Comment

https://doi.org/10.1038/s41577-024-01049-x

Ultra-processed foods: increasing

the risk of inflammation and
immune dysregulation?
Katherine A. Maki, Michael N. Sack & Kevin D. Hall Check for updates

Ultra-processed foods (UPFs) are industrially and facilitate the translocation of damage-associated and pathogen-­
associated molecular patterns (DAMPs and PAMPs, respectively)
formulated products that contain synthetic through reduced-fidelity barriers, as well as perturbing immune
ingredients but minimal whole-food ­regulation through reduced SCFA signalling.
In parallel, gut bacteria adapt to the diet through shifts in gene
components. Diets high in UPFs are associated
expression and enzymatic output4, and changes in dietary nutrients
with increased risk of immune dysregulation- alter the microbiota composition through the preferential expansion
linked diseases such as inflammatory bowel of bacteria fed their preferred, accessible nutrients5. In mice, study diets
that mirror the standard nutrient ratios of UPFs (increased saturated fat,
disease and potentially autoimmune disease. sugar and salt) or are supplemented with additives (such as sodium ben-
Several putative mechanisms have been zoate, emulsifiers and/or colourants) resulted in decreased abundance
of bacteria associated with epithelial barrier integrity, and increased
proposed to explain this association, and these
abundance of bacteria linked to proinflammatory lipopolysaccharide
need urgent research attention. and flagellin production2–4,6. In addition, UPFs and their individual
components have been shown to increase the expression of virulence
Consumption of ultra-processed foods (UPFs) is increasing glob- genes in normally mutualistic gut bacteria (such as Escherichia coli and
ally and UPFs now comprise more than half of the food supply in the Bacteroides thetaiotaomicron), leading to a shift from polysaccharide to
USA and the UK. UPF consumption is linked to obesity and its down- host glycan metabolism, an increase in epithelial adherence, and other
stream complications, including inflammation and immune system dys- pathogenic consequences that are associated with intestinal and sys-
function. However, several properties of UPFs have been hypothesized temic inflammation4,6. So far, the microbial community responses of
to affect the immune system independently of obesity. Studying such gut bacteria to UPF diets are poorly characterized. Also, the extent
UPF effects and elucidating their mechanisms in humans will require to which certain microbial substrates (such as particular glycans and
domiciled controlled-feeding trials. amino acids) are increased in UPFs, and their downstream implications
for the host, are unknown. There are still limited data on whether the
Putative effects of UPFs on the immune system changes in expression of virulence genes are driven by a deficiency of
UPFs often contain emulsifiers, microparticles (such as titanium dio­ specific nutrients, poor nutrient profiles (such as reduced dietary fibre
xide), thickeners, stabilizers, flavours and colourants. Human data and high dietary sodium) and/or specific additives in UPFs. Thus, fur-
are limited, but emerging evidence in mice suggests that these UPF ther research is needed to understand the dose response and temporal
constituents modify the gut microbiota, increase intestinal barrier per- associations of UPF exposure on bacterial metabolism.
meability and directly engage immune surveillance systems — effects If the major systems to ameliorate UPF-associated gastrointestinal
that could individually or synergistically increase the risk of immune- pathology (intestinal barrier integrity and immune surveillance) are
mediated diseases1–3. For example, exposure of mice to low concentra- dysregulated owing to effects on the gut microbiota, then inflamma-
tions of emulsifiers decreased mucus barrier integrity and facilitated tory responses are likely to be amplified (Fig. 1). In parallel, UPF com-
increased bacterial translocation across the epithelial barrier2. Germ- ponents such as titanium dioxide may traverse the intestinal barrier
free mice were protected from these effects, which implicates the gut to function as DAMPs that initiate immune surveillance programmes,
microbiota as being involved in the pathology associated with expo- potentially involving dendritic cells, macrophages, innate lymphoid
sure to emulsifiers. Both intestinal and systemic levels of inflamma- cells, mucosal-associated invariant T cells, and regulatory and effector
tory markers produced in response to UPFs correlated with microbial T cells. The direct effects of distinct UPF components on all these cell
proximity to epithelial cells2, but the mechanisms that ­underlie the types remain to be defined.
strain-specific bacterial effects of UPFs are unknown.
The gut microbiota has an important role in nutrient metabo- Human intervention and observational studies
lism and absorption. Normally, bacterial metabolism of dietary fibre Increased UPF consumption in humans is associated with differences
generates short-chain fatty acids (SCFAs) that sustain the integrity of in the diversity of the gut microbiome, specific bacterial responses and
the intestinal barrier and signal through G-protein-coupled receptors markers of systemic inflammation in observational studies. However,
to dampen local and systemic immune responsiveness. The relative most of these data are limited by cross-sectional analyses, taxonomic
paucity of fibre in high-UPF diets may negate these beneficial effects resolution to the genus level only, and many external or environmental

nature reviews immunology

 ↓ Microbiota-accessible may affect the gut barrier and immune regulation likely encompass
UPF nutrients direct signalling to immune cells, effects on immunometabolism,
consumption ↑ UPF components
metabolite-mediated effects on the mucosal barrier, and epigenetic
effects. Although human observational studies have provided prelimi-
↓ Bacterial diversity nary evidence of relationships between the microbiota and inflamma-
↑ Expression of bacterial
↓ SCFAs tory responses to UPFs, disentangling the health outcomes associated
virulence genes
↑ Invasive/adherent bacteria with UPF additives versus known UPF characteristics (such as increased
energy density, hyper-palatability, or levels of saturated fat, sugar
and salt) will require tightly controlled longitudinal studies in which
Gut lumen the various characteristics of UPFs and relevant human-specific fac-
Degradation Bacterial invasion
Mucus layer
of mucus layer of epithelium tors (such as biological sex and diet adherence) can be measured and
factored into clinical interpretation of research results.
Gastrointestinal The specific mechanisms that link UPFs with inflammation and
epithelium immune dysregulation remain poorly characterized. Given the dif-
ferences between mouse and human immune systems, we strongly
↑ Permeability
advocate controlled-feeding studies in domiciled humans, using diets
varying in UPFs, to characterize responses of the gut microbiota, circu-
lating levels of PAMPs and DAMPs, and immune phenotypes (for exam-
ple, ClinicalTrials.gov ID: NCT05290064). In parallel, backtranslation of
↑ Pro-inflammatory
cytokines human findings to pre-clinical research will further our understanding
↓ Anti-inflammatory of host- and microbiota-mediated responses to UPFs. As the effects of
cytokines
UPFs on tissue-specific cellular expression are now tractable in humans
Treg cells
TH17 cells using the expanding repertoire of ‘multiomic’ analyses, combining
analysis of strain-level bacterial variations with functional profiling of
↑ Immune cell ↑ Cytokines and circulating immune cells should identify drivers of this inflammation.
recruitment chemokines There is an urgent need for this knowledge given the epidemiological
links between UPF consumption and premature colorectal cancer,
Fig. 1 | Potential mechanisms linking high UPF consumption to pathogenic higher prevalence of inflammatory bowel diseases10, and systemic
changes in the gut microbiota and dysregulated immune cell signalling. disorders such as obesity, type 1 diabetes and hypertension7.
With high levels of ultra-processed food (UPF) consumption, there may be
decreased availability of microbiota-accessible nutrients and increased Katherine A. Maki 1, Michael N. Sack2 & Kevin D. Hall 3
exposure to UPF components, such as food additives. Diets high in UPFs are 1
Translational Biobehavioral and Health Disparities Branch, National
thought to affect the gut microbiota through several mechanisms, including Institutes of Health Clinical Center, National Institutes of Health,
decreased bacterial diversity, increased expression of bacterial virulence Bethesda, MD, USA. 2Laboratory of Mitochondrial Biology and
genes, and increased abundance of invasive or adherent bacterial strains. These
Metabolism, National Heart Lung and Blood Institute, National
changes may result in decreased production of short-chain fatty acids (SCFAs),
Institutes of Health, Bethesda, MD, USA. 3National Institute of Diabetes
increased bacterial invasion of the gastrointestinal epithelium, increased
and Digestive and Kidney Diseases, National Institutes of Health,
bacterial consumption and degradation of the mucus barrier, and an increase
in gastrointestinal epithelial permeability. As a result, cytokine or chemokine
Bethesda, MD, USA.
production and immune cell recruitment may lead to a dysregulation of e-mail: [email protected]
immune cell homeostasis and inflammation, including decreased levels of anti-
inflammatory cytokines and increased levels of pro-inflammatory cytokines and Published online: xx xx xxxx
chemokines. TH17 cells, T helper 17 cells; Treg cells, regulatory T cells.
References
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Summary and future directions
Our emerging understanding highlights that diets high in UPFs may Acknowledgements
dysregulate a finely balanced system of communication between the This work was supported by the Intramural Research Program of the National Institutes of Health.

gut microbiota and immune cells that is also dependent on mucus and Competing interests
intestinal barrier fidelity. The mechanisms by which UPF constituents The authors declare no competing interests.

nature reviews immunology