A controlled feeding trial reveals striking differences in how refined starch and added sugar affect immune cells after substantial weight loss on a very-low-carbohydrate diet.
Study: Effects of refined carbohydrates on immune markers after weight loss on a very-low-carbohydrate diet: A randomized controlled feeding trial.
In a recent randomized controlled trial (RCT) published in the journal Cell Press Blue, researchers examined the effects of refined carbohydrate intake on immune cell populations and activation markers in people who had experienced considerable weight loss following a very-low-carbohydrate diet (VLCD).
They found that refined grain consumption was associated with elevated adipsin levels and increased complement-related signaling. Metabolic and immune pathways were also upregulated in circulating leukocytes, while activation markers increased in helper T cells, natural killer (NK) cells, neutrophils, monocytes, and dendritic cells. Mouse studies suggested that starch intake may activate a branch of the innate immune system known as the complement pathway, contributing to inflammatory changes.
Foods consumed daily may influence immune responses and metabolic pathways. Nutrient excess may create a positive energy balance, which may eventually contribute to obesity and persistent, low-grade inflammation. By modifying their diet, people may consume more nutrients that are known to reduce inflammation and associated disease risk. Refined grains are widely consumed because they are inexpensive and readily available. Compared with whole grains, they are digested rapidly and contain less fiber. This can cause sharp increases in blood glucose after meals, potentially increasing inflammation.
About the study
In this ancillary analysis of the FB4 controlled feeding trial, researchers investigated whether reintroducing refined carbohydrates into the diet after considerable weight loss could influence the immune profile.
The analysis included 44 participants for cytokine profiling, 42 for RNA-seq, and 40 for CyTOF (mean age, 35 years; body mass index, 25 to 31 kg/m2). Researchers evaluated the impact of three isocaloric diets on immune cell populations and activation markers after a 15% weight reduction over three to four months. After three weeks of residential isocaloric VLCD feeding, the participants were randomly allocated to VLCD (control) or high-carbohydrate diets with elevated sugar (HC-Sugar) or starch (HC-Starch) content. In the HC-Starch and HC-Sugar interventions, both diets provided 57% of energy from carbohydrates and 25% of energy from whole grains, while 20% of energy intake came from refined grains and added sugars, respectively.
Before randomization, serum β-hydroxybutyrate (BHB) levels indicated ketosis (2.7-3.1 mM). Most participants had normal-to-low levels of insulin, glucose, C-reactive protein (CRP), and triglycerides. The team used cytometry by time-of-flight (CyTOF), whole-blood transcriptomics, RNA sequencing (RNA-seq), gene set variation analysis (GSVA), and multiplexed cytokine analysis to assess immune cell proportions and biological pathways. Evaluations were performed before randomization and after 10 weeks on the assigned diets.
Animal studies modeled starch and sugar refeeding in mice using maltodextrin and sucrose solutions, respectively. Murine plasma treated with cobra venom factor (CVF) served as a positive control for complement activation during Western blot analysis of serum collected after the dietary challenges.
Results
HC-Starch feeding significantly altered circulating NK cell proportions and increased activation markers for monocytes, NK cells, neutrophils, T cells, and dendritic cells. Supporting these findings, metabolic and immune pathways were upregulated among HC-Starch group participants. In particular, high starch intake activated pathways involved in bacterial and fungal immunity, antigen presentation, and complement and T cell activation, with mitochondrial pathways showing the highest scores. By comparison, HC-Sugar feeding downregulated these pathways.
Complement component 3a receptor 1 (C3AR1) expression in leukocytes decreased significantly following HC-Sugar feeding. The HC-Sugar group also showed reduced expression of ADIPOR1, a receptor for adiponectin, while HC-Starch showed the opposite trend. Public immune-cell gene-expression data indicated that C3AR1 is expressed mainly by basophils and monocytes, whereas ADIPOR1 is concentrated primarily in neutrophils.
Cytokine analysis and murine studies suggest that changes in adipsin and complement signaling may help explain the immune activation associated with starch intake. In mice, maltodextrin increased insulin and glucose levels significantly more than sucrose. After maltodextrin challenge, CD4+ and CD8+ T cells increased CD69 and CD25 expression, NK cells increased TIGIT expression, and the proportion of classical monocytes increased; these monocytes expressed higher levels of CD62L and CD11b. Neutrophils showed reduced CD62L expression, consistent with recent activation.
The team observed elevated pNF-κB, a marker of inflammatory signaling, in helper T cells, neutrophils, and myeloid dendritic cells (mDCs), along with upregulation of the interleukin-15 receptor subunit alpha (IL-15RA) and CD38 following high-starch intake. Correlation analyses showed that changes in adipsin correlated with C-X-C motif chemokine ligand 8 (CXCL8) transcript abundance, neutrophil phosphorylated signal transducer and activator of transcription 3 (p-STAT3), total monocyte and CD8+ T cell numbers, and p-STAT3 in CD8+ central memory T cells. Total NK cell number correlated with C3AR1 expression.
Adipsin increased most among HC-Starch participants, whereas adiponectin decreased significantly in the HC-Starch and HC-Sugar groups and remained unchanged among VLCD controls. In the HC-Sugar group, genes linked to interferon-gamma production, including IFNG and IFNG-AS1, showed increased expression.
Post-intervention, the VLCD group remained in dietary ketosis, though mean BHB levels decreased modestly. BHB levels were completely suppressed in both high-carbohydrate groups, which also had significantly higher postprandial blood glucose levels. CRP decreased in all groups to below 10 mg/L, with the greatest reductions in the HC-Sugar group.
Conclusion
The findings suggest that starch-rich diets may contribute to inflammation following weight loss on a VLCD, and that the type of carbohydrate can influence circulating immune responses in this setting. The authors cautioned that lower immune pathway activity with HC-Sugar should not be interpreted as an overall benefit of sucrose or fructose, because suppression of complement-mediated responses could impair host defense.
The study measured circulating rather than tissue-resident immune cells, did not test microbiome contributions, and lacked functional immune assays, so it could not establish whether either diet impaired or improved immune function. The 10-week intervention may also not reflect chronic dietary effects. The small analysis groups and the participants' recent substantial weight loss after prolonged carbohydrate restriction also limit how broadly the findings can be applied.
In future studies, researchers could investigate tissue-level changes, the effects of the gut microbiome on immune cell trafficking, and changes in body composition and adipose tissue. These analyses could test whether repeated postprandial glucose spikes lead to compensatory adipsin upregulation and sustain complement-mediated insulin secretion.
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