Diet Influences Intestinal Permeability and Leaky Gut

Dermatological disease

General

Dietary allergy & environmental factors ➔ gut microbiome sensitivity ➔ dysbiosis ➔ LGS ➔ disturb skin ecosystem ➔ cause multiple skin conditions: Acne (two major bacteria: Propionibacterium acnes & Staphylococcus epidermidis), aging skin (also exposure to UV), psoriasis, atopic dermatitis, eczema, seborrheic dermatitis, vitiligo, epidermolysis bullosa, rosacea (long‐term treating by antibiotics), blepharitis, malaria and attractiveness to mosquitoes, & skin cancer

(+) Probiotics, Prebiotics

(−) Process food (emulsifiers), Gluten, some skin care and cosmetic products (may alter skin microbiome)

Ellebrecht et al. (2016), Kong et al. (2012), Maguire and Maguire (2017)

Eczema

Food allergens ➔ ↑ IgE & IgG4, IL‐10, CLA positive T‐cell & TNFα ➔ intestinal mucosal damage & increase intestine permeability ➔ skin reaction (erythematous rash, urticaria, & angioedema) & GI, respiratory, & cardiovascular symptoms of anaphylaxis;

More children than adults

(+) Dietary restriction with allergic food

(−) Common allergic food: Cow's milk, egg, wheat (gluten), soy, peanut, fish, cashew (varies with individuals)

Hauk (2010), Jaervinen et al. (2003), McAllister et al. (2019), Pike et al. (1986), Sicherer and Sampson (1999)

Psoriasis

Disturbs of the Firmicutes/Bacteroidetes Ratio ➔ microbiota dysbiosis, ➔↑ IL 1,2,6,8,12,17,23, TNFα, INF‐γ, ↓SCFAs, ↑TMAO;

Patients presents with positive antigliadin antibodies;

Associates with metabolic syndrome, DM, Crohn's disease, ulcerative colitis, cardiovascular disease & cancer

(+) Probiotics, Fatty fish, Vitamin D

(−) Western diet, Gluten, chronic consumption of alcohol

Codoñer et al. (2018), Hidalgo‐Cantabrana et al. (2019), Lerner et al. (2017), Polak et al. (2021), Scher et al. (2015), Shi et al. (2020), Watanabe and Tatsuno (2017), Yu et al. (2019)

Diseases of the circulatory system (cardiovascular disease – CVD)

General

Obesity/Western diet ➔ gut dysbiosis, disrupt TJ; choline/carnitine ‐ ↑TMA ➔ ↑gut permeability ➔ ↑LPS, activation of TLR4, signal transduction including NF‐κB ➔ metabolic endotoxemia, TMAO ➔ inflammation, platelet aggregation, cholesterol‐laden macrophage foam cell formation ➔ CAD

Ketogenic diets ➔ ↓total cholesterol, LDL‐cholesterol, triglycerides, HbA1C, & ↑HDL‐cholesterol in human research; however, there were some conflicts with rodent model research

(+) Probiotics, Prebiotics, Dietary fish oil and oily fish (ω−3FAs), Ketogenic diets, Food rich in polyphenols such as resveratrol, EGCG, & curcumin, quercetin, Fruit polyphenol including berries

(−) Western diet, Processed food, Gluten, Heated vegetable oil

Amar (2018), Khurana et al. (2013), Kosinski and Jornayvaz (2017), Lourida et al. (2013), Merendino et al. (2013), Miles and Calder (2012), Mitchell et al. (2015), Moludi et al. (2020), Okuyama et al. (2016), Snelson et al. (2021), Tang et al. (2019), Villa‐Rodriguez et al. (2019), Watanabe and Tatsuno (2017)

Athero-sclerosis

Obesity/HFD ➔ gut dysbiosis, disrupt TJ; choline/carnitine ‐ ↑TMA ➔ ↑gut permeability ➔ ↑LPS ➔ TMAO ‐ oxidative stress, ↑platelet reactivity & thrombus potential, macrophage foam cell activation, endothelial cell activation, plaque localization, & vascular inflammation, & ↓reverse cholesterol transport ➔ Atherosclerosis

Animal‐based diet ➔ ↑bile‐tolerant microorganism such as Alistipes, Bilophila, Bacteroides & ↓Firmicutes

(+) Probiotics, Prebiotics, Plant‐based diet (↑SCFAs), Food rich in polyphenols, EVO

(‐) Western diet, Processed food

Karlsson et al. (2012), Khurana et al. (2013), Miyake and Yamamoto (2013), Moludi et al. (2020), Tang et al. (2019), Woodhouse et al. (2018)

Heart failure (HF)

Disrupt gut dysbiosis & disrupt TJ; choline/carnitine ‐ ↑TMA ➔ ↑gut permeability ➔ ↑LPS, ↑ TNFα, IL‐6 & CRP ➔ TMAO ‐ oxidative stress, ↑platelet reactivity & macrophage foam cell activation, endothelial cell activation, plaque localization, & vascular inflammation, & ↓reverse cholesterol transport oxidative stress, plaque localization, platelet activation ➔ HF, MI & stroke

(+) Probiotics, Prebiotics

Fukui (2016), Nagatomo and Tang (2015), Tang et al. (2019)

Hyper-tension (HTN)

HFD/high salt diets & other dietary factors ➔ disrupt gut microbiota ➔ ↑gut permeability ➔ ↑I‐FABP, LPS, TH17, IL22; ↑TMA – TMAO ➔ dysfunctional sympathetic‐gut communication ➔ HTN

High‐salt diet ➔ change gut microbiota through an effect on TH17 lymphocytes pathway

EVO decrease systolic BP

(+) Mediterranean diet, High fiber food, Fruit, Oily fish, Paleolithic type diet, Low‐gluten diet, Food rich in polyphenols (fruits, tea, vegetables)

(‐) Animal fat, Processed meat, High‐salt diet, High‐gluten diet, Heated vegetable oil

Amar (2018), de Punder and Pruimboom (2013), Hul et al. (2018), Jaworska et al. (2017), Kaličanin et al. (2020), Khurana et al. (2013), Kim, Ruby Goel, et al. (2018), Leong et al. (2010), Li et al. (2017), Okuyama et al. (2016), Santisteban et al. (2017), Sayon‐Orea et al. (2015), Siti et al. (2019), Tang et al. (2019)

Myocardial Infarction (MI)

Obesity/high‐fat diet ➔ gut dysbiosis, disrupt TJ; choline/carnitine ‐ ↑TMA ➔ ↑gut permeability ➔ ↑LPS ➔ TMAO ‐ oxidative stress, ↑platelet reactivity & thrombus potential, macrophage foam cell activation, endothelial cell activation, plaque localization, & vascular inflammation, & ↓reverse cholesterol transport oxidative stress, plaque localization, platelet activation ➔ Atherosclerosis ➔ MI, heart failure & stroke

(+) Probiotics, Prebiotics, Plant‐based diet (↑SCFAs), Food rich in polyphenols, EVO

(‐) Western diet, Processed food

Carrera‐Bastos et al. (2018), Khurana et al. (2013), Miyake and Yamamoto (2013), Moludi et al. (2020), Tang et al. (2019), Woodhouse et al. (2018)

Diseases of the digestive system

Acute Pancreatitis (AP)

Disruption of gut barrier & gut permeation in early stage of AP ➔ lower level of occludin and ZO‐1 expression &↑inflammatory cytokines ➔ intestinal dysbiosis: ↑Enterococcus & ↓ Bifidobacterium ➔ infection & pancreatic necrosis ➔ systemic inflammation & complications

(+) Probiotics

Capurso et al. (2012), DeMeo et al. (2002), Fukui (2016)

Alcoholic liver disease (ALD)

Alcohol ➔ gut dysbiosis/SIBO ‐ ↑Escherichia coli, Enterobacteria, Alcaligenes, Meagsphaera, & ↓Lactobacillus & Bifidobacterium ➔ ↑intestinal permeability ➔ LPS endotoxin and other PAMPs ➔ activate Kupffer cells ➔ ↑TNFα, IL‐6, IL‐1β, TLR4, MPO ➔ hepatocyte damage ➔ ↑AST & ALT ➔ ALD (through Gut‐liver axis)

Probiotics ➔ ↑Lactobacillus, Bifidobacterium & ↓ Escherichia coli, Enterobacteria, Alcaligenes, & Actinobacteria; ↑Claudin‐1, Occludin, ZO‐1, Symplerin, p130, & HIF‐2α ➔ ↓intestinal permeability

(+) Probiotics, Prebiotics, Zinc, Niacin, Appropriate nutritional intake, Dietary fatty acids

Fukui (2016), Hong et al. (2019), Sung et al. (2016), Zhou and Zhong (2017)

Autoimmune hepatitis

Genetics, food antigens, food‐borne pathogens & environmental cues disturb diversity of microbiota ➔ ↑plasma LPS, ↓duodenal TJ proteins ➔ imbalanced bidirectional gut‐liver axis ➔ dysbiosis ‐ ↑aerobic bacteria & ↓anaerobic bacteria ➔ autoimmunity ➔ autoimmune hepatitis

Autoimmune hepatitis is associated with CD, MS, & RA

(+) Probiotics, High‐fiber diet

(‐) Western diet, Gluten, Long time alcohol consumption (↑gram negative bacteria), Excessive food intake

Iqbal et al. (2017), Lerner et al. (2017), Lopetuso et al. (2015), McAllister et al. (2019), Plaza‐Díaz et al. (2020)

Celiac Disease (CD)

90% of CD patients genetically associate with HLA DQ2/DQ8 haplotypes; tTG2 involved; CD triggered by gliadin fraction of wheat gluten & prolamines of barley & rye; Gluten releases toxic peptides in stomach ➔ ↑plasma IgA, IgG, IgM ➔ against gluten peptides, & antibodies against TG2 & EMA ➔ TJ disassembly by upregulating zonulin pathway, ➔ gut dysbiosis ‐ ↓Bifidobacteria, Firmicutes, Lactobacilli & Streptococceae & ↑Bacteroides, Bacterioidetes, Bacteroides fragilis, Prevotella, E. Coli, Proteobacteria, Haemophilus, Serratia, Klebsiella ➔↑intestinal permeability ➔ gut & systemic inflammation

1% population with this gluten‐induced, cell‐mediated disorder; CD associates with multiple autoimmune diseases & psychological diseases such as atopic dermatitis, autoimmune hepatitis, anxiety, MS, depression, schizophrenia & panic disorder, dermatitis herpetiformis, HT, RA, Sjogren's syndrome, T1D

(+) Lifelong Gluten Free Diet – the only available treatment for CD (Allowed grains: Corn, Millet, Rice Buckwheat, Sorghum, Wild rice, Teff), Probiotics

(‐) Prohibited grains: Wheat, Rye, Barley, Kamut, Triticale (wheat‐rye hybrid), Spelt, Oats, FODMAP diet

Cardoso‐Silva et al. (2019), de Punder and Pruimboom (2013), DeMeo et al. (2002), Drago et al. (2006), Fasano (2011), Ferrari et al. (2021), Caio et al. (2020), Leffler et al. (2015), McAllister et al. (2019), Neunlist et al. (2003), Rallabhandi (2012), Severance et al. (2016), Valitutti and Fasano (2019), Weaver and Herfarth (2021)

Cirrhosis

Gut microbiota disrupted ➔ altering bile acid homeostasis, ↓beneficial taxa like Lachnospiraceae, Bacteroidetes, Roseburia, Blautia, & Ruminococcaceae, ↑Proteobacteria, Fusobacterium spp., Veillonellaceae, Streptococcaceae & ↓ SCFA ➔ dysbiosis & bacterial overgrowth ➔ disrupt TJ & ↑gut permeability ➔ release both LPS & FGF 19 (produce by bile acid bind to FXR) to portal circulation ➔ ↑proinflammatory cytokines ➔ portal hypertension & cirrhosis (through gut–liver–immune system axis & Gut–liver axis);

Gut dysbiosis ➔ ↑ammonia, & ↑glutamine in astrocytes ➔ astrocyte swelling ➔ oxidative stress ➔ systemic inflammation through Gut‐liver‐brain axis

Fructose drinks ➔↓TJ & AJ proteins ➔ ↑plasma bacterial endotoxin levels ➔ endotoxemia.

Dietary choline may remove fat from hepatocytes.

High‐protein diet may ↑Prevotella & Oscillospira.

Physical exercises can regulate intestinal permeability & improve microbiota diversity

(+) Probiotics, Prebiotics, Synbiotics, High‐protein diet ‐ egg, meat, Cruciferous vegetable (due to rich in dietary choline)

(‐) High fat & high‐sugar diet, Unlimited fat diet, Choline‐deficient diet, Alcohol ingestion, Excess fructose intake like fructose drinks

Arab et al. (2018), Cho et al. (2021), Fukui (2016), Miyake and Yamamoto (2013), Norman et al. (2012), Plaza‐Díaz et al. (2020), Sharma and Singh (2016), Wang et al. (2019), Woodhouse et al. (2018)

Fatty liver disease

Poor diet habit, obesity/metabolic syndrome, type 2 DM, alcohol/drugs ➔ alteration of gut microbiota and bacteria overgrowth ➔ increase intestinal permeability ➔ ↑LPS, activation of TLR4 & TLR9 ➔ ↑Serum TNF‐α, IL‐1β, IL‐6, CCL2, CCL5, CXCL8, & ↑ROS ➔ Oxidative stress, fibrosis, inflammation ➔ FLD (through Gut‐liver axis);

Oxidative stress ➔ neurodegenerative disease;

LPS ➔ oxidative stress, plaque localization, platelet activation ➔ MI, CVD, peripheral artery disease

(+) Mediterranean diet, especially EVO; Probiotics, Prebiotics, Synbiotics, Vitamin E

(‐) Diet rich in fat, milk, dairy products, Excessive alcohol intake, Excessive fructose intake

Ferro et al. (2020), Hossen et al. (2020), Li et al. (2013), Miyake and Yamamoto (2013), Ohlsson et al. (2017), Safari and Gérard (2019), Woodhouse et al. (2018)

Inflamma-tory bowel disease (IBD)

Types of IBD:

Ulcerative Colitis (UC)

Crohn's disease (Crohn's)

Genetic (some with HLA‐B27 ‐ HLA‐DQ2/8 positive) & environmental factors (dietary patterns/components, malnutrition, medication & food allergy, for instance, excessive intake of FODMAP diet) ➔ SIBO ➔ ↑ intestinal permeability (↓Paneth cell antimicrobial function in Crohn's & ↓goblet cells & altered mucus function in UC) ➔ luminal changes in colon ➔ intestinal inflammation ➔ IBD

Gut dysbiosis in IBD: IBD showed reduced common commensals – Bifidobacterial & Bacteroides fragilis & ↑Proteobacteria & Actinobacteria. Yersinia & Pseudomonas triggers Crohn's, & Samonella, Campylobacter jejuni, Clostridium difficile, Adenovirus, & Mycoplasma associated with Crohn's relapsing. Fusobacterium varium in colon may cause UC, & E. coli may maintain UC

Dietary emulsifiers ➔ ↓β‐diversity & cause gut dysbiosis

Phytochemicals suppress pro‐inflammatory cytokines like TNFα, IL‐1β, IL‐6 & IFN‐ γ.

Ginger can maintain Caco‐2 and HT‐29/B6 cells and prevent pro‐inflammatory TNFα and TJ dysfunction

T‐cells response to enteric bacteria ➔ ↑mucosal 5‐HT & dopamine, & ↓ tissue 5‐HT & NE ➔ related to CNS disorder

(+) Low FODMAP diet, Mediterranean diet, Gluten‐free diet (especially for HLA‐DQ2/8 positive IBD patients), Green tea, Probiotics, Prebiotics, Vitamin D, folic acid, Zinc, Glutamine, Dietary fibers (to produce SCFAs), Psyllium (↓severity of UC), Ginger (especially for Crohn's), Red wine extract

(‐) High FODMAP diet, Gluten (mainly HLA‐DQ2/8‐positive Crohn's patients), Processed food including dietary emulsifiers, Food rich in ω−6FA, NSAIDs (Crohn's), Antibiotics (Crohn's), Smoking (Crohn's)

Arrieta et al. (2009), Bancil et al. (2021), Beguin et al. (2013), Cordain et al. (2000), DeMeo et al. (2002), Fukui (2016), Guagnozzi et al. (2012), Hossen et al. (2020), Kikuchi et al. (2019), Kim, Keogh, and Clifton (2018), Lacerda et al. (2021), Li et al. (2019), Llewellyn et al. (2018), Luettig et al. (2016), Magnuson et al. (2016), Malíčková et al. (2017), McAllister et al. (2019), Michielan and D'Incà (2015), Nanayakkara et al. (2016), Neish (2009), Nunes et al. (2019), Sasson et al. (2021), Scaldaferri et al. (2013), Shin and Lim (2020), Van Buiten et al. (2018), Vazquez‐Roque et al. (2013), Weaver and Herfarth (2021), Yeoh et al. (2013), Yoon et al. (2018)

Irritable Bowel Syndrome (IBS)

Genetic (some with HLA) & diet (Food triggers or aggravates 2/3 of IBS patients.) ➔ ↑serum Zonulin level ➔ ↑Serum TNF‐α, IL‐1β, IL‐6 ➔↑epithelial permeability ➔ low‐grade intestinal inflammation.

IBS patients present visceral hypersensitivity due to neuronal dysfunction of ENS.

(+) Low FODMAP diet, Probiotics

(‐) High FODMAP diet, Gluten

Barbaro et al. (2020), Camilleri and Gorman (2007), Guagnozzi et al. (2012), Martín et al. (2022), Nanayakkara et al. (2016), Niesler et al. (2021), Rinninella, Cintoni, et al. (2019), Wu et al. (2021)

Liver steatosis

Bidirectional communication between the gut & liver through Gut–liver axis. Primary bile acid from liver & Ig A ➔ Eubiosis.

Dietary habits, age, ↓physical activities, & other causes (such as NAFLD, MAFLD, ALD, drugs, food contaminants of environment origin, etc.) ➔ gut dysbiosis ➔ ↑intestinal permeability ➔ secondary bile acids metabolites ➔ portal vein ➔ filtration of damaging agents like MAMPs or PAMPs ➔ ↑ cytokines (TNFα, IL‐1β, IL‐6, IL‐12, IL 18), chemokines (CXCL1, CXCL2, CCL2, CCL5, CCL3, CCL4), NO & ROS ➔ systemic inflammation ➔ multiple liver diseases including liver steatosis & cirrhosis.

Physical exercises can modify insulin sensitivity & glucose metabolism, and ↑Bacteriodetes/Firmicutes ratio, ↑SCFAs, ↑T‐reg cells ➔ improve microbiota diversity, regulate intestinal permeability & anti‐inflammatory cytokines – positive effects on immune system.

(+) Probiotics, Synbiotics, Mediterranean diet, High‐protein diet: egg, meat, Cruciferous vegetable (due to rich in dietary choline)

(‐) Western‐style diet (high fat & high sugar diet), Low adherence to Mediterranean diet, High salt intake, Unlimited fat diet, Choline‐deficient diet, Alcohol ingestion, Excessive fructose intake, Excessive caloric intake

Chen, Zhang, et al. (2020), Di Ciaula et al. (2020), Di Palo et al. (2020), Kim, Ruby Goel, et al. (2018), Plaza‐Díaz et al. (2020), Woodhouse et al. (2018)

Necrotizing enterocolitis

LPS induces the intestinal barrier dysfunction, impaired TJ protein, ➔ activates IL‐1β, IL‐6, IL‐8 & TNFα ➔ systemic inflammation

(‐) Corn gluten meal

Bai, Gu, et al. (2019), Ling et al. (2016)

Disease of the genitourinary system

Chronic Kidney disease (CKD)

Chronic intake of Western diet including heat‐treated food (leaking albumin to urine), ↓intake dietary fibers (↓potassium), prolonged GI transit time due to lacking of physical activities, dietary restrictions & comorbidities (mainly DM & CVD), change intestinal microbiota diversity (↑proteolytic microbes) ➔ gut dysbiosis, SIBO ➔ ↑intestinal permeability ➔↑ blood ammonia & uremic toxicity ➔ renal injury, fibrosis & systemic inflammation through Gut‐kidney axis

(+) Dietary fiber like fruits & vegetables (for potassium), Mediterranean diet, Probiotics, Prebiotics, Low‐protein diet

(‐) Western diet, Processed food, Gluten

Briskey et al. (2017), Fukui (2016), Hobby et al. (2019), Ondrussek‐Sekac et al. (2021), Sabatino et al. (2017), Snelson et al. (2021), Yang et al. (2019)

Diseases of the musculoskeletal system

Ankylosing Spondylitis (AS)

Immunity through Gut–Joint Axis – IL‐23/Th17 ➔ chronic inflammation; Oral microbiota dysfunction ➔ periodontitis; intestinal dysbiosis (↑Lachnospiraceae, Prevotellaceae, Rikenellaceae, Porphyromonadaceae, Bacteroidaceae & decreasing Ruminococcaceae families) ➔ immune response (↑total IgA) ➔ decreasing zonulin ➔ Leaky gut;

90‐95% of AS patients present major risk gene ‐ HLA‐B27

(+) Dietary fish oil & oily fish, Probiotics (with fermented food), Prebiotics; Low starch intake

(‐) Smoking, Western diet, Gluten

Chen et al. (2015), Ciccia et al. (2014, 2017), Costello et al. (2015), de Punder and Pruimboom (2013), Fasano (2012), Obrenovich (2018), Rath et al. (1999), Tito et al. (2017), Welsby and Goriely (2016), Yang et al. (2016), Yeoh et al. (2013), Yu et al. (2015)

Muscle wasting

Gut–brain–muscle crosstalk: Lactobacillus species pluralis (spp.) ➔ reduce gut permeability ➔ ameliorate muscle wasting

(+) Probiotics (Fermented food like Kimchi), Prebiotics Synbiotics

van Krimpen et al. (2021)

Rheumatoid Arthritis (RA)

Oral microbiota dysfunction: dental caries & periodontitis ➔ develop ACPA; Gut dysbiosis: food antigens, food‐borne pathogens disturb immune homeostasis & cause T‐lymphocytes/antibody reaction ➔ reducing common commensals – Bifidobacterial & Bacteroides fragilis ➔ impaired TJ ➔ systemic inflammation ➔ RA

Adley (Coix lachrymal‐jobi L., an annual crop) has anti‐inflammatory and immunological activities, such as ↓TNFα and IL8 and intestinal TJ permeability.

Legumes (Lectin) and nightshades (lectin & alkaloids) ➔↑intestinal permeability & innate immune cell activation ➔ RA symptoms.

(+) Dietary fish oil & oily fish, Probiotics, Ginger, Adley (Coix lachrymal‐jobi L.)

(‐) Nightshades, Legumes, Western diet, Gluten

Cordain et al. (2000), Farshchi et al. (2017), Lerner et al. (2017), Lopetuso et al. (2015), Simopoulos (2008), Vojdani (2015)

Disease of the respiratory system

Asthma

Environmental allergens activate immune system – TH2 ➔ Gut dysbiosis, ↓ratio of Bacteroidetes/Firmicutes, ↓Bifidobacterium, Lactobacillus, ↑Escherichia coli, Streptococcus & Staphylococcus ➔ ↑intestinal permeability ➔ ↑TNF & IL‐6, LPS, lower expression of TLR4 ➔ inflammation through Gut–lung axis ➔ asthma

Dietary fiber regulates SCFA & ↓gastric acid to protect duodenal mucosa

(+) Probiotics, Prebiotics, Synbiotics, Dietary fiber, Plant gums, Plantain family seeds

(‐) Allergic cascade intake, Western diet

Farshchi et al. (2017), Fasano (2012), Hijazi et al. (2004), Sahagu´n et al. (2015), Simopoulos (2008), Trivedi and Barve (2020), Trompette et al. (2014)

Endocrine or metabolic diseases

Diabetes Mellitus (DM)

Type I DM (T1D)

Type II DM (T2D)

T1D: Factors influence gut microbiota composition: delivery mode ‐ cesarean section (CS) ↑risk of childhood onset T1D than virginal delivery due to ↓ gut microbiota diversity (mainly ↓Bacteroidetes phylum) from mother; Starting cereal diet early (cDNA clones of diverse wheat storage globulins ➔ islet damage); Geographic difference: highest in Sardinia & Finland, & lowest in China & Venezuela due to genetic (HLA class II genes) & environmental effects; Immunological status; Using antibiotics – induce the proliferation of pathogen like Clostridium difficile & S. enterica; Viral infection

Dietary related antigens ➔ ↑zonulin ➔ microbiota dysbiosis ➔ ↓TJ ➔↑APC ➔ ↑IgA, LPS, T cell activation ➔ PLN immune response ➔ β cell autoimmunity ➔ insulin deficiency

T2D: T2D associated with visceral obesity; Lower microbial diversity ➔ dysbiosis ➔↑LPS, ↑zonulin, ↑intestinal permeability ➔ ↓saccharolytic microbes ➔↓SCFA (SCFA suppress proinflammatory mediators like TNFα, IL‐1β, IL‐6, & NO) ➔ endotoxemia, insulin resistance & chronical inflammation

T1D: (+) Hydrolyzed formula, Gluten‐free diet or delayed introduce gluten, ω−3FAs, Probiotics

(‐) Early diet: Cereal, Cow milk

T2D:

(+) Dietary fish oil and oily fish (ω−3 FAs), Probiotics, Prebiotics, Synbiotics, Mediterranean diet, Fermented food like Kimchi, yogurt, Food rich in polyphenols like cinnamon & grapes

(‐) Western diet, Processed food, Gluten, Heated vegetable oil

T1D: Bekkering et al. (2013), Cardwell et al. (2008), de Kort et al. (2011), Fasano (2020), Gianchecchi and Fierabracci (2017), Li and Atkinson (2015), Petersa and Wekerle (2019), Sapone et al. (2006), Simpson et al. (2009)

T2D: An et al. (2013), Bekkering et al. (2013), de Kort et al. (2011), Ejtahed et al. (2012), Fasano (2020), Jayashree et al. (2014), Lopetuso et al. (2015), Lourida et al. (2013), Merendino et al. (2013), Miles and Calder (2012), Moreno‐Navarrete et al. (2012), Okuyama et al. (2016), Patra et al. (2016), Sabatino et al. (2017), Snelson et al. (2021), Watanabe and Tatsuno (2017), Zhang et al. (2014)

Hashimoto Thyroiditis (HT)

Thyroid–Gut Axis: HT, Graves' disease & thyroid carcinoma share similar mechanism, all cause dysbiosis ➔ stimulate GALT & TLR ➔ change TSH & T3 level; HPT Axis ➔ ATTA.

↓selenium & zinc ➔ decrease T4 ➔ T3; ↓iron & iodine ➔ impaired thyroid hormone synthesis.

Gluten‐free diet decrease thyroid antibody titers.

HT related to Hepatitis C, Helicobacter pylori, Yersinia enterolitica & Borrelia burgdorferi infection

HT often presents CD.

(+) Selenium, Zinc, Vitamin D, Iron, Iodine, Copper, Probiotics, Mediterranean diet, Oily fish, Gluten‐free diet

(‐) Gluten, Processed meat

Bodinham et al. (2014), Cayres et al. (2021), Fasano (2020), Kaličanin et al. (2020), Fenneman et al. (2020), Knezevic et al. (1769), Krysiak et al. (2019))

Metabolic endotoxemia

HFD ➔ gut dysbiosis, SIBO, ↓IAP activity, ↑CM & bile ➔ ↑intestinal permeability ➔ LPS & TLR4 ➔ ↑TNFα, IL‐1β, IL‐6 ➔ chronic low‐grade inflammation ➔ metabolic endotoxaemia ➔ many chronic diseases such as obesity, DM, atherosclerosis

(+) Probiotics, Prebiotics, Flavonoids, ω−3FAs

(‐) HFD, Western diet

Kaliannan et al. (2015), Moreira et al. (2012))

Obesity

HFD, excessive gluten diet ➔ change gut microbiota, ↑Lactobacillus, Staphylococcus aureus, Enterobacter cloacae strain B29, ↓Faecalibacterium prausnitzii ➔ ↑LPS ➔ disrupt TJ & ↑gut permeability ➔ ↑TLR4 & MLCK activation, ↑release TNFα, IL‐1β, IL‐6, IL‐8 ➔ endotoxaemia ➔ systemic inflammation ➔ obesity.

Obesity associated with metabolic disorders including T2DM, insulin resistance, liver diseases and diseases in multiple systems.

(+) Food rich in polyphenols Probiotics, Prebiotics, Flavonoids

(‐) HFD, Gluten, Heated vegetable oil

Bekkering et al. (2013), Casselbran et al. (2015), Di Palo et al. (2020), Frazier et al. (2011), Gerard (2016), Gil‐Cardoso et al. (2016), Hul et al. (2018), Kim and Ko (2018), Guercio Nuzio et al. (2017), Okuyama et al. (2016), Shi et al. (2021), Silva et al. (2020), Stenman et al. (2016), Zak‐Gołąb et al. (2013))

Immune disease

Systemic Lupus Erythematosus (SLE)

Dysbiosis in gut microbiome (↓Firmicutes/Bacteroidetes ratio) ➔ Leaky Gut ➔ ↑ LPS (↑soluble CD 14) & proinflammatory cytokines (IL17, IL 21‐23 & IFNα) ➔ systematic inflammation, cell apoptosis, anti‐dsDNA Ig production;

Fc gamma receptor IIb dysfunction ➔ ↓immune response;

Related to RA, T1D, MS, & IBD

(+) Dietary fish oil and oily fish (ω−3FAs), Probiotics, Prebiotics

(‐) Western diet, Nightshades

Abdelhamid and Luo (2018), Lopetuso et al. (2015), Mu et al. (2017), Thim‐uam et al. (2020), van der Meulen et al. (2016), Watanabe and Tatsuno (2017)

Neoplasms

General

Disruption of microbiota ➔ gut dysbiosis ➔ MAMPS ➔ ↑ LPS, activate TLRs, & release proinflammatory cytokines ➔ carcinogenesis

Bacteria associated with carcinogenesis such as Helicobacter pylori, Fusobacterium nucleatum, Streptococcus gallolyticus, Bacteroides fragilis, Salmonella typhi, Chlamydia pneumonia, Mycoplasma sp., Prevotella sp., Bacillus sp. ➔ genotoxicity, release of ROS, RNS ➔ carcinogenesis

Very low‐carbohydrate ketogenic diets ➔ ↓serum glucose & insulin growth factor ➔ delay cancer progression

Intestinal mucosa release SCFAs to protect carcinogens.

Glutenous diets ➔ ↑risk of lymphoma (usually non‐Hodgkin's lymphoma) due to associate with CD especially silent & latent CD

(+) Probiotics, Prebiotics, Mediterranean diet, Vegetarian diet, Japanese diet, very low‐carbohydrate Ketogenic diets, Dietary fish oil and oily fish (ω−3FAs), Dietary phytochemicals, Resveratrol, Vitamins, Essential minerals

(‐) Western diet, Processed food, Gluten

de Punder and Pruimboom (2013), Ferrari et al. (2021), Hoggan (1997), Klein et al. (2012), Laura Soldati et al. (2018), Merendino et al. (2013), Miles and Calder (2012), Raza et al. (2019), Shabbir et al. (2021), Snelson et al. (2021), Watanabe and Tatsuno (2017)

Gliomas

↑zonulin expression ➔ altered gut TJ ➔ altered BBB ➔ glioma C6 conditioned media ‐ ↑HGF, VEGF, zonulin, PGE2, & ↓EGF ➔ IL‐1β, IL‐6, IL‐8, TNFα, CXL13 ➔ gliomas

(+) Ketogenic diet

(‐) High‐calorie diet

Díaz‐Coránguez et al. (2013), Jonathan et al. (2020), Skardelly et al. (2009))

Neurological and psychological diseases

General

Leaky gut ➔ leaky brain: through MGB axis, GBNM axis, HPA axis & multiple pathways like neuroendocrine immune, ANS, & ENS. The BBB includes endothelial cells, TJ, pericytes, basement membrane & astrocyte end‐feet ensheathing the capillary wall. Brain presents similar junctional proteins as gut TJ proteins.

Gastro‐intestinal‐derived hormonal secretion, commensal bacteria produce neurotransmitters & neuromodulators: Lactobacillus, Bifidobacterium (produces GABA), Escherichia, Bacillus & Saccharomyces (produces NE), Bacillus (produces dopamine), Lactobacillus (produces acetylcholine), Candida, Streptococcus, Escheridia, Enterococcus spp. (produces serotonin) & Lactobacillus plantarum (may stimulate BDNF).

Gut bacterial composition manipulates behavior. Dysbiosis ➔ altering TJ at BBB ➔ dysregulation of MGB axis ➔ dysfunction of GABA, serotonin & BDNF ➔ releasing pro‐inflammatory cytokine: IL‐1, IL‐6, IL‐18 (bacterial cell wall LPS induced), TNF, IFN; inhibiting IL‐10, IL‐12, IL‐15 & T‐cells; & chemically related to 5HT, 5HIAA, & HVA ➔ effect on brain & behavior.

Chronic stresses in adult effects gut microbiota ➔ IL‐1 & IL‐6 & ↑cortisol release through HPA axis. Stress ↓gluten tolerance ➔ “hyper‐excitable celiac brain”.

Dietary aquaporin (corn, soybean, spinach leaf, tomato aquaporins) may cross‐react with brain astrocytic endfeet ➔ broken BBB ➔ neuroautoimmunity ➔ neurological disorders.

Dietary fiber produces SCFAs. SCFAs – the key signaling metabolite (Eubiosis) – regulate & maintain the BBB.

(+) Probiotics, Prebiotics, Ketogenic diet, Yogurt, Dietary fiber (produces SCFA)

(‐) Gluten (for some diseases); Antibiotic use; Western diet; Dietary aquaporins ‐ corn, soybean, spinach leaf, tomato aquaporins (related to demyelinating diseases, Gluten ataxia, Guillain Barre syndrome, Miller Fisher syndrome, MS, motor neuron disease, myasthenia gravis, etc.)

Braniste et al. (2014), Cryan et al. (2020), Dinan and Cryan (2017), Galland (2014), Kuwahara et al. (2020), Lambert et al. (2018), Mittal et al. (2017), Obrenovich (2018), Osadchiy et al. (2019), Rahman et al. (2018), Rea et al. (2020), Rieder et al. (2017), Rutsch et al. (2020), Seguella et al. (2019), Slyepchenko et al. (2017)

Aging

Human keeps stable & diversity of gut microbiota till 40 years. Changing diet, using antibiotics & medications, ↓exercises, & ↑stress ➔ ↓ microbiota diversity ➔ low grade, chronic inflammation, ↑IL‐6 & TNF with changing Bacteroidaceae & Erysipelotrichaeae; thinner mucus & ↓mucin with changing Clostidiaceae, Akkermansiaceae, Bifidobacteriaceae, & Bacteroidaceae; ↓immune tolerance/immune senescence with changing Clostidiaceae, Bifidobacteriaceae, Lachnospiraceae, & Coriobacteriaceae; & ↓ SCFA ➔ aging & frailty.

Bland food ➔ ↓microbiota diversity.

If ↑ microbiota diversity ➔ less aging.

(+) Probiotics, Prebiotics, Mediterranean diet, High‐fiber diet, Food rich in polyphenols such as resveratrol, EGCG, curcumin & quercetin

(‐) Bland & low‐fiber food (often in nursing homes), Antibiotics & medications, High saturation fat diet, High‐sugar diet

Cryan et al. (2020), DeJong et al. (2020), Khurana et al. (2013)

Alzheimer's disease (AD)

AD is the most common form of dementia. Aging ➔ ↓microbial diversity & naïve T cells ➔ ↑risk of AD. Obesity, HTN & T2DM also disrupt gut & BBB permeability ➔ ↑risk of AD. APOE gene – risk of AD

APOE gene, aging & unbalanced diet ➔ ↑Verrucomicrobia, Escerchia/Shigella, Proteobacteria, & Pseudomonas aeruginosa, & ↓Eubacterium hallii, Bacillus fragilis, Bacteroides fragilis, Eubacterium rectale, & Faecalibacterium prausnitzii ➔ disturb intestinal permeability & BBB permeability through MGB axis, communicating with vagal & spinal nerve & HPA axis ➔ dysbiosis of microbiota (gut, mouth, nose) ➔ ↑ secretion of β‐amyloid (Aβ) & LPS ➔ ↑IL‐1β, IL‐6, IL‐18, TNFα & IFN‐γ in neurons, microglia, & astrocytes; imbalance of GABA, serotonin, histamine, & dopamine, &↓SCFA ➔ Aβ plaques & neurofibrillary tangles ➔ neuroinflammation, cognitive deficits & neurodegeneration ➔ AD

Western diet ➔ ↑Flavobacterium, Runella, & Flectobacillus ➔ ↑ IL‐1β & NF‐κB ➔ disrupt GB axis ➔ inflammation

AD patients showed ↓melatonin level. Using melatonin may prevent AD or slow down AD progression

(+) Mediterranean diet, Ketogenic diet, Probiotics, Prebiotics, Vitamins (B compound), ω−3FAs, High fiber diet, Polyphenol ‐ high consumption of vegetables & fruits, Antioxidants, Melatonin

(‐) Western diet, Antibiotics, Dietary aquaporin

De‐Paula et al. (2018), Fan et al. (2019), Fox et al. (2019), Kesika et al. (2021), Khurana et al. (2013), La Rosa et al. (2018), Lambert et al. (2018), Liu et al. (2020), Lourida et al. (2013), Megur et al. (2020), Moreno‐Navarrete et al. (2012), Obrenovich (2018), Rutsch et al. (2020), Saji et al. (2020), Shabbir et al. (2021), Sochocka et al. (2019), Vogt et al. (2017)

Amyotrophic Lateral Sclerosis (ALS)

Through MGB axis: intrinsic or extrinsic factors ➔ change gut microbiota diversity ➔ disturbance of TJ proteins & intestinal barrier ➔ ↑LPS, ↑IL‐1β, IL‐6, TNFα, IFN‐γ ➔ Disruption of BBB & BSCB (endothelial cells, TJ, pericytes, basal lamina & astrocytic foot processes) ➔ neuropathy of ENS (multi‐functional RNA‐binding protein TDP43 linking between ENS & CNS) ➔ ↓GABA, glial cell loss, proteostasis‐associated defects, glutamate excitotoxicity; dysfunction of mitochondrial, oxidative stress, SOD‐1, TCP‐43, C9orf72, jettisoned, organelles; cytoskeletal, axonal, & transport vesicle defects ➔ ALS

Use Probiotics ‐ “BUGS as DRUGs” (Obrenovich et al., 2020) for neurodegenerative diseases including ALS

(+) Probiotics, Prebiotics, Symbiotics, Polyphenols, Flavonoids, Caffeine

Blacher et al. (2019), Fang (2018), Niesler et al. (2021), Obrenovich (2018), Obrenovich et al. (2020)

Anorexia nervosa (AN)

Poor diet or insufficient food intake like protein‐deficient diet, plus stress ➔ alter gut‐brain interaction through MGB axis, HPA axis, & vagus nerve ➔ gut dysbiosis ➔ ↓SCFA, serotonin, & BDNF at hippocampus area & ↑cortisol & cytokines ➔ neuroinflammation, cognitive dysfunction & mood changes.

AN associate with Crohn's disease & IBS.

(+) Probiotics, Prebiotics, Vitamins & minerals, Diet with high fiber & low saturated fat

(‐) Western diet, Processed food

Herpertz‐Dahlmann et al. (2017)

Anxiety disorder

Gut dysbiosis plus chronic stress through MGB axis ➔ ↓SCFA‐producing bacteria & ↑Escherichia‐Shigella, Fusobacterium, & Ruminococcus gnavus ➔ Brain chemical imbalance (↓serotonin, GABA & dopamine & ↑cortisol & NE), glia abnormalities ➔ central & peripheral persistent low‐grade immune inflammation through HPA axis & ANS ➔Anxiety.

Anxiety related to IBD, CD.

Fermented food ↑ SCFAs, GABA, & ↓LPS, IL‐1β, IL‐6, TNFα, & NF‐κB and improve TJ and gut barrier function.

(+) Vitamin B2, 3, 6, & 12; Probiotics, Prebiotics, Fermented food

(‐) Gluten, HFD

Aslam et al. (2020), Dinan and Cryan (2017), Jianga et al. (2018), McAllister et al. (2019), Plaza‐Díaz et al. (2020), Rudzki and Maes (2020)

Attention deficit hyperactivity disorder (ADHD)

Genetic, epigenetic, & dietary factors ➔ imbalanced gut microbiomes, ↑Bacteroides uniformis, Bacteroides ovatus, & Sutterella stercoricanis ➔ ↑zonulin ➔ ↑permeability in GI system & BBB through MGB axis ➔ glia abnormalities ➔ ADHD (inattention, hyperactivity, impulsivity & impairment of social function)

Comorbidity with ASD

(+) Probiotics, Prebiotics, Synbiotics, Vitamins

(‐) High fat intake, High sugar intake, High refined grains intake, Antibiotics

Chou et al. (2018), Wang et al. (2020), Özyurt et al. (2018), Partty et al. (2015), Proctor et al. (2017), Rudzki and Maes (2020)

Autism spectrum disorder (ASD)

Prenatal stress (maternal infection, inflammation & antibiotics, & maternal high fat diet), diet ➔ ↓gut microbiota diversity, alter microbiota, ↑Firmicutes/Bacteroidetes ratio, ↑Acidobacteria, Enterobacteriaceae, Pseudomonadaceae, Veillonellaceae, & Megamonas; ↑Lactobacillus spp. & Desulfovibrio spp., & ↑GI Candida albicans ➔ ↑zonulin & LPS ➔ ↑permeability in GI system & disrupt BBB through MGB axis, HPA axis, ANS (vagus nerve) ➔ ↑IL‐6, IL‐1β, IL‐8, TNFα & IFN‐γ; alteration of serotonin, GABA, dopamine, glutamate, SCFAs & Treg cells; accumulation of AGEs in the brain through AGE‐RAGE axis ➔ ASD.

Ketogenic diet regulates mitochondrial function & improve mood balance of the brain, but may have adverse effects, such as constipation, hypercholesterolemia, etc.

Gluten‐ and casein‐free diet – prevent immune response to gluten (antibodies against gluten in ASD is different with celiac disease) & casein, & ↓urinary peptide and improve behavior.

ASD related to IBD (UC & Crohn's Disease).

(+) Ketogenic diet, Probiotics, Prebiotics, Mother's milk (↑SCFA), Gluten & casein‐free diet

(‐) Gluten, Casein (cow & goat's milk, ice cream, butter & cheese), Gluten, Dietary aquaporin

Esnafoglu et al. (2017), Fattorusso et al. (2019), Fowlie et al. (2018), Galland (2014), Hughes et al. (2018), Józefczuk et al. (2018), Karakuła‐Juchnowicz et al. (2017), Lambert et al. (2018), Mayer et al. (2014), Obrenovich (2018), Özyurt et al. (2018), Tagliabue et al. (2017)

Bipolar disorder (BD)

Through Gut–brain axis: Stress & other factors ➔ ↑IgM/IgA response to LPS & other Gram‐negative bacteria ➔ gut dysbiosis ➔ intestinal permeability ➔ ↑proinflammatory cytokines: IL‐2, IL‐6, IL‐1β, TNFα & ↓anti‐inflammatory cytokines: IL‐4 ➔ disrupt TJ protein of BBB ➔ ↑BBB permeability ➔ imbalance of neurotransmitters: 5‐HT, tryptophan, kynurenine, picolinic acid, quinolinic acid ➔ immune system dysfunction ➔ BD.

BD is associated with metabolic & cardiovascular diseases

(+) Probiotics

(‐) Smoking

Chen, Park, et al. (2020), Doney et al. (2021), Painold et al. (2019), Simeonova et al. (2020)

Dementia

Change in microbiota ➔↑Enterotype I & III bacteria & ↑serum triglyceride & serum C‐reactive protein, ↓Clostridia & its phylum Firmicutes & ↓SCFAs & indole‐3‐pyruvic acid ➔ gut dysbiosis & disrupt BBB through MGB axis cause glia abnormalities ➔ ↓memory, & other cognitive deficits

(+) Mediterranean diet, Low fat diet with calorie restriction, ω−3FAs

(‐) Western diet with high fat & sugar, Gluten, Alcohol

Wang et al. (2020), Lourida et al. (2013), Merendino et al. (2013), Obrenovich (2018), Rudzki and Maes (2020), Shabbir et al. (2021), Watanabe and Tatsuno (2017)

Epilepsy

Through MGB axis or GMB axis: Genetic & environmental factors ➔ disrupt gut microbiota diversity ➔ disrupt TJ protein ZO‐1, claudin‐5, & occludin ➔ TJ disassembly ➔ ↑ intestinal permeability ➔ ↑IL‐17A, IL6, IL1β, IFN‐γ ➔ breakdown BBB ➔ Epilepsy

Approximately 1/3 patients with epilepsy have drug resistance. Ketogenic diet is used for drug resistant epileptic patients. After Ketogenic diet therapy, epilepsy patients showed ↑ in gut Bacteroidetes, Actinobacteria phylum & ↓Proteobacteria

Genetic disorder ‐ GLUT1 DS often associates with epilepsy

(+) Ketogenic diet, Probiotics, Prebiotics, Vitamins, Minerals

Arulsamy et al. (2020), Dahlin and Prast‐Nielsen (2019), Fan et al. (2019), Rahman et al. (2018), Rinninella, Cintoni, et al. (2019)

Major depressive disorder (MDD)

Food antigens plus physiological & psychological stress ➔ altered microbiota (such as ↑Actinomycineae, Coriobacterineae, Lactobacillaceae, Streptococcaceae, Clostridiales, Eubacteriaceae, Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae; ↓Bacteroidaceae, Rikenellaceae, Lachnospiraceae, Acidaminococcaceae, Veillonellaceae, Sutterellaceae) through MGB axis, more specifically MGIG axis.

Dysbiosis, SIBO, parasitic & fungal infection ➔ ↑BBB permeability & autoimmunity ➔ ↑TNFα, IL‐1β, IL‐6, IFN‐γ, NF‐κB, O&NS, & hsCRP, ↓IL‐4, also ↑ serum IgA & IgM to LPS of G‐ enterobacteria, ↑I‐FABP ➔ brain chemical imbalance: ↓serotonin, NE, dopamine, GABA, BDNF & ↑cortisol ➔ glia abnormalities ➔ central & peripheral persistent low‐grade immune inflammation through HPA axis & ANS ➔ MDD;

Gluten sensitivity ➔ ↑ serum IgG ➔ effect to MDD;

HFD ➔ ↑the ratio of Firmicutes to Bacteroidetes & Proteobacteria (G‐ LPS contained bacteria);

Fermented foods can increase lactic acid bacteria such as Lactobacillus, Streptococcus, Enterococcus, Lactococcus, Bifidobacterium, & Leuconostoc and ↑SCFAs, GABA, & ↓LPS, IL‐1β, IL‐6, TNFα, & NF‐κB, improve gut barrier function and anti‐inflammation.

MDD is associated with IBS, obesity, T2DM & chronic fatigue syndrome, & they share similar mechanisms.

(+) Mediterranean diet, Low fat diet with calorie restriction, Cabbage (AHR ligands – anti‐inflammatory properties), Probiotics, Prebiotics, Fermented foods, Vitamin B2, 3, 6, & 12

(‐) Western diet with high fat & sugar, Gluten, Alcohol, Pesticides, Drugs (NSAIDs, antibiotics)

Alvarez‐Mon et al. (2019), Aslam et al. (2020), de Punder and Pruimboom (2013), Doney et al. (2021), Fukui (2016), Fung et al. (2017), Karakuła‐Juchnowicz et al. (2017), Liśkiewicz et al. (2021), McAllister et al. (2019), Obrenovich (2018), Plaza‐Díaz et al. (2020), Rudzki and Maes (2020), Slyepchenko et al. (2017)

Migraine headache (MH)

Disrupt gut microbiota ➔ ↑intestinal permeability, ↑LPS, IL‐1β, IL‐6, TNFα, & ↓SCFA, ↓5‐HT & serotonin ➔ BBB dysfunction ➔ inflammation through gut–brain axis ➔ may act on trigeminovascular system ➔ MH

Food allergy ➔ ↑ serum IgG ➔ MH

MH is associated with CD, IBD, anxiety & depression.

(+) Probiotics, prebiotics, Ketogenic diet, Ginger

(‐) Food allergy

Dai et al. (2017), Fan et al. (2019), Karakuła‐Juchnowicz et al. (2017), Luettig et al. (2016), Nouri et al. (2014), Parohan et al. (2020), Roos et al. (2017)

Multiple Sclerosis (MS)

Through gut–brain axis & HPA axis: one of the factors is dietary factor (mainly Western diet) ➔ ↑lactulose/mannitol ratio, disturb commensal gut microbiota (such as ↑Methanobrevibacter, Akkermansia; ↓Butyricimonas) ➔↑serum zonulin ➔ Gut dysbiosis ➔ ↓Treg/Th17 ratio at intestinal mucosa, ↑LPS ‐ damage intestinal barrier ➔ NF‐κB & AP‐1 ➔ exdotoxemia & ↑TNFα, IFN‐γ, IL1β, 2, 6, 18, hs‐CRP, RANKL, ROS ➔ gut inflammation (similar to IBD) & chronic systemic inflammation ➔ breakdown BBB ➔ damage nerve fibers and myelin sheath at brain, spinal cord & optical nerve.

Hypercaloric diets ➔ postprandial inflammation; Antigens ➔ ↓ SCFAs;

Food contains lectin & alkaloids may influence nerve, brain, muscle & GI function negatively.

Two special diets for MS: 1. Swank Diet: A low‐fat diet eliminated all red meat and dairy; 2. Wahls Elimination Diet: modified Paleo diet, exclude all grains, dairy, legumes & nightshades and emphasized fruits and vegetables, meat and fish.

(+) Two special diets for MS: 1. Swank Diet, 2. Wahls Elimination Diet; Mediterranean Diet (Gluten limits to whole grain); Ketogenic diet, Probiotics; Vegetables, Seafood & fish oil; Seaweed & Algae; Fermented food; Multivitamins/minerals

(‐) Western diet; Nightshades; Gluten; Cow's milk (bovine milk casein); Sweeteners; Dietary aquaporins; Smoking

Berer et al. (2017), Buscarinu et al. (2018, 2019), Camara‐Lemarroy et al. (2018, 2020), Cantarel et al. (2015), Chen et al. (2018), Chu et al. (2018), de Punder and Pruimboom (2013), Esposito et al. (2018), Jangi et al. (2016), Lambert et al. (2018), Lerner et al. (2017), Lopetuso et al. (2015), Norman et al. (2012), Nouri et al. (2014), Ochoa‐Repáraz et al. (2018), Pellizoni et al. (2021), Rahman et al. (2018), Raza et al. (2019), Reynders et al. (2020), Riccio and Rossano (2015), Rutsch et al. (2020), Shahi et al. (2017), Wahls et al. (2019)

Parkinson's Disease (PD)

Unbalanced nutrition, aging, ↑ toxins, infection, & use of antibiotics ➔ microbiota dysbiosis (such as ↑Blautia, Coprococcus, Roseburia, Proteobacteria; ↓Faecalibacterium, Prevotellaceae) ↓SCFA, ↑LPS, & accumulation of α‐syn in ENS (↑oxidative stress & localized inflammation) ➔ ↑gut permeability & BBB permeability ➔ ↑enteric glial‐related proinflammatory markers such as GFAP, Sox‐10, IL‐6, IL‐1β, TNFα ➔ bidirectional communication between the brain & gut through gut–brain axis, MGB axis, GBNM axis, ENS, Vagus nerve & innate immunity (via TLR signaling) ➔ accumulation of α‐syn & Lewy bodies in CNS & widespread in other nervous systems ➔ neurodegeneration & neuroinflammation ➔ PD

Antibiotic use is still a controversial topic for PD patients in research articles (e.g., using antibiotics is a negative effect for microbiota; Koutzoumis et al., 2020), but antibiotics such as Rifaximin is effective to treat SIBO (Aho et al., 2021)

(+) Mediterranean diet, Ketogenic diet, Food contains PUFA, ω−3FA, High fiber diet, Probiotics, Prebiotics, Synbiotics (such as fermented milk), Polyphenol ‐ high consumption of vegetables & fruits, Caffeine

(‐) Western diet (high intake of animal protein, saturated fat, refined grain, sugar, alcohol, high salt diet, high fructose corn syrup & low intake of fruits & vegetables)

Aho et al. (2021), Cryan et al. (2020), Fan et al. (2019), Fang (2018), Fung et al. (2017), Gatta and Scarpignato (2017), Koutzoumis et al. (2020), O'Donovan et al. (2019), Obrenovich (2018), Rutsch et al. (2020), Uyar and Yildiran (2019)

Schizophrenia

Multiple risk factors such as infection, inflammation, antibiotics use, stress, toxins, genes (HLA), food antigens ➔ breakdown TJ, AJ, & BBB ➔ ↑intestinal & BBB permeability through gut‐brain axis ➔ ↑C1q, cytokines, MHC, pentraxin, sCD14, TLRs ➔ autoimmunity & glia abnormalities ➔ Schizophrenia

Schizophrenia presents a non‐celiac IgG sensitivity. tTG & deamidation modify toxic peptides from broken‐down gluten proteins may be attacked by T‐cell immune response.

Schizophrenia is associated with CD, metabolic & cardiovascular diseases.

(+) Gluten & casein‐free diet, Probiotics, Prebiotics, High in fruits, vegetable & fiber

(‐) Gluten, Bovine milk casein, Western diet, Smoking

Barber et al. (2019), McAllister et al. (2019), Rudzki and Maes (2020), Severance et al. (2016), Simeonova et al. (2020), Turner (2009), Wahls et al. (2019))

Stroke

Disruption of microbiota diversity, ↑proteobacteria & ↓Bacteroides, Prevotella, & Faecalibaterium, ↓blood trimethylamine N‐oxide ➔ disrupt TJ protein ZO‐1, claudin‐5, & occludin ➔ TJ disassembly ➔ ↑ intestinal permeability & breakdown BBB ➔ ↑D‐Lactate & IFABP (markers of intestinal barrier integrity); ↑IL‐17A, IL‐17 γδ T cells, IFN‐γ & TMA ➔ TMAO ➔ ischemic stroke

After stroke ➔ ↑gut permeability ➔ systemic inflammation

(+) Mediterranean diet, ACN rich diet or ACN supplements

(‐) Western diet (red meat, processed meat & saturated fat)

Camara‐Lemarroy et al. (2021), Cryan et al. (2020), Lourida et al. (2013), Manolescu et al. (2019), Psaltopoulou et al. (2013), Rahman et al. (2018), Tang et al. (2019)

Ophthalmological diseases

Age related macular degeneration (AMD)

The pathogenesis is through gut–retina axis. Western diet interrupts ecosystem. Reduce gut microbiota – mainly Bacteroidetes & Firmicutes ➔ ↓TJ protein – ZO1 & Occludin ➔ ↑ intestinal permeability ➔ low‐grade chronic systemic inflammation

(+) ω−3FAs rich food: dietary fish oil and oily fish, wild plants, eggs, nuts, & berries; Low fat, Low glucose/fructose diet; Vitamin C, E, D, Zinc, β‐carotene, Lutein, Zeaxanthin

(‐) Western diet, Smoking

Fasano (2012), Merendino et al. (2013), Miles and Calder (2012), Rinninella et al. (2018), Schleicher et al. (2013), Simopoulos (2008), Watanabe and Tatsuno (2017)

Dry eye syndrome

Similar as AMD. Increased inflammatory cytokines (IL‐1, IL‐6, & TNFα) in tears

Similar as AMD

Simopoulos (2008), Solomon et al. (2001)