Biology subjects

Anantha Krishnan, A.

Publications and source records attributed to Anantha Krishnan, A..

3 recordsLinked to original sources

bioRxiv2026

Wall stiffening is a primary contributor to motility loss in Crohn's disease: an electromechanical modeling study

Fibrotic strictures are among the most disabling complications of Crohn's disease, permanently narrowing the bowel and impairing motility, yet no approved therapy reverses them. Chronic inflammation alters pacemaker-network coupling, smooth-muscle excitability, and calcium-dependent contractility, while fibrosis thickens the bowel wall, narrows the lumen, and changes tissue mechanics. The relative contributions of these coupled electrical, contractile, and structural alterations to motility loss remain unclear. To address this gap, we develop an integrated electromechanical finite-element framework for fibrostenosing Crohn's disease that couples a fibrosis-driven growth model with a FitzHugh-Nagumo electromechanical model. A full-factorial 25 design of experiments is used to quantify the relative effects of electrical diffusivity, excitation threshold, peak active stress, wall stiffness, and hypertrophic remodeling on cyclic lumen-volume deformation. Motility is quantified by the standard deviation of lumen volume over one contraction cycle. Within the parameter ranges examined, increased wall stiffness emerged as the dominant contributor to motility loss, followed by impaired smooth-muscle contractility. Changes in excitation threshold, hypertrophic remodeling, and electrical diffusivity produced substantially smaller effects. Pairwise interactions were small relative to the dominant main effects, indicating that the mechanisms contributed largely through their individual effects. Our findings suggest that limiting wall stiffening while preserving smooth-muscle contractile function may provide a therapeutic strategy for maintaining intestinal motility in fibrostenosing Crohn's disease.

bioengineering↗

bioRxiv2026

A Biophysical Model of Human Colonic Motor Pattern Generation in Health and Disease

PurposeColonic motility disorders, including diarrhea-predominant irritable bowel syndrome and slow-transit constipation, impose a major clinical burden. Although high-resolution colonic manometry reveals characteristic spatiotemporal motor patterns, such as high-amplitude propagating contractions and cyclic motor pattern in healthy individuals, these patterns are often altered or absent in disease. Understanding how these patterns arise from underlying pacemaker, neural, and mechanical mechanisms is essential for improving treatment strategies. MethodsWe developed a biophysical whole-colon model that integrates an Interstitial Cells of Cajal-inspired oscillator network, enteric nervous system reflexes, a pressure-gated modulation element motivated by rectosigmoid brake behavior, and a nonlinear tube law describing colon wall mechanics. The model simulates spatiotemporal pressure patterns along the colon and allows systematic variation of physiological parameters associated with pacemaker activity, neural reflex control, and distal gating. ResultsA small set of parameters reproduces three illustrative motility patterns corresponding to healthy motility, diarrhea-predominant irritable bowel syndrome, and slow-transit constipation. The simulated pressure maps recapitulate key features observed in high-resolution manometry, including propagation direction, regional patterning of contractions, and case-specific changes in amplitude and coordination. Sensitivity analysis suggests that proximal excitation strength and waveform morphology strongly influence global motility metrics. ConclusionOur study presents a simple, biophysical framework for reproducing clinically observed colonic motor patterns and exploring their disruption in disease. More broadly, the model may help interpret clinical manometry in mechanistic terms and support hypothesis-driven in silico studies of colonic motility disorders.

biophysics↗

bioRxiv2026

Modeling Inflammation-Driven Colon Hypertrophy and Motility Changes in Gulf War Illness

Gastrointestinal (GI) symptoms are a prominent feature of Gulf War Illness (GWI). Animal models attribute them to pyridostigmine bromide (PB) exposure, which induces smooth muscle hypertrophy, neuroinflammation, and motility impairment. However, animal studies only provide static snapshots of disease progression and can only partially resolve how inflammatory, neuronal, and biomechanical processes interact dynamically over time. To address this gap, we developed a computational model that couples cytokine kinetics, macrophage activation, and an excitatory-inhibitory neuronal imbalance to predict smooth muscle hypertrophy and colonic motility changes in GWI. The model was calibrated using data from mice exposed to PB under acute (7-day exposure and measurement) and chronic (7-day exposure and 30-day measurement) conditions, reproducing measured cytokine IL-6 elevations, macrophage accumulation, circular muscle thickening, and shifts in excitatory and inhibitory gene expression. Simulations captured reduced excitatory stress, and sustained loss of inhibitory relaxation, consistent with organ-bath recordings. Sensitivity analyses identified macrophage persistence as a dominant regulator of chronic inhibitory dysfunction, whereas excitatory pathways exhibited relative robustness and recovery. Thus, our model provides a systems-level view of how acute PB-induced inflammation evolves into chronic dysmotility and establishes a first step towards a virtual platform for testing hypotheses and interventions translatable to neuroimmune GI disorders. HighlightsO_LINeuroinflammation model predicts colon hypertrophy and motility in GWI C_LIO_LICalibrated to acute (day 7) and chronic (day 30) PB-exposed mouse data C_LIO_LIReproduced IL-6 rise, CD40+ persistence, colon thickening, and ChAT/Nos1 shifts C_LIO_LIPredicted excitatory stress rebound but sustained inhibitory relaxation loss C_LI

bioengineering↗