Paradoxical nutrient hyperabsorption despite diarrhea: Insights from jejunal transcriptomic reanalysis in Linghu’s obesity-diarrhea syndrome

Abstract

The transcriptomic changes in the jejunum involved in Linghu’s obesity-diarrhea syndrome (ODS) are revealed in the previous study. In the present study, we performed a reanalysis of differentially expressed genes related to nutrient absorption from this dataset and found that gene sets involved in the digestion and absorption of three major nutrients - fats, carbohydrates, and proteins - were predominantly upregulated in the jejunal epithelium of patients with ODS. These changes specifically pertain to fat digestion and absorption, carbohydrate uptake and transport, and protein catabolism. These findings suggest that the jejunum of patients with ODS may exhibit a unique state of “diarrhea-hyperabsorption”. In this article, we provide an in-depth discussion of this phenomenon and propose hypotheses, aiming to offer insights for the study of the pathological mechanisms underlying ODS and its clinical management.

Key Words: Obesity; Chronic diarrhea; Hyperabsorption; Jejunum; Transcriptome

Core Tip: The jejunal mucosa of patients with Linghu’s obesity-diarrhea syndrome exhibits a unique state of “diarrhea-hyperabsorption”, involving fat digestion and absorption, carbohydrate uptake and transport, and protein catabolism. We hypothesize that this hyperabsorption state may be co-induced by physiological compensation, pathological drivers, and microbial dysbiosis. These findings provide a novel perspective for the clinical management of patients with obesity-diarrhea syndrome.

INTRODUCTION

The global obesity epidemic has not only triggered a surge in cardiovascular diseases and type 2 diabetes, but has also profoundly altered gastrointestinal homeostasis[1,2]. Compared with individuals with a normal body weight, individuals with obesity have a significantly greater risk of developing chronic diarrhea[3,4]. In clinical practice, Professor Linghu[5] has defined this unique clinical phenotype, characterized by the coexistence of obesity and unexplained chronic diarrhea, as Linghu’s obesity-diarrhea syndrome (ODS). However, the pathophysiological mechanisms underlying this syndrome remain elusive.

Traditionally, it is believed that one of the core pathophysiological processes of chronic diarrhea involves intestinal hypermotility and a significantly shortened transit time[6]. The rapid passage of chyme through the intestinal lumen inevitably decreases the contact time between nutrients and the intestinal mucosal surface, thereby leading to secondary malabsorption. Consequently, patients with chronic diarrheal diseases are more likely to experience weight loss. Why is it, then, that ODS patients, despite experiencing long-term diarrhea, not only avoid emaciation but also continue to maintain a strikingly high body mass index? How exactly do they absorb and store calories during such drastically shortened intestinal transit times? To unravel this paradox, we must turn our attention to the primary site of nutrient absorption: The proximal small intestine (jejunum). However, jejunal mucosal alterations in this patient population remain largely uninvestigated.

In our previous study, based on high-throughput sequencing, we systematically compared the transcriptional profiles of the proximal jejunal mucosa among ODS patients (JOD group), obese individuals without diarrhea (JO group), and normal-weight healthy controls (JC group). ODS patients exhibited significant transcriptomic alterations[7]. Through a targeted reanalysis of this previously published dataset, this exploratory study aimed to characterize the expression patterns of genes related to the digestion and absorption of macronutrients in the jejunal epithelium of ODS patients.

THE UNIQUE “DIARRHEA-HYPERABSORPTION” STATE IN PATIENTS WITH LINGHU’S ODS

Our previous study revealed that the genes whose expression differed between the JOD and JO groups were enriched primarily in Kyoto Encyclopedia of Genes and Genomes pathways related to the digestion and absorption of various nutrients (e.g., lipids, minerals, and vitamins)[7]. To further explore the expression trends of functional gene sets, we performed gene set enrichment analysis[7,8] (https://www.gsea-msigdb.org/gsea/index.jsp). The screening criteria were set as follows: |Normalized Enrichment Score| ≥ 1, nominal P < 0.05, and false discovery rate q < 0.25. The results revealed that, compared with both the JC and JO groups, a total of 554 gene sets tended to be upregulated in the JOD group, with 48 gene sets involved in nutrient absorption (e.g., lipid digestion and absorption, carbohydrate uptake and transport, and protein catabolism). In contrast, among the 95 downregulated gene sets, we found no significant enrichment of anti-absorptive or pro-secretory pathways. These findings suggest that the jejunum of patients with ODS may exhibit a “hyperabsorptive” state (Figure 1), which is primarily attributable to active upregulation of absorptive genes rather than suppression of opposing mechanisms. This may explain the apparent paradox of how ODS patients can maintain or even develop obesity despite chronic diarrhea, a condition typically associated with rapid intestinal transit and nutrient loss.

Figure 1 The hypothesis diagram of jejunal hyperabsorption state in patients with Linghu’s obesity-diarrhea syndrome. sER: Serine; TAG: Triacylglycerol; BCAAs: Branched-chain amino acids. Nano banana was used to assist the preliminary layout design of Figure 1, Nano banana was used strictly for minor layout adjustments to Figure 1, and the authors manually finalized the content and design of all figures.

In ODS patients, the upregulated gene sets related to lipid metabolism involved processes such as digestion, absorption, modification, synthesis, and transport. Such a systematic enhancements across the entire lipid-processing cascade suggest that these transcriptomic alterations are not merely isolated molecular anomalies. Rather, they likely represent a global adaptive adjustment by the body in response to long-term nutritional, metabolic, and energetic demands.

In terms of carbohydrate metabolism, the gene sets responsible for carbohydrate uptake and transport tended to be upregulated in patients with ODS. Given that the absorptive efficiency for digestible carbohydrates (such as starch and monosaccharides) in the healthy human small intestine approaches a saturation limit[9], merely increasing the number of transporters is unlikely to substantially increase the absolute “absorptive capacity”. Therefore, we reasonably speculate that this gene upregulation leads not to increased sugar absorption, but to an accelerated rate of uptake. This “fast-forward mode” may well explain the rapid postprandial blood glucose spikes commonly observed in the obese population[10]. Obesity-related insulin resistance is believed to be the primary mechanism leading to elevated postprandial blood glucose peaks. However, our study suggests that this “peak” effect may be directly attributed to the enhanced rapid glucose uptake capacity of small intestinal epithelial cells, thereby contributing to postprandial hyperglycemia and potentially exacerbating the development of systemic insulin resistance.

In ODS patients, gene sets related to protein catabolism, glycoprotein metabolism, and protein polymerization were upregulated. Physiologically, these alterations suggest two possibilities. First, enterocytes may accelerate the intracellular enzymatic cleavage of dipeptides and tripeptides, more efficiently converting them into free amino acids for transport into the systemic circulation to meet the increased metabolic demands of the obese individuals. Second, given the rapid turnover rate of small intestinal epithelial cells and the role of proteins as vital functional components (e.g., enzymes, cytoskeletal elements, and transporters)[11], the dynamic balance of protein synthesis and degradation is critical for maintaining intestinal barrier integrity. The observed upregulation of these pathways implies that enterocytes may reside in a “high-turnover” state, enabling them to respond rapidly to external environmental shifts and maintain tissue homeostasis. Interestingly, despite the increase in intracellular protein catabolism, pathways associated with direct amino acid uptake at the apical membrane (e.g., solute carrier family 1 member 1 and solute carrier family 7 member 5) were not significantly altered. ODS is frequently accompanied by gut microbiota dysbiosis, which leads to an abnormal abundance of specific amino acids (e.g., branched-chain amino acids) in the gut lumen. We speculate that the robust intracellular catabolism may be a secondary response to increased levels of amino acid substrates.

It is worth highlighting that some of the observed upregulation could represent an epithelial stress response rather than a functional adaptation. Chronic inflammation and rapid transit may impose stress on jejunal enterocytes, leading to non-specific transcriptional changes that are not directly beneficial for nutrient absorption. We cannot exclude the possibility that certain upregulated genes serve as stress markers rather than active contributors to absorptive function.

THE “DIARRHEA-HYPERABSORPTION” HYPOTHESIS IN PATIENTS WITH LINGHU’S ODS

The intestinal uptake of the three major macronutrients (lipids, carbohydrates, and proteins) is not a passive diffusion event. Instead, it is a dynamically coordinated active process that relies on precise adjustments ranging from macroscopic intestinal motility to microscopic molecular transport[12]. Ultimately, nutrient absorption efficiency is governed by a combination of external regulatory factors, such as luminal substrates, the physicochemical state of the gut, commensal microbial metabolites, neuroendocrine signaling, and immune-inflammatory agents[13]. These diverse signals funnel down to influence the critical physical and physiological parameters that determine absorption, including substrate properties, concentration, and total amount; the effective absorptive surface area (e.g., villus length and microvillus density); mucosal contact time; digestive enzyme activity and quantity; transporter density and function; transcellular electrochemical gradients; and local blood/lymphatic perfusion. Alterations in the overall digestion and absorption of nutrients typically arise from three distinct triggers: (1) Physiological adaptation: Compensatory changes in response to chronic energy surplus or shifts in metabolic demands; (2) Pathological remodeling: Structural or functional impairment of the intestinal mucosa resulting from chronic inflammation, genetic anomalies, or metabolic disorders; and (3) Microbial-driven dysregulation: Shifts in absorption patterns mediated by the gut microbiota and its metabolites (e.g., short-chain fatty acids and branched-chain amino acids)[14].

Based on the transcriptomic features observed in this study and the possible pathophysiological alterations associated with obesity and chronic diarrhea, we propose the following hypothesis to elucidate the potential mechanisms underlying ODS.

The “compensatory hyperabsorption” hypothesis

Kinetic compensation: ODS patients often present with intestinal hypermotility, which decreases chyme residence time in the jejunum. Previous studies have shown that obesity is associated with increased jejunal villus height and mucosal surface area[15]. On this basis, we hypothesize that ODS patients may initiate a structural and functional “expansion” mechanism - including increased villus length/density and upregulation of transporters - to compensate for the reduced luminal contact time. Future studies should examine villus morphology in ODS patients to test this hypothesis.

Diet-induced metabolic adaptation: The intestinal epithelium exhibits remarkable metabolic plasticity, and its molecular characteristics are highly dependent on dietary composition and substrate load. In high-fat diet models, the small intestinal mucosa actively participates in the regulation of systemic energy balance by upregulating genes related to fatty acid oxidation, protein metabolism, and bile secretion[16]. Therefore, dietary habits and composition may be key drivers in the pathogenesis of ODS. Consequently, large-scale dietary epidemiological surveys are needed in the future to systematically compare differences in dietary patterns between obese individuals with and without diarrhea.

The “pathologically driven hyperabsorption” hypothesis

Beyond physiological adaptation, the “hyperabsorption state” observed in ODS patients is most likely the result of synergistic interactions among multiple pathological factors. These factors collectively form a complex positive feedback loop that further exacerbates the dysregulation of nutrient metabolism.

Intestinal mucosal barrier dysfunction and chronic low-grade inflammation: Our previous study suggested that, compared with obese individuals without diarrhea, ODS patients exhibit more pronounced intestinal mucosal barrier dysfunction and increased intestinal permeability, which may involve the synergistic effects of multiple mechanisms including reduced synthesis of antimicrobial peptide-related molecules, impaired DNA repair, and mitochondrial dysfunction[7]. Intestinal barrier dysfunction may promote the penetration of bacterial antigens and endotoxins into the intestinal mucosa, leading to systemic and tissue-specific chronic inflammation[17]. On the one hand, under the influence of mild proinflammatory cytokines (e.g., tumor necrosis factor-α and interleukin-6), tight junction proteins undergo remodeling, which may allow nonspecific, paracellular permeation of glucose and certain small-molecule nutrients[9]. This increase in passive diffusion may synergize with active transport to collectively increase total absorptive capacity. On the other hand, the activation of local immune cells in the intestinal mucosa may release cytokines, stimulating intestinal epithelial cells to accelerate turnover, thereby maintaining a population of newly generated epithelial cells with high metabolic activity and enzyme-secretion potential and consequently increasing the overall digestive enzyme secretion capacity[11].

Genetic and epigenetic programming: The development of obesity and its complications often involve specific genetic signatures[18]. We hypothesize that in ODS patients, particular genetic polymorphisms may provide a “predisposed genotype” for hyperabsorption. Even under conditions of accelerated intestinal motility and reduced luminal transit time, this genetically predetermined efficient transport mechanism may still maintain a high substrate flux, thereby preventing excessive energy loss.

Neurohormonal axis imbalance: Studies have reported that obese patients often exhibit altered secretion patterns of glucagon-like peptide-2. Glucagon-like peptide-2 induces villus hyperplasia, elongation of microvilli, and significantly promotes the translocation of apical membrane transporters, thereby increasing the “physical absorptive surface area”[19]. In addition, local insulin resistance in the intestinal mucosa leads to the unconstrained synthesis and secretion of ApoB-48, allowing lipids to be assembled into chylomicrons with extremely high efficiency and subsequently released into the bloodstream[20]. Altered sensitivity of vagal afferent signals and the enteric nervous system may cause the intestine to mistakenly perceive a state of “energy deficiency”, thereby reflexively regulating epithelial cell absorptive function and maintaining high-capacity operation even when energy is already in excess.

The “microbial dysbiosis” hypothesis

The gut is a highly complex ecosystem composed of trillions of microorganisms. These commensal microbes not only participate in host digestion and energy metabolism but also profoundly influence immune and metabolic regulation. Accumulating evidence indicates that obesity is closely associated with alterations in upper small intestine microbiota diversity; however, the causal relationship between the two remains unclear[21]. Dysbiosis of the upper small intestine microbiota may affect dietary digestion and absorption through the following pathways.

Exogenous enzyme-assisted digestion: Specific obesity-associated bacterial taxa (e.g., Prevotella species and certain Bacteroides species) possess genomes that are significantly enriched in carbohydrate-active enzymes and proteases. These microbial populations secrete extracellular digestive enzymes that assist the host in degrading otherwise indigestible dietary components (e.g., resistant starch, complex dietary fibers, and complex protein structures)[22]. Under conditions of accelerated jejunal motility and rapid chyme transit, this microbe-driven “predigestion” process is particularly critical, as it directly increases the amount of absorbable free nutrient substrates reaching the jejunal segment. Consequently, even with reduced transit time, the intestinal epithelium can still obtain sufficient nutrients.

Microbial biosynthesis: Clinical studies have confirmed that obesity-associated microbiota (specifically Prevotella copri and Bacteroides vulgatus) exhibit an enhanced capacity for the de novo biosynthesis of branched-chain amino acids[23]. This leads to marked elevations in the luminal concentrations of free amino acids, such as valine and leucin. Consequently, jejunal epithelial cells adaptively upregulate the expression of cytosolic peptidases and metabolic enzymes to accelerate intracellular amino acid turnover and metabolism. Although this passive increase in metabolic activity maintains intracellular homeostasis, it results in a massive influx of branched-chain amino acids into the systemic circulation. Systemic elevation of branched-chain amino acids has been proven to be a key driver of insulin resistance[23], which further exacerbates the metabolic derangements in ODS patients.

Microbial metabolite signaling regulation: By secreting metabolites, the microbiota alters the physicochemical environment of the intestinal lumen, thereby regulating host nutrient absorption. Dysbiosis modulates bile salt hydrolase activity, shifting the ratio of conjugated to unconjugated bile acids. This not only affects lipid emulsification efficiency but also feedback-regulates intestinal transit speed and the expression of nutrient transporters through the activation of farnesoid X receptor and Takeda G protein-coupled receptor 5 receptors in the jejunal mucosa[24]. Moreover, changes in certain genes may also result secondarily from microbial dysbiosis, offering no direct benefit to the host.

As a cross-sectional transcriptome-wide association study based on human tissue, this study revealed correlations between gene expression changes and clinical phenotypes; however, certain limitations remain. The present study is based on a previously published dataset without additional validation data; thus, our findings are hypothesis-generating. Moreover, alterations at the transcriptional level do not necessarily translate to enhanced transport activity, as posttranscriptional regulation of gene expression (e.g., mRNA translation efficiency and protein stability) and posttranslational modifications (e.g., glycosylation and phosphorylation) may significantly influence the ultimate transport activity. Additionally, although our three groups were matched for gender, age, key metabolic parameters, and medication use, residual confounding (e.g., dietary pattern, gut microbiota, and physical activity) cannot be fully excluded. Finally, the bulk transcriptomic data used in this study do not account for changes in cell type composition. An increased proportion of enterocytes relative to secretory cells (e.g., goblet or Paneth cells) could produce an apparent upregulation of absorption-related genes without requiring per-cell transcriptional changes. Future single-cell RNA sequencing or flow cytometric sorting of intestinal epithelial subpopulations would help address this limitation.

Therefore, to directly address the lack of functional validation, we recommend that future studies focus on the following areas: (1) Proteomic validation, such as targeted proteomics of key transporter proteins to confirm changes at the protein level; (2) Functional physiological assays, including Ussing chamber studies for ex vivo nutrient flux and stable isotope-labeled absorption tests for in vivo assessment; (3) Improved confounding control, particularly through standardized dietary assessments and detailed diarrhea phenotyping (e.g., Bristol Stool Scale, frequency); and (4) Correlation analyses between transporter expression levels and clinical endpoints, including body mass index trajectory over time, diarrhea severity (e.g., frequency, consistency, and urgency), and key metabolic parameters (e.g., blood glucose, lipid profiles, and insulin resistance indices). These approaches are essential to validate the functional significance of our hypothesis-generating findings.

CONCLUSION

In conclusion, the jejunum in patients with Linghu’s ODS is not in a conventionally presumed state of “malabsorption”. Instead, the jejunal mucosa exhibits a “hyperabsorptive” phenotype, which is speculated to be co-induced by physiological compensation, pathological drivers, and microbial dysbiosis. These findings not only advance our understanding of this syndrome but also provide a novel perspective for clinical management. For patients with ODS, conventional antidiarrheal therapy aimed at slowing intestinal motility may prolong the contact time of chyme in the small intestine. However, whether this leads to exacerbated fat accumulation remains unclear, and further studies are needed to evaluate the effects of current antidiarrheal therapy and to explore more appropriate intervention strategies.