5-Exposição Continua Aos Químicos Da Dieta

Continuous exposure to diets chemical
complexity and chronic health risks
Miguel A. Faria
Miguel Faria ‘ November 8th, 2021 ‘ AHI-MICF
LAQV-REQUIMTE/Faculty of Pharmacy, University of Porto, Portugal
Alimentação Humana I, MICF

November 8th, 2021
Outline
• Diets chemical complexity (dark matter concept)

• New types of compounds to be considered
• Fate of compounds in the human body
• Chronic inflammation linking diets and health (NCDs)
• in vitro methods and models
• Trends on future research (diets/health)
Barabási, A.-L. et al. 2019. The unmapped chemical complexity of our diet. Nat. Food. https://doi.org/10.1038/s43016-019-0005-1
Díez-Sainz et al. 2021. Potential Mechanisms Linking Food-Derived MicroRNAs, Gut Microbiota and Intestinal Barrier Functions in the Context of Nutrition and Human Health. Front. Nutr. 8. https://doi.org/10.3389/fnut.2021.586564
Diets chemical complexity
• Macronutrients
• Micronutrients
✓ proteins, carbohydrates, fats, minerals, vitamins, and water
✓ 180 key nutritional components in national food composition
databases (TCAP, USDA)
+ Bioactives (polyphenols, alkaloids, terpenoids, etc.)

+ Contaminants (pesticides, mycotoxins, PAHs, etc)
+ Additives (preservatives, antioxidants, etc.)
+ Flavors (aroma compounds)
>26000 compounds in the more complete databases

https://foodb.ca/ * http://phenol-explorer.eu/ *https://cosylab.iiitd.edu.in/flavordb/
85% unquantified
(invisible to epidemiological/nutritional studies)
Dark matter of nutrition
Many documented important health effects may be linked to untracked chemicals

Patients with coronary heart disease have greater risk of dying if they have high blood levels of
trimethylamine N-oxide (TMAO)
trimethylamine
Western diet
Mediterranean diet
Of the 6 compounds involved in this

pathway, only choline is tracked in food
by the USDA database.
The other compounds are part of the
nutritional ‘dark matter’ (in red).
3,3-dimethylbutan-1-ol

Compounds identified in databases however unquantified
invisible to epidemiological/nutritional studies
The number of compounds will increase as databases are completed by research!
Bibliographical Unidentified secondary

data mining plants metabolites

Bibliographical mining using estimated to be ca. > 50000
natural language and AI algorithms
The number of secondary metabolites is estimated to
exceed 50,000 compounds microRNA from
Emergent plants (xenomiRs)
Contaminants New roles discovered for existing molecules
Molecules being discovered (mainly of biological origin)

or introduced (agrochemicals, pharmaceuticals)
Farit et al. KNApSAcK Family Databases: Integrated Metabolite–Plant Species Databases for Multifaceted Plant Research, Plant and Cell Physiology, Volume 53, Issue 2, February 2012, https://doi.org/10.1093/pcp/pcr165
Contaminants
Regulated Unregulated
Ensured by European Union (EU) rules recently discovered and potentially of concern to human health
New substances
Mycotoxins (citrinin)
Cyanogenic glucosides (amygdalin)
Alkaloids (pyrrolizidine alkaloids atropine and scopolamine)
Perchlorate (found in nitrate fertilizers)
Microplastics (MPs) (found in sea salt, honey, sugar, water)
Nanomaterials (NMs) (TiO2)
POPs (Polybrominated flame retardants (PBFRs) - Organophosphorus

flame retardants (OPFRs) - UV filters - Perfluoroalkyl substances (PFASs)
Improved analytical methodologies
Substances migrating from food packaging, POPs
Emerging concerns on well-known contaminants
Pharmaceuticals, personal care products, hormones and veterinary drugs
that pass from the waste stream into the water stream, and are now being
found in the food supply chain
https://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/contaminants_in_the_food_chain.pdf
Campo J, Picó Y. Emerging contaminants and toxins [Internet]. Second Edition. Chemical Analysis of Food. Elsevier Inc.; 2020. 729–758 p. Available from: http://dx.doi.org/10.1016/B978-0-12-813266-1/00017-6
xenomiRs (microRNA from plants)
✓ non-coding single-
stranded RNA (18-24 nt)
regulating post-
transcriptional gene
expression through
binding and promoting
degradation of their
mRNA targets
https://commons.wikimedia.org/wiki/User:Kelvinsong
Díez-Sainz E, et al. Potential Mechanisms Linking Food-Derived MicroRNAs, Gut Microbiota and Intestinal Barrier Functions in the Context of Nutrition and Human Health. Front Nutr. 2021;8. doi: 10.3389/fnut.2021.586564
xenomiRs (microRNA from plants)
✓ miRNAs participate in several biological functions in plants and animals (metabolism, immune system
development and immune responses, proliferation, cell death, differentiation or embryogenesis
✓ In vascular plants miRNAs could be transferred locally between cells and over long-distances by the phloem
vasculature, which suggest a role for RNA molecules in transmitting information beyond their cell of synthesis
✓ Plant miRNAs have gained special attention in recent years for their potential role as cross-kingdom gene
expression regulators, influencing plant interactions with animals and microorganisms
✓ In animals, diet is the primary source of plant miRNA uptake, subsequently being detected in fluids and tissues
of a wide range of species such as mice, pigs and humans (xenomiRs).
xenomiRs vs gut microbiota vs intestinal permeability
• xenomiRs can be implicated in the

crosstalk of immune system with
both, intestinal barrier and gut
microbiota
• Gut microbiota might be involved in
the release of xenomiRs
encapsulated in extracellular
vesicles.
• xenomiR might promote or hinder
its absorption depending on its
effect on intestinal permeability

(Gut microbiota have an impact on
intestinal barrier integrity and
function and can be affected by
xenomiRs)
• The increase in intestinal permeability enhances xenomiR paracellular transport across the gut barrier, to
eventually reach the circulatory system and potentially exert a physiological function.
xenomiRs putative physiological effects
Plant miRNAs identified for their involvement in cross-kingdom gene regulation.

Trivedi, R., Asif, M.H., Trivedi, P.K., 2018. Dietary plant miRNAs as an augmented therapy : cross-kingdom gene regulation. RNA Biol. 15, 1433–1439. https://doi.org/10.1080/15476286.2018.1551693
Dietary compounds fate in the human body
Digested Absorbed Metabolized

Diet • Hydrolyzed bioaccessible GI epithelium bioavailable • Gi epithelium
fraction fraction
• Oxidized • Liver, …
non-bioaccessible bioactive
FOODOME fraction fraction
Food sp. 1
Food sp. 2
Food sp. 3 FOOD

…
Additives METABOLOME
Contaminants Colonic fermentation
… • microbiome
Bioactivity
Excretion synergism, addition, antagonism
Scalbert, et al. 2014. Narrative Review The food metabolome : a window over dietary exposure 1 – 3. Am J Clin Nutr 99, 1286–1308. https://doi.org/10.3945/ajcn.113.076133.The
Interactions between food compounds
Single compound (drug)

proteins/gene
networks
Food
4318 compounds
(FoodDB)
Meal
Meal x n dietary compounds

High increment in complexity
(tens of thousands of DCs)
https://towardsdatascience.com/hyperfoods-9582e5d9a8e4
Veselkov,et al. 2019. Hyperfoods: Machine intelligent mapping of cancer-beating molecules in foods. Sci. Rep. 9, 1–12. https://doi.org/10.1038/s41598-019-45349-y
Diets chemical complexity and human health
FOOD HEALTH
Diet Related diseases
Non-communicable diseases
(NCDs)
LIFETIME DAILY CHRONIC
EXPOSURE TO FOODOME
• nutrients
• bioactives vs toxicants
Cardiovascular
• complexity
• Interactions Cancer
Type 2 diabetes
Neurodegeneration
Burden of NCDs worldwide
Global deaths by cause

Data are for 2005. Source: (WHO) Diet Related NCD are responsible for
about 50% of deaths worldwide
Non-modifiable risk factors

age, sex, and genetic make-up
Modifiable risk factors

WHO typically refers to four major ones

for NCDs: poor diet, physical
inactivity, tobacco use, and harmful
Miguel Faria ‘ 29 June 2021

alcohol use (WHO, 2011a).
Bloom et al. The Global Economic Burden of Non-communicable Diseases. World Economic Forum
Burden of NCDs worldwide
The world population is growing and getting older

Fast facts on NCDs
• Every two seconds, a person dies
prematurely from an NCD
• 85% of premature deaths occur in low- and
middle-income countries
• Low- and middle-income countries are
estimated to surpass $500 billion per year

in economic losses due to NCDs.
• Every $1 invested in proven NCD
interventions in low- and lower middle-
income countries will generate at least $7
in increased economic
development/reduced health care costs by
2030.
Bloom et al. The Global Economic Burden of Non-communicable Diseases. World Economic Forum
Diets chemical complexity and human health
FOOD HEALTH
complexity Diet Related diseases
Interactions
bioactives vs toxicants
(NCDs)
LIFETIME DAILY CHRONIC
EXPOSURE TO FOODOME
Inflammation
• Inflammation is broadly defined as a protective response of the organism to stimulation by invading pathogens or
endogenous signals from damaged cells, thus resulting in the elimination of the initial cause of injury.
• Evolutionarily conserved process
The classical definition

(signs/pillars) of inflammation
have persisted in modern times
Celsus (30 bc–38 ad)

rubor
tumor
dolor
calor
Galen (129–210 ad)

functio laesa (loss of function)
• Inflammation is also characterized by the activation of immune and non-immune cells

• Is controlled by a complex host of extracellular mediators and regulators
cytokines, growth factors, eicosanoids (prostaglandins), complement and peptides.
Netea et al. 2017. A guiding map for inflammation. Nat. Immunol. 18, 826–831. https://doi.org/10.1038/ni.3790
Inflammation induction
The immunological mechanisms leading to the induction of inflammation during the first stages of host defense against
invading pathogens
PAMPs pathogen-associated
molecular patterns
conserved structures on pathogens
DAMPs danger-associated
molecular patterns
endogenous stress signals
AAT a1-antitrypsin
AMPs antimicrobial peptides
MAC membrane attack complex
ROS reactive oxygen species
CRP C-reactive protein
MBL mannose-binding lectin
M macrophage or monocyte
CCL CC-motif chemokine ligand
TH1 type 1 helper T cells
TH17 IL-17-producing helper T cells
Inflammation resolutions vs Chronic inflammation
Elimination of the Return to

stressing agent homeostasis
Additional anti-inflammatory
mechanisms involve:
• stress hormones
(corticosteroids and
AAT a1-antitrypsin catecholamines)
TH1 type 1 helper T cells • lipoxins, resolvins
THreg regulatory helper T cells • maresins and protectins

However, the presence of certain social, state of low-grade
psychological, environmental and biological non-infective (‘sterile’)
factors (+diet) has been linked to the inhibition of systemic chronic inflammation (SCI)
resolution of acute inflammation
Furman et al. 2019. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832. https://doi.org/10.1038/s41591-019-0675-0
Chronic inflammation
Deep molecular profiling

• whole-blood gene expression (transcriptome)
• immune proteins as cytokines and
chemokines (immunome)
• cell subset frequencies, such as CD8+
• T cell subsets, monocytes, natural killer cells,
B cells and CD4+ T cell subsets
Systemic Chronic Inflammation – causes and consequences
Food Composition Related

Food Contaminants
Diet and inflammation – Inflammatory index total of 1943 articles were reviewed and scored.
A Dietary Inflammatory index was created in 2014
The DII represents a tool for assessing the inflammatory potential of the diet that can be applied to any
population in which dietary data have been collected
A total of 6500 articles were reviewed and scored

IL-1β, IL-4, IL-6, IL-10, TNF-α and CRP
One of three possible values was assigned to each article based on the effect of the food parameter
on inflammation:
‘+1’ was assigned if the effects were pro-inflammatory (significantly increased IL-1β, IL-6, TNF-α or CRP, or
decreased IL-4 or IL-10)
‘−1’ if the effects were anti-inflammatory (significantly decreased IL-1β, IL-6, TNF or CRP, or increased IL-4 or IL-10)
‘0’ if the food parameter did not produce any significant change in the inflammatory marker
Shivappa et al. 2014. Designing and developing a literature-derived, population-based dietary inflammatory index. Public Health Nutr. 17, 1689–1696. https://doi.org/10.1017/S1368980013002115
Diet and inflammation – Inflammatory index (DII)scored.
45 Food parameters included in the dietary inflammatory index, inflammatory effect scores
By calculating the DII it

is possible to predict
the overall
inflammatory potential
of a meal/food/diet.
More bioactives?
Contaminants?

Shivappa et al. 2014. Designing and developing a literature-derived, population-based dietary inflammatory index. Public Health Nutr. 17, 1689–1696. https://doi.org/10.1017/S1368980013002115
Diet and inflammation – contaminants induced chronic inflammation
Low doses of unavoidable contaminants • Brain-gut-microbiota axis
Long period of exposure • Impact on neuro- immuno-endocrine modulation
Sarron et al. 2020. Early exposure to food contaminants reshapes maturation of the human brain-gut-microbiota axis. World J. Gastroenterol. 26, 3145–3169. https://doi.org/10.3748/wjg.v26.i23.3145
Interactions between contaminants, exemple
Mycotoxins
• Ubiquitous dietary contaminants, regulated by EU
• Frequent co-occurrence in foods
CYTOTOXICITY
Sobral, et al. 2018. Toxicological interactions between mycotoxins from ubiquitous fungi: Impact on hepatic and intestinal human epithelial cells, Chemosphere, 202, https://doi.org/10.1016/j.chemosphere.2018.03.122
Diet and inflammation – microbiota dysbiosis
healthy microbiota in
adult humans is
principally composed of
Firmicutes and
Bacteroidetes phylum
(over 1000 species)
Newborn
SCFA
Active on receptors on
enteroendocrine cells inducing

the secretion of gut hormones
such as glucagon-like peptide 1
(GLP1), as well as NT γ-
aminobutyric acid (GABA), and
serotonin (5-HT)
(indirect signaling to the brain via the
Food Contaminants?
systemic circulation or vagal pathways)
Dysbiosis: 1) Loss of beneficial bacteria, 2) Overgrowth of potentially pathogenic bacteria, and 3) Loss of overall bacterial diversity
Sarron et al. 2020. Early exposure to food contaminants reshapes maturation of the human brain-gut-microbiota axis. World J. Gastroenterol. 26, 3145–3169. https://doi.org/10.3748/wjg.v26.i23.3145
Studies of Diets chemical complexity effects in human health
FOOD HEALTH
Efficacy studies in humans

EFSA health claim evaluation process is the provision of robust evidence clearly demonstrating a physiological cause-and-
effect relationship, from at least one well designed dietary intervention study or randomized controlled trial (RCT)
• High number of dietary

patterns/compounds/combinations
• Need for omics strategy to detect chronic
inflammation
• Hightroughput and expensive assays
In vitro tests/models
Lucey, A., Heneghan, C., Kiely, M.E., 2016. Guidance for the design and implementation of human dietary intervention studies for health claim submissions 378–394. https://doi.org/10.1111/nbu.12241
in vitro human cell-based studies
• in vitro assays can INFOGEST
Gi DIGESTION
overcome limitations in vitro static digestion or semi-dynamic
of individual variation • Oral MEALS OR
• Gastric
• Intestinal FOODS
• The number and type
of assays are almost
unlimited Transfer digests to Digested,transported and metabolized
apical compartment fraction reaching systemic circulation
and target organs
Apical Media
Transfer transported and

Other barriers:
Polarized cell barrier metabolized basolateral media BBB

(Caco-2/HT29)
Daily - Up to 10 days
Basolateral Media
HepaRG cells
Target cells Gene expression

• Vascular epithelium
INTESTINAL ABSORPTION / METABOLIZATION • Imunne system cells (transcriptomics)
• Neurons
OMICS
Multiorgan approach simulation in Transwell co-culture experimental setup. Proposed model covers gastrointestinal digestion, intestinal absorption and
metabolization, hepatic metabolization, and target cells exposition
Advanced in vitro models
Human physiomimetic model integrating microphysiological systems (MPS) of the gut, liver, and brain for studies of
neurodegenerative diseases within the gut-liver-brain-aixs
Massachusetts Institute of Technology, Cambridge, MA, USA

Advanced in vitro models
microphysiological systems – MPS

gut, liver, and brain for studies of neurodegenerative diseases within the gut-liver-brain-aixs
chronic
MEALS OR
FOODS
inflammation
assessment
Trapecar et al. 2021. Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases. Sci. Adv. 7, eabd1707. https://doi.org/10.1126/sciadv.abd1707
Putting all together!
Effects of diet on health (an integrated approach)

Artificial Intelligence

Multidisciplinary teams
Nutrimetabonomics
Advanced equipment and techniques
Claus et. al. 2013. Nutrimetabonomics: Applications for nutritional sciences, with specific reference to gut microbial interactions. https://doi.org/10.1146/annurev-food-030212-182612
Subramanian et al. 2020. Precision medicine in the era of artificial intelligence: implications in chronic disease management. J. Transl. Med. 18, 1–12. https://doi.org/10.1186/s12967-020-02658-5
"Dis-moi ce que tu manges, je te dirai ce que tu es"
Anthelme Brillat-Savarin, Physiologie du Gout, 1826
Will we ever get a clear idea about what we should eat?

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Continuous exposure to diets chemical

complexity and chronic health risks

LAQV-REQUIMTE/Faculty of Pharmacy, University of Porto, Portugal

Alimentação Humana I, MICF

• Diets chemical complexity (dark matter concept)

• Trends on future research (diets/health)

+ Bioactives (polyphenols, alkaloids, terpenoids, etc.)

+ Flavors (aroma compounds)

>26000 compounds in the more complete databases

Many documented important health effects may be linked to untracked chemicals

Of the 6 compounds involved in this

Dark matter of nutrition

The number of compounds will increase as databases are completed by research!

Bibliographical Unidentified secondary

data mining plants metabolites

Molecules being discovered (mainly of biological origin)

POPs (Polybrominated flame retardants (PBFRs) - Organophosphorus

of a wide range of species such as mice, pigs and humans (xenomiRs).

• xenomiRs can be implicated in the

effect on intestinal permeability

Plant miRNAs identified for their involvement in cross-kingdom gene regulation.

Digested Absorbed Metabolized

Food sp. 3 FOOD

Excretion synergism, addition, antagonism

Single compound (drug)

Meal x n dietary compounds

Global deaths by cause

Non-modifiable risk factors

Modifiable risk factors

WHO typically refers to four major ones

Miguel Faria ‘ 29 June 2021

The world population is growing and getting older

estimated to surpass $500 billion per year

The classical definition

Celsus (30 bc–38 ad)

Galen (129–210 ad)

• Inflammation is also characterized by the activation of immune and non-immune cells

Elimination of the Return to

THreg regulatory helper T cells • maresins and protectins

Miguel Faria ‘ 29 June 2021

Deep molecular profiling

Food Composition Related

A total of 6500 articles were reviewed and scored

IL-1β, IL-4, IL-6, IL-10, TNF-α and CRP

By calculating the DII it

Miguel Faria ‘ 29 June 2021

enteroendocrine cells inducing

Efficacy studies in humans

• High number of dietary

Transfer transported and

Polarized cell barrier metabolized basolateral media BBB

Target cells Gene expression

Massachusetts Institute of Technology, Cambridge, MA, USA

microphysiological systems – MPS

Effects of diet on health (an integrated approach)

Miguel Faria ‘ 29 June 2021

Will we ever get a clear idea about what we should eat?

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