanines, saponins, and lectins (Kuang et al.,  2023, Konijeti et al.,2017, Gauree et al., 2017, and Iablokov et al., 2010)
Furthermore, increased micronutrient availability  in the carnivore diet due to lower phytate content and increased mineral  density of animal based foods may contribute to higher regenerative capacity  and better immune regulation during carnivore diets (O'Hearn 2020 and Beal et  al., 2022).
The relatively low dietary fiber content is a  promoted benefit for some conditions of the gastrointestinal tract since  soluble dietary fiber may interfere with the activities of pancreatic enzymes  and digestion of protein, whereas insoluble fiber could provoke bloating and  distension (Tan et al., 2007; Tan et al., 2012). Casual observations and  self-claimed benefits are weight loss, improved glucose control, reduced  medication needs, and improvements in gut health (Lennerz et al., 2021).  However, scientific confirmation under tight regulation is still needed.
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Figure 2. Mineral and vitamin density per calorie is significantly higher in animal-based foods compared to plant-based foods, and especially grains, which exhibit the lowest nutrient density. Adapted from Beal et al., 2022, with permission from the MOJO Institute.
Figure 2. Mineral and vitamin density per calorie is significantly higher in animal-based foods compared to plant-based foods, and especially grains, which exhibit the lowest nutrient density. Adapted from Beal et al., 2022, with permission from the MOJO Institute.
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Hypothesized Mechanisms of the Carnivore Diet

The carnivore diet may offer some advantages over  the VLCKD, particularly for patients with IBD. These are:
  • Decreased Plant Toxins: Plants contain various toxins. Lectins, solanines, and saponins are associated with autoimmunity and inflammation (Kuang et al., 2023, Konijeti et al.,2017, and Iablokov et al., 2010).
  • Direct SCFA Supply: With the direct provision of SCFAs and the growth stimulation of SCFA-producing bacteria, the carnivore diet may bypass pre-existing dysbiosis, which is highly prevalent in the IBD population. (Alsharairi et al., 2021, Parada Venegas et al., 2019 and Kaur et al. 2011).
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Figure 3. A ketogenic diet supports the proliferation of SCFA-producing bacteria, in turn potentially modifying epigenetic control of gene expression and thus regulating intestinal tissue inflammation in IBD. Adapted from Alsharairi et al., 2021. Graphic provided with the permission of the MOJO Institute, Hennef, Germany.
Figure 3. A ketogenic diet supports the proliferation of SCFA-producing bacteria, in turn potentially modifying epigenetic control of gene expression and thus regulating intestinal tissue inflammation in IBD. Adapted from Alsharairi et al., 2021. Graphic provided with the permission of the MOJO Institute, Hennef, Germany.
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3.
Reduced Omega-6 (Linoleic Acid) consumption: Linoleic Acid may directly induce inflammation in the intestinal epithelium via formation of oxidative linoleic acid metabolites (OXLAMs) and consequent dysregulation of the Endocannabinoid System (Deol et al., 2023). Carnivore diets more closely resemble the pre-modern consumption of <2g/day linoleic acid vs. the modern consumption of 29g/day (Mercola et al., 2023).
4.
Higher Micronutrient Density: Animal Foods are more dense in most micronutrients (vitamins and minerals) compared with plant foods and lack anti-nutrients such as phytates (O'Hearn, 2020, Beal et al., 2022), which may improve immune regulation and regenerative capacity of intestinal epithelial cells.
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Figure 4. The Oxidative Metabolism of Glucose and Fatty Acids into ATP in Mitochondria Requires Multiple Micronutrients Including Vitamins and Minerals. These micronutrients are more concentrated in animal products than in plant based foods. Illustration by MOJO Studio, Hennef, Germany.
Figure 4. The Oxidative Metabolism of Glucose and Fatty Acids into ATP in Mitochondria Requires Multiple Micronutrients Including Vitamins and Minerals. These micronutrients are more concentrated in animal products than in plant based foods. Illustration by MOJO Studio, Hennef, Germany.
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5.
Reduced Dietary Fiber: Soluble fiber inhibits activity of pancreatic enzymes and protein sequestration while insoluble fiber increases bloating and tension possibly contributing to intestinal pathologies (Tan et al., 2007, Tan et al., 2012).
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Figure 5. Dietary fiber can contribute to bloating and straining, as was revealed by an experimental study in which 63 patients were subjected to three levels of fiber intake: no fiber restriction, medium fiber restriction, and complete fiber restriction over six months. Results indicated that while all patients on the high-fiber diet remained symptomatic, none of the patients on the zero-fiber diet exhibited symptoms after six months. Figure adapted from Tan et al., 2012, courtesy of the MOJO Institute, Hennef, Germany.
Figure 5. Dietary fiber can contribute to bloating and straining, as was revealed by an experimental study in which 63 patients were subjected to three levels of fiber intake: no fiber restriction, medium fiber restriction, and complete fiber restriction over six months. Results indicated that while all patients on the high-fiber diet remained symptomatic, none of the patients on the zero-fiber diet exhibited symptoms after six months. Figure adapted from Tan et al., 2012, courtesy of the MOJO Institute, Hennef, Germany.
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Possible Concerns

A carnivore diet has been subject to some stringent  criticisms in terms of potential individual health risks:
  • Gout Risks: The supersaturation of uric acid can -under the wrong circumstances- lead to the deposition of monosodium urate monohydrate crystals in the tissues, with resultant gout arthritis. Gout can be manifested by the elevation of serum urate, acute gouty arthritic attacks, the formation of tophi, gouty nephropathy, and uric acid stones. Meat itself has not been established as a causative agent, but the high amount of purine within it can serve as a triggering factor in causing episodes of gout arthritis in a pre-existing metabolic dysregulation. Our own clinical experience shows that a ketogenic/carnivore diet can even alleviate gout medium term. Hypothetically, this could be due to reduced oxidative stress since uric acid acts as an antioxidant, reduced availability of dietary monosodium (glutamate), or perhaps increased exercise in our patient population since muscle activity induces myokine secretion, hence helping in the conversion of uric acid to allantoin for excretion through the kidneys (Roman 2023). Indeed, recent reviews have confirmed our observation of reduced uric acid in very low carbohydrate ketogenic diets (Gohari et al., 2023).
  • Carcinogenicity: The World Healths Organizations (WHO) International Agency for the Research of Cancer (IARC) has classified Processed Meat as carcinogenic (Class I), and unprocessed Red Meat as possibly carcinogenic (Class IIa). No causal relationships have been established and no causal agents in red meat have been identified to date. By the classification standards of IARC, the classification is to be based on an associative relationship and does not establish the magnitude of risk. Recent systematic reviews have argued that evidence even for the proposed associative relationship between unprocessed red meat and negative health outcomes (including cancer) is lacking, and recommendations for reduced consumption of unprocessed red meat are not backed by scientific data (Lescinsky et al., 2022 and Bradley et al., 2019).
  • Dyslipidemia and Cardiovascular Risks: For a given population on a standard diet, increased serum total LDL Lipoprotein molecular mass (measured in mg/dl) has been considered causal in the progression of atherosclerosis (Libby 2021). On ketogenic diets, total serum LDL lipoprotein mass can and most likely will increase; however, the size of the LDL particle becomes larger, thereby reducing the number of atherogenic particles (Westman et al. 2006, Falkenhain et al., 2021, and Froyen 2021, and Qiao et al., 2022). A reduction in the number of the atherogenic small and dense LDL lipoproteins and concurrent increase in the lipoprotein size is associated with improved cardiovascular risk markers such as reduced BMI, body weight, inflammatory markers, sdLDL, Triglycerides, Lipoprotein A, Apolipoprotein B, Blood Glucose, HbA1c, Insulin, and Blood Pressure, and increased HDL. During ketogenic diets LDL Lipoproteins serve other functions as in standard diets and are not to be interpreted as signs of metabolic dysfunction (Norwitz et al., 2022). Therefore, increased serum LDL on a ketogenic diet has to be evaluated differently than increased serum LDL on a standard diet and statin therapy is usually not warranted in a low-carbohydrate ketogenic diet (Diamond et al., 2022)
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Figure 6. Low Density Lipoproteins (LDL) vary by size. Smaller Lipoproteins have a higher propensity to oxidize and paracellularly pass the endothelium to assist in the progression of atherosclerosis. Under ketogenic diets lipoproteins tend to increase in size without increasing the particle number, resulting in higher serum weights (measured in mg/dl). According to best available evidence this increase in mass, while at the same time increasing size with stable or even decreased particle numbers (as measured by reduced apolipoprotein B unter ketogenic conditions) does not constitute an increased cardiovascular risk and does not warrant statin therapy. Adapted from Qiao et al., 2022, courtesy of the MOJO Institute, Hennef, Germany.
Figure 6. Low Density Lipoproteins (LDL) vary by size. Smaller Lipoproteins have a higher propensity to oxidize and paracellularly pass the endothelium to assist in the progression of atherosclerosis. Under ketogenic diets lipoproteins tend to increase in size without increasing the particle number, resulting in higher serum weights (measured in mg/dl). According to best available evidence this increase in mass, while at the same time increasing size with stable or even decreased particle numbers (as measured by reduced apolipoprotein B unter ketogenic conditions) does not constitute an increased cardiovascular risk and does not warrant statin therapy. Adapted from Qiao et al., 2022, courtesy of the MOJO Institute, Hennef, Germany.
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No proposed risk has so far been conclusively  confirmed nor denied. Small associations have been spotted between intake of  meat and gout, cancers, and cardiovascular events absent identification of  causal relationships or conclusive causal agents. On the other hand, there are  also no conclusive trials to indicate the long-term safety of a carnivore or  meat-intensive diet. Hence further research is warranted.

Testing the Hypothesis – Study Design and Methodology

The hypothesis can be tested in a 12-week clinical  study, investigating safety, feasibility, and clinical efficacy of a carnivore  diet in a cohort of IBD patients.

Study Objectives

The primary objective is to establish the  feasibility and safety of a carnivore diet in a cohort of IBD patients.  Secondary objectives will assess clinical and functional outcomes at 1, 6, and  12 weeks with the IBDQ-32, SCCI, and CDAI. Other measures will include heart  rate variability, bioimpedance, blood pressure, body measurements, body  temperature, breath analysis, gut microbiota, inflammation markers, urea and  electrolyte levels, liver function, fasting insulin, HbA1c, vitamin and mineral  status, and lipid profile. Table 1 provides a detailed listing of the blood parameters to be measured, which  include but are not limited to inflammation markers, LFT, lipid profile,  vitamins, mineral levels, and other biomarkers as needed.
Table 1. Comprehensive lift of blood markers to be evaluated before and after.
Table 1. Comprehensive lift of blood markers to be evaluated before and after.
Alkaline Phosphatase
Bilirubin (Serum)
Calcium (Serum)
Chloride (Serum)
Cholesterol (Serum)
HDL (Serum)
LDL (Serum)
CK (Serum)
CK-MB (Serum)
Iron (Serum)
Protein Electrophoresis (Serum)
Total Protein (Serum)
GOT (Serum)
GPT (Serum)
Uric Acid (Serum)
Urea (Serum)
HbA1 (EDTA)
Potassium (Serum)
Creatinine (Serum)
LDH (Serum)
Sodium (Serum)
Inorganic Phosphate (Serum)
Transferrin (Serum)
Triglycerides (Serum) 		Full Blood Count (EDTA)
Reticulocytes (EDTA)
Quick/INR (Citrate)
PTT (Citrate)
Thrombin Time (Citrate)
Indirect Bilirubin (Serum)
Minerals 11+4 (Heparin)
hsCRP (Serum)
TNF-alpha (Serum)
Ferritin (Serum)
Vitamin B1 bioactive (Serum)
Vitamin B2 bioactive (Serum)
Vitamin B6 bioactive (Serum)
Vitamin B9 bioactive (EDTA)
Vitamin B12 bioactive (Serum)
25-OH-Vitamin D (Serum)
Amino Acids Metabolism (EDTA Plasma)
Amino Acids Neuro (EDTA Plasma)
Lactate/Pyruvate (Fluoride 3x)
Nitrotyrosine (Serum)
Carnitine (Serum)
Fatty Acids of Erythrocyte Membrane (EDTA) 		Lipoprotein (a) (Serum)
TSH Basal (Serum)
Apo-Lipoprotein B (Serum)
Homocysteine (Serum centrifuged)
Cortisol Awake Response (Saliva)
Molecular Genetic Profile
Microbiota (Stool)
SCFA (Short-Chain Fatty Acids) (Serum)
SCFA (Short-Chain Fatty Acids) (Stool
Pancreatic Elastase (Stool)
Bile Acids (Stool)
Alpha-1-Antitrypsin (Stool)
Zonulin (Stool)
Calprotectin (Stool)
MDA-LDL (Serum)
AGE (Serum)
IL-6 (Serum)
BDNF (Serum)
Lipopolysaccharide Binding Protein (LBP) (Serum centrifuged)
IFABP (Serum)
Participants will keep a food diary daily and  monitor their blood ketone levels.

Study Design

This prospective study should enroll a minimum of  12 IBD patients in a 12-week non-randomized, single-arm pilot study. All  participants will be taken through written informed consent.

Participant Criteria

Inclusion  criteria:
  • Diagnosis of IBD as per Montreal classification
  • Aged 18-70 years.
Exclusion  criteria:
  • Pregnant or intending to become pregnant within the next 3 months.
  • Currently abusing substances.
  • On ketogenic or carnivore diet in last 6 months.
  • Currently Vegan or vegetarian diet and unwilling to switch to carnivore diet.
  • Hospitalization during the last 3 months.
  • Participation in another research project.
  • Inability to fill out the initial questionnaires.
  • Active liver, kidney, or cardiovascular diseases, kidney stones, severe hyperlipidemia.
Metabolic disorders that will be an exclusion criteria:
  • Glycogen storage disease type 1 (von Gierke disease).
  • Carnitine palmitoyltransferase deficiencies (CPT I/II).
  • Primary carnitine deficiency.
  • Carnitine-acylcarnitine translocase deficiency.
  • Pyruvate carboxylase deficiency.
  • Succinyl-CoA acetoacetate transferase deficiency.
  • Various fatty acid oxidation disorders.
  • Acute intermittent porphyria.

Implementation and Follow-Up

Participant Training

The participants will be trained once in an  educational workshop, given at the Kick-off event of the study, about:
  • Nutritional science behind the ketogenic and carnivore diets.
  • Appropriate foods and sample recipes.
  • Targeted ketone and glucose levels.
  • Food measurement-grams.
  • Preparation for diet initiation across environments.
  • Overcoming obstacles-quality, procurement, and preparation.
  • Dining out, traveling, and illness guidelines.
  • Medication guidelines.
  • Prevention/management of potential side effects; for example hypoglycemia or hyperketosis.
  • Why diets may fail.
  • Modifications for illness-more water, no concern for ketone level.
  • Fitting the diet into larger ecological, spiritual, and economic contexts.

Ketone Monitoring

The nutritional and socio-medical history will be  obtained through digital intake interviews with the participants. Continuous  monitoring of glucose/ketones will be done with monitoring devices, the data of  which is managed daily by the specialist. The participants will have digital  access to a community platform, where they can find recipes and instructions.  Group exchanges in this online format should also be possible. Once a week,  video calls with the specialist and mentor will be used to discuss practical  and emotional problems arising from dietary adherence.

Discussion

Chronic complex illnesses such as IBD can be  frustrating for both patients and therapists, because of a lack of promising  treatment options that resemble full reconstitution/regeneration. The need to  advance medical knowledge and care for patients afflicted by these diseases is  rising. The carnivore diet -a possible new regenerative immunotherapy- seems  promising. Yet, for patients with IBD, being put on a radical carnivorous diet  would require multifaceted consideration of ethical, ecological, economic concerns  and individual health needs.
Fully informed consent -as in all medical  therapies- is needed, where all possible benefits and risks should be  presented. Ecologically, a diet with a high intake of animal products has  sustainability concerns, which are yet unclear; hence, this too will require  discussion in light of finding ethical and sustainable ways of sourcing animal  products. Economically, dietary cost and food access need consideration to  ensure that it will place no undue burden on the patients or that it will not  further exacerbate health disparities.
From the point of view of individual health, even  if there is plenty of anecdotal evidence, in particular, as to the benefits,  the adverse effects should be carefully and intensively investigated. High  animal product consumption entails risks for diseases such as gout,  cardiovascular diseases, and particular types of cancer. These risks should be  assessed and followed closely for therapeutic carnivore diets in order to  attend to the subjects' long-term safety and vitality.
The following  monitoring protocols are necessary:
  • for gout risk, check uric acid levels on a regular basis.
  • for cancer risk, perform long-term monitoring of biomarkers for cancer.
  • for cardiovascular risk, evaluate lipid profiles including Apolipoprotein B as a measure of particle number, blood pressure, visceral body fat and markers of systemic inflammation such as hsCRP.
In summary, academia and clinical medicine needs a  multi-disciplinary approach, which has to integrate nutrition, behavioral  psychology, immunology, gastroenterology, and bioethics. By balancing and  reviewing all aspects, we want to explore the healing potential of a carnivore  diet while ensuring the safety of the patient and also regarding the possible  ethical, ecological as well as economic issues.
We hereby summarize the current best available  evidence for a therapeutic carnivore diet as a regenerative immunotherapy and  hypothesize that it could make a significant difference in the management of  IBD and perhaps bring relief to patients unresponsive to current treatments.  Such a therapeutic carnivore diet requires very considered planning,  transparent reporting, and dedication to responsible and comprehensive patient  care. An experimental design to test our hypothesis was proposed. This review,  hypothesis, and experimental design guarantee a comprehensive framework for  investigating the carnivore diet as a novel regenerative immunotherapy in IBD,  which can have a clinical application based on such findings. Insights from  this would extend beyond the specific focus to wider applications in other  chronic inflammatory diseases.

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